Clinical Regimens Research Articles

Clinical Characteristics and Prognosis of Patients with Primary Testicular Diffuse Large B-Cell Lymphoma

To analyze the clinical manifestations, therapeutic response and prognosis of patients with primary testicular diffuse large B-cell lymphoma (PT-DLBCL). Thirty-eight patients with PT-DLBCL were enrolled, who hospitalized from January 2010 to April 2021, and their clinical characteristics, treatment regimen and efficacy were collected and analyzed retrospectively. The median age of the patients was 56 years old (ranged from 38 to 79 years). There were 4 cases (10.5%) with bilateral lesions, 13 cases (34.2%) with left lesions, and 21 cases (55.3%) right lesions. There were 2 cases(5.3%) with B symptoms, 6 cases (15.8%) of germinal center B-cell-like(GCB) subtype and 32 cases(84.2%) of non-GCB subtype. Efficacy was evaluated in 36 cases, including 10 cases with CHOP regimen, 21 cases with R-CHOP regimen (7 cases were treated with rituximab combined with high-dose methotrexate injection chemotherapy at intervals of R-CHOP regimen), and 5 cases with other regimens. In 36 patients, the efficacy evaluation of initial chemotherapy showed that the overall response rate (ORR) was 86.1%, 29 cases (80.6%) reached complete response (CR), and 2 cases (5.5%) reached partial response (PR). The R-CHOP group was superior to CHOP group in ORR (95.2% vs 60.0%, P=0.027) and CR (90.4% vs 50.0%, P=0.022). Of the 36 patients, 7 cases had central nervous system(CNS) recurrence and 4 cases had contralateral testicular recurrence. Compared with the CHOP group, the CNS recurrence rate in the R-CHOP group was significantly lower (4.8% vs 50.0%, P=0.007), and the testicular recurrence rate in the R-CHOP group was also lower than the CHOP group, but the difference was not statistically significant (4.8% vs 30.0%, P=0.087). The median follow-up time was 27(3-135) months, and the 5-year PFS and OS were 71% and 74%, respectively. Kaplan-Meier univariate analysis showed that the R-CHOP regimen significantly improved the patients' PFS (P=0.024) and OS (P=0.025) compared with the CHOP regimen. PT-DLBCL is mainly treated with comprehensive treatment. Compared with CHOP regimen, R-CHOP regimen can improve the CR rate and ORR, reduce CNS recurrence and contralateral testicular recurrence, and improve the patients' survival. Patients may benefit from high-dose methotrexate combined with rituximab interlaced with R-CHOP regimen.

Real-world outcomes of Selexipag for treatment of pulmonary hypertension in an Asian population

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Selexipag is an oral selective prostacyclin IP receptor agonist indicated for treatment of pulmonary arterial hypertension (PAH). Data on its real-world safety and efficacy in Asians is lacking. Purpose We sought to evaluate the clinical characteristics, treatment regimens and outcomes of patients initiated on selexipag in a tertiary cardiac centre in Asia. Methods This was a retrospective study on all patients initiated on selexipag from January 2017 to December 2020. Baseline and follow up characteristics including demographics, functional status and clinical data were collected. Clinical outcomes evaluated included hospitalisation for PH related complications and all-cause mortality. Patients were risk stratified using the COMPERA 2.0 risk scores. Results A total of 36 PAH patients were treated with selexipag. At baseline, most patients were WHO functional class II or III (36.4% and 51.5% respectively), with a NT-proBNP of 1335 pg/ml (557 – 2918) and 6 minute walk test (6MWT) duration of 327.5 ±126.4 meters. Selexipag was initiated at 200mcg twice daily dosage for all except one patient (started at 200mcg once daily) and the maximum tolerated dose ranged from 200mcg twice daily to 1400mcg twice daily, with majority tolerating up to a dose of 600mcg twice daily (58.3%). Side effects were reported in 23 patients (63.9%), of which headache (27.8%), diarrhea (30.6%) or musculoskeletal symptoms (27.8%) were predominant. After a median follow up duration of 25.9 ± 23.1 months, selexipag was stopped in 20 patients (55.6%), of which eight patients were due to PAH progression requiring alternative therapy, and 12 patients due to side effects from selexipag. At baseline, patients were classified into low (8.3%), intermediate-low (30.6%), intermediate-high (33.3%) and high risk (27.8%) respectively. Patients who continued on selexipag at follow up showed no change (46.2%), improvement (15.4%) and deterioration (38.5%) in risk score. In the overall cohort of 36 patients, majority (75%) had at least one hospitalisation for PAH related complications and 15 patients (41.7%) demised. Conclusion In this real-world study, while selexipag was associated with a stable or improved PAH risk scores in majority of patients, there was a subset of patients with disease progression or intolerance to the medication. Further studies are warranted to identify patients who will benefit most from this therapy.

A PK/PD model for the evaluation of clinical rifaximin dosage for the treatment of dairy cow mastitis induced by Escherichia coli

Escherichia coli (E. coli) is an opportunistic pathogen that can cause clinical mastitis in dairy cows worldwide. Mastitis produces severe symptoms in dairy cows, such as udder inflammation, the production of harmful substances, reduced milk production, and altered milk quality. Intramammary injections of rifaximin have a beneficial effect on dairy cow mastitis, especially for mastitis caused by E. coli. However, we do not know whether the currently accepted clinical administration scheme is reasonable. Therefore, the purpose of this experiment was to evaluate the clinical dosing regimen for curing mastitis induced by E. coli. In this study, the pharmacokinetics of four single dose groups (50, 100, 200, and 400 µg/gland) were studied in CD-1 lactating mice, and the main pharmacokinetic parameters were obtained by non-compartment and two-compartment model of Phoenix 8.1 software. A total of 5,000 colony-forming units (CFU) of E. coli ATCC25922 were injected into the mammary glands of mice under anatomic microscope guidance. After 12 h of growth in vivo, the mouse mastitis model was successfully developed. In pharmacodynamics experiment, 12 different dosing regimens (doses ranged from 25 to 800 µg/gland and two dosing intervals of 12 and 24 h) were used to study the therapeutic potential of rifaximin for mastitis. The PK/PD model was established by integrating pharmacokinetics and pharmacodynamics using the inhibitory sigmoid Emax model. The optimal antibacterial effect was 2log10CFU/gland reduction of bacterial colony counts in vivo, when the magnitude of AUC24/MIC exceeded 57.80 h. A total of 57.80 h of AUC24/MIC was defined as a target value in the Monte Carlo simulation. The clinically recommended dosage regimen of 100 mg/gland every 12 h in a day achieved a 91.08% cure rate for the treatment of bovine mastitis caused by E. coli infection.

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae.

This study aimed to examine specific niches and usage for the aztreonam/amoxicillin/clavulanate combination and to use population pharmacokinetic simulations of clinical dosing regimens to predict the impact of this combination on restricting mutant selection. The in vitro susceptibility of 19 New-Delhi metallo-β-lactamase (NDM)-producing clinical isolates to amoxicillin/clavulanate and aztreonam alone and in co-administration was determined based on the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC). The fractions of a 24-h duration that the free drug concentration was within the mutant selection window (fTMSW) and above the MPC (fT>MPC) in both plasma and epithelial lining fluid were determined from simulations of 10,000 subject profiles based on regimens by renal function categories. This combination reduced the MIC of aztreonam and amoxicillin/clavulanate to values below their clinical breakpoint in 7/9 K. pneumoniae and 8/9 E. coli, depending on the β-lactamase genes detected in the isolate. In the majority of the tested isolates, the combination resulted in fT>MPC > 90% and fTMSW < 10% for both aztreonam and amoxicillin/clavulanate. Clinical dosing regimens of aztreonam and amoxicillin/clavulanate were sufficient to provide mutant restriction coverage for MPC and MIC ≤ 4 mg/L. This combination has limited coverage against NDM- and extended-spectrum β-lactamase co-producing E. coli and K. pneumoniae and is not effective against isolates carrying plasmid-mediated AmpC and KPC-2. This study offers a potential scope and limitations as to where the aztreonam/amoxicillin/clavulanate combination may succeed or fail.

Efficacy and safety of camrelizumab combined with albumin-bound paclitaxel as third- or later-line regimen in patients with advanced non-small cell lung cancer.

The clinical efficacy and safety of camrelizumab as a third- or later-line regimen in patients with advanced non-small cell lung cancer (NSCLC) have not been determined in large clinical trials. This study aimed to evaluate the clinical efficacy and safety of camrelizumab in combination with albumin-bound paclitaxel as a third- or later-line treatment for patients with advanced NSCLC. A total of 257 patients with advanced NSCLC who were histopathologically confirmed and failed in clinical second-line therapy regimens at Jiangxi Province Cancer hospital from January 2018 to December 2021 were retrospectively selected. Patients with advanced NSCLC were divided into the single treatment group (STG) of camrelizumab, and the combined treatment group (CTG) of camrelizumab in combination with albumin-bound paclitaxel according to the treatment regimen. The primary outcomes of interest were clinical efficacy[objective response rate (ORR) and disease control rate (DCR)], progression-free survival (PFS), and overall survival (OS). Survival data were analyzed using the Kaplan-Meier method, and the log-rank test was performed. Additionally, Cox proportional hazard regression was used to analyze the correlation of prognosis and baseline characteristics between subgroups, to identify the potential independent risk factors for PFS and OS. Furthermore, the occurrence of side effects was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03). Of the 257 patients with advanced NSCLC included in the research, 135 patients received camrelizumab, and 122 patients received camrelizumab plus albumin-bound paclitaxel. The ORR of CTG and STG was 59.84% and 50.38%, and the DCR was 77.05% and 65.93%, respectively. The median PFS in CTG was higher than that in the STG (5.27 vs. 3.57 months, P = 0.0074), and the median OS was longer (7.09 vs. 6.47 months, P < 0.01). The lines of treatment, metastases, and PD-L1 expression levels were independent risk factors for the mPFS and mOS of patients with advanced NSCLC. The occurrence of adverse events was similar between camrelizumab and camrelizumab plus albumin-bound paclitaxel groups. Camrelizumab combined with albumin-bound paclitaxel as the third- or later-line regimen greatly prolonged PFS and OS of advanced NSCLC patients. A prospective clinical trial is warranted.

Impact of Clinical Parameters and Induction Regimens on Peripheral Blood Stem-Cell Mobilization and Collection in Multiple Myeloma Patients

Introduction: High-dose chemotherapy (HDCT) followed by autologous blood stem-cell transplantation (ABSCT) remains the standard consolidation therapy for newly diagnosed eligible multiple myeloma (MM) patients. As a prerequisite, peripheral blood stem cells (PBSCs) must be mobilized and collected by leukapheresis (LP). Many factors can hamper PBSC mobilization/collection. Here, we provide a comprehensive multiparametric assessment of PBSC mobilization/collection outcome parameters in a large cohort. Methods: In total, 790 MM patients (471 [60%] male, 319 [40%] female) who underwent PBSC mobilization/collection during first-line treatment were included. Evaluated PBSC mobilization/collection outcome parameters included the prolongation of PBSC mobilization, plerixafor administration, number of LP sessions, and overall PBSC collection goal/result. Results: 741 (94%) patients received cyclophosphamide/adriamycin/dexamethasone (CAD) and granulocyte-colony-stimulating factor (G-CSF) mobilization. Plerixafor was administered in 80 (10%) patients. 489 (62%) patients started LP without delay. 530 (67%) patients reached the PBSC collection goal at the first LP session. The mean overall PBSC collection result was 10.3 (standard deviation [SD] 4.4) × 106 CD34+ cells/kg. In a multiparametric analysis, variables negatively associated with PBSC mobilization/collection outcomes were female gender, age >60 years, an advanced ISS stage, and local radiation pre-/during induction, but not remission status postinduction. Notably, the identified risk factors contributed differently to each PBSC mobilization/collection outcome parameter. In this context, compared to all other induction regimens, lenalidomide-based induction with/without antibodies negatively affected only the number of LP sessions required to reach the collection goal, but no other PBSC mobilization/collection outcome parameters. In contrast, the probability of reaching a high collection goal of ≥6 × 106 CD34+ cells/kg body weight was higher after lenalidomide-based induction compared to VCD/PAD or VAD – taking into account – that a higher G-SCF dosage was given in approximately one-third of patients receiving lenalidomide-based induction with/without antibodies. Conclusion: Considering the identified risk factors in the clinical setting can contribute to optimized PBSC mobilization/collection. Moreover, our study demonstrates the necessity for a differentiated evaluation of PBSC mobilization/collection outcome parameters.

Dosing and efficacy of extracorporeal shockwave therapy for diabetic foot ulcer healing: a systematic review protocol

Background: Effective interventions to improve diabetic foot ulcer (DFU) healing are urgently required. Extracorporeal shockwave therapy (ESWT) has the potential to transform DFU care, but is limited by uncertainties around clinical effectiveness and optimal dosing regimen. This protocol outlines the methodology of a systematic review that will address these unknowns. Methods: Databases and the grey literature will be searched for randomised controlled trials (RCTs) comparing ESWT plus standard ulcer care to standard ulcer care ± sham ESWT in patients with a DFU. The primary outcome of the review is time to ulcer healing. Two independent reviewers will screen search results against pre-determined eligibility criteria and extract data onto a pre-piloted spreadsheet. A meta-analysis is planned to compare time to healing for ESWT versus standard care and different doses of ESWT. The Risk of Bias 2 and GRADE tool will be used to assess the quality of the evidence. Outputs, dissemination, impact: The review will provide an estimate of the effect of ESWT on DFU healing and the impact of the ESWT dose on DFU healing. The systematic review will be submitted for publication in a peer-reviewed journal. A plain English summary will be produced. Outputs from the review will guide patient care and research.

Effect of retrograde intrarenal surgery on the inflammatory reaction, renal function indicators and clinical efficacy in male patients with kidney stones

To investigate the effect of retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotripsy on the inflammatory reaction, renal function indicators and clinical efficacy in male patients with kidney stones. 122 male patients with kidney stones were separated into the study group (n = 61) and the control group (n = 61) in terms of distinct clinical treatment regimens. The study group was treated with retrograde intrarenal surgery, while the control group was treated with percutaneous nephrolithotripsy. Inflammatory reaction indicators (Interleukin-6 (IL-6), Interleukin-10 (IL-10), serum tumor necrosis factor-α (TNF-α)), renal function indicators (blood urea nitrogen (BUN), serum creatinine (Scr), blood uric acid (BUA), serum β2 microglobulin (BMG)) and other clinical indicators (operative time, hospital stay, intraoperative blood loss, Visual analogue scale (VAS) pain score, complications) were observed and compared. Upon the treatment, significantly lowered inflammatory factors including IL-6, IL-10, TNF-α and renal function indicators including BUN, Scr, BUA, BMG were shown in study group. Notably shortened operative time and hospital stay were presented in study group with lowered intraoperative blood loss and pain score. The total incidence of complications in study group was 3.28%, significantly lower than 14.75% in control group. Compared with percutaneous nephrolithotripsy, retrograde intrarenal surgery for the treatment of male kidney stones with a diameter of less than 3 cm can improve the inflammatory reaction of male patients, maximize the preservation of renal function indicators, and eminently promote the clinical comprehensive efficacy.

A retrospective analysis to estimate trough concentrations of teicoplanin in patients with suspected or documented Gram-positive infections

Teicoplanin is a glycopeptide antibiotic commonly used to treat Gram-positive bacterial infections in the clinic. The aim of this study was to provide a therapeutic reference for the clinical application and dosage regimen adjustment of teicoplanin by identifying factors associated with its plasma trough concentration (Ctrough). A retrospective study was performed on patients with suspected or documented Gram-positive infections who were hospitalized from November 2017 to January 2020 and treated with teicoplanin while undergoing routine therapeutic drug monitoring (TDM). A total of 112 Ctrough trough measurements were obtained from 72 patients were included in this study. SPSS software was used for correlation analysis and receiver operator characteristic curve (ROC) analysis. The Ctrough for teicoplanin showed statistically significant relationships (P<0.05) with PLT, Scr, CLcr, eGFR, BUN and Cys-C. ROC curve analysis revealed that CLcr and eGFR were more sensitive and specific for Ctrough compared to the other factors. These findings should be considered in the clinical application of teicoplanin and for its dosage adjustment.

Sirolimus-induced pulmonary hemorrhage of an infant with massive cervicofacial lymphatic malformation: A case report.

Lymphatic malformations (LMs) are uncommon congenital abnormalities of the lymphatic system. As more than half of these lesions develop in the head and neck, LMs can be life-threatening if associated with airway involvement. LMs necessitate a multidisciplinary treatment approach, frequently including surgery and sclerotherapy. We present a case report of a 32-week pre-term male infant with a massive cervicofacial LM necessitating delivery via ex-utero intrapartum treatment (EXIT). The patient was treated with numerous rounds of sclerotherapy, systemic sirolimus, and surgical debulking, but ultimately died at 4 months of age due to acute pulmonary hemorrhage, which may have been related to sirolimus due to the absence of any other associable organ involvement or derangement. We document the patient's clinical course and treatment regimen, highlighting the myriad modalities employed to treat these challenging lesions, and describe a potentially lethal complication of sirolimus therapy not previously described in the treatment of pediatric LM.

Prevalence and dynamics of NAFLD-associated fibrosis in people living with HIV in Vienna from first presentation to last follow-up.

Non-alcoholic fatty liver disease (NAFLD) is frequent in people living with HIV (PLWH) and may be aggravated by metabolic comorbidities and antiretroviral therapy (ART)-associated adverse effects. We retrospectively assessed epidemiological, clinical and laboratory parameters and ART regimens at HIV diagnosis (BL) and at last follow-up (FU) in 1458 PLWH without viral hepatitis coinfection attending our HIV clinic in 2014-2016. Fibrosis was non-invasively assessed by the NAFLD fibrosis score (NFS). The median age of subjects was 37.8years, 77.4% were male and 67.2% on ART, median CD4+ count was 356.0cells/µL. At BL, 503 (34.5%) and 20 (1.4%) PLWH had dyslipidemia and diabetes, respectively. According to the NFS 16 (1.3%) showed advanced fibrosis (NFS ≥ 0.676), among which 1 (6.3%) had diabetes, 7 (43.8%) had dyslipidemia, and 5 (31.3%) were on HIV-protease inhibitors (PI). In addition, 191(15.1%) had intermediate NFS results, while fibrosis was ruled out (NFS ≤ 1.455) in 1065 (83.7%) PLWH. After amedian follow-up of 6.3years, 590 (42.8%) had dyslipidemia and 61 (4.4%) had diabetes. Also, 21 (1.6%) showed advanced fibrosis, of which 10 (47.6%) had diabetes, 4 (19.0%) had dyslipidemia, and 9 (42.9%) were on PI-based ART, 223 (17.4%) had intermediate NFS results, while 1039 (81.0%) showed no fibrosis. During FU, advanced NAFLD fibrosis occurred in 1.3-1.6% of PLWH. Dyslipidemia, diabetes, and PI-based ART were associated with advanced NAFLD fibrosis. Prospective investigations of NAFLD severity and risk factors in PLWH are warranted.

Sonodynamic therapy suppresses matrix collagen degradation in vulnerable atherosclerotic plaque by modulating caspase 3 - PEDF/HIF-1α - MMP-2/MMP-9 signaling in macrophages.

The rupture of vulnerable atherosclerotic plaque is the main cause of acute ischemic vascular events, and is characterized by pathological degradation of matrix collagen in the fibrous cap. In a previous study, we reported that 5-aminolevulinic acid-mediated sonodynamic therapy suppressed collagen degradation in rabbit plaque. However, the underlying molecular mechanism has yet to be fully elucidated. We applied sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) to balloon-denuded rabbit and apolipoprotein E-deficient (ApoE-/-) mouse models to observe collagen content in plaque. Cultured human THP-1 and mouse peritoneal macrophage-derived foam cells were used for in vitro mechanistic studies. We observed that DVDMS-SDT decreased plaque area and increased the percentages of collagen and smooth muscle cells and reduced the percentage of macrophages in rabbit and ApoE-/- mouse advanced plaques. In vitro, DVDMS-SDT modulated the caspase 3-pigment epithelium-derived factor/hypoxia-inducible factor-1α (PEDF/HIF-1α)-matrix metalloprotease-2/9 (MMP-2/MMP-9) signaling in macrophage foam cells. Our findings show that DVDMS-SDT effectively inhibits matrix collagen degradation in advanced atherosclerotic plaque by modulating caspase 3-PEDF/HIF-1α-MMP-2/MMP-9 signaling in macrophage foam cells and therefore represents a suitable and promising clinical regimen to stabilize vulnerable plaques.

1695. Combination Therapy for the Investigational Polymyxin SPR206 and Meropenem (MEM) Increases the Rapidity and Extent of Killing of Pseudomonas aeruginosa (PA) and Prevents the Bacterium from Emerging Resistant to Both Antibiotics

Abstract Background The CDC lists multidrug-resistant PA as a Serious Threat pathogen causing 32,200 hospital infections and 2,700 deaths in the US in 2017. PA resistance is frequent with antibiotic monotherapies. SPR206 is a next generation polymyxin that, in a first in human study, was generally safe and well tolerated at the potential therapeutic dose of 100 mg IV Q8h. The aim of this study was to quantify the dose-range PA killing activity of SPR206 monotherapy in a hollow fiber infection model (HFIM) and to assess if the combination of SPR206 and MEM more effectively reduces bacterial burden and prevents development of resistance than either drug alone. Methods Agar dilution MICs and mutation frequencies (MFs) for SPR206, PMB, &amp; MEM were performed for PA ATCC 27853. A 10-day HFIM dose range study simulating the free PK profiles for SPR206 (50 – 600 mg IV Q8h) quantified PA killing and possible regrowth. A HFIM study compared single vs combination SPR206 100 mg IV Q8h over 1h and MEM 2g IV Q8h over 1h regimens for enhanced PA killing and resistance suppression. Results The SPR206, PMB, &amp; MEM MICs were 0.5, 0.5, and 0.25 mg/L, respectively. The MFs for SPR206 and PMB to 3x, 5x and 8x MIC were -6.2, -6.9, &amp; -7.7 log CFU and -5.3, -6.4, &amp; -7.7 log CFU, respectively. The MF for 3x MIC of MEM was -6.8 log CFU. In a dose-range HFIM, simulated regimens for 50 – 600 mg IV Q8h showed a dose-response effect, with 2.9 – 7.3 log CFU/mL reductions in PA seen at 5h. All regimens had regrowth by isolates with SPR206 MICs of 1 – 8 mg/L. In a HFIM study simulating the SPR206 and MEM clinical regimens, alone and in combination, SPR206 alone killed 5 log CFU/mL of PA at 5h, followed by regrowth. MEM alone killed 3.5 log CFU/mL of PA at 5h, with maximum kill seen on Day 4, followed by regrowth. SPR206 plus MEM killed 0.8 log CFU/mL more PA at 5h vs SPR206 alone and had undetectable PA counts by day 4. Combination therapy prevented regrowth (see figure). Conclusion Conclusions: SPR206 (100 mg IV Q8h) killed 5 log CFU/mL of PA at 5h, but regrowth ensued. SPR206 plus MEM produced 0.8 log CFU/mL more killing of PA at 5h. The killing activity of the 2-drug regimen combined with its resistance prevention effect resulted in undetectable PA counts by Day 4 of treatment. Disclosures Arnold Louie, MD, Curza, Inc.: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support Nicole Cotroneo, B.S., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Weiguo Liu, M.D., Spero Therapeutics: Grant/Research Support David Brown, M.B.A., Curza, Inc.: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support Jenny Myrick, B.S., Spero Therapeutics: Grant/Research Support George Drusano, M.D., Curza: Advisor/Consultant|Curza: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support.

Progress of triazole antifungal agent posaconazole in individualized therapy.

Posaconazole is the second-generation triazole antifungal agent with widespread clinical application. Posaconazole exposure is influenced by various factors such as drug interactions, disease state and diet, resulting in a high interindividual variability in many patients and failure to ensure therapeutic efficacy. Therefore, it is necessary to conduct individualized therapy on posaconazole to ensure the efficacy and safety of treatment. Articles were identified through PubMed using the keywords such as "posaconazole," "therapeutic drug monitoring" and "Population pharmacokinetics" from 1 January 2001 to 30 April 2022. In this paper, we review the individualized treatment studies of posaconazole from the three aspects of therapeutic drug monitoring, population pharmacokinetic study and Monte Carlo simulation to provide reference for in-depth individualized posaconazole dosing studies. This review suggests that therapeutic drug monitoring should be performed in patients taking posaconazole to adjust the dosage and assess the efficacy and cost-effectiveness of posaconazole under different clinical conditions and different dosing regimens through Monte Carlo simulations. In the future, a more detailed delineation and comprehensive examination of posaconazole PPK for specific populations requires further study.

Multimodal treatment concepts of local radiation therapy with immunotherapy : Rationale for combination therapy and possible clinical treatment strategies

Immunotherapy has been established in the treatment of cancer in general and specifically in uro-oncology. The rationale to combine these therapies with radiotherapy is based on the biological effects of irradiation, which exceed the "physical" properties of irradiation to kill tumor cells. Depending on radiation dose and fractionation as well as tumor model or tumor entity used, irradiation can lead to immune stimulation or immune inhibition. As immune response is not limited to the local tumor microenvironment but occurs on asystemic level, asuccessful anticancer immune response after irradiation of one metastasis can lead to systemic tumor control (abscopal effect). Clinical trials test combination regimens in locally advanced tumors in the curative setting to improve survival rates and in the metastatic setting to prolong survival in palliative treatment. In addition, radiotherapy is used for local treatment of oligometastases and oligoprogression under palliative systemic therapy.

The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii.

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fTMSW) and above the MPC (fT>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

Early Transcriptional Activity of Vtr-297 - Results from an Ongoing Phase I Clinical Trial

VTR-297 (Trichostatin A) is a pan-inhibitor of histone deacetylases types 1, 2, 4, 6, and 10. Histone deacetylase inhibitors (HDACi) are well-known small molecules that increase the acetylation of lysine residues by inhibiting the activity of histone deacetylase enzymes. These anticancer agents affect epigenetic and non-epigenetic transcriptional regulation and are already part of effective clinical practice and hematology regimens. As HDACi are known for their relatively wide transcriptional modulation, we have conducted a high throughput screen to elucidate early transcriptional effects related to exposure to Trichostatin A (TSA) on patient-derived, clinical time-series samples. NCT03838926 is an ongoing, open-label, dose-escalation, phase I clinical trial for subjects with relapsed or refractory hematologic malignancies. Enrolled patients were assigned to receive one currently tested dose (1.25 / 2.50 / 5.00 mg; IV infusion) in 28-day cycles, 3-times a week for three weeks with one week off (IV administration days 1,3,5,8,10,12,15,17 and 19) until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was safety/tolerability and maximum tolerated dose (MTD) of VTR-297 (TSA). Currently, twelve patients enrolled in the study, including Multiple Myeloma (MM, n=5), Non-Hodgkin's Lymphoma (NHL, n=5), and Hodgkin's Lymphoma (HL, n=2) across the first three dose-escalation cohorts that completed (1.25 / 2.50 / 5.00mg). No significant drug-related toxicities were reported, and MTD was not reached (recruitment is currently ongoing in the fourth dose cohort of 10mg). As a part of the exploratory analysis of whole blood (PBMC), patient samples were collected on cycle1 day1 (C1D1; pre-infusion, 15min-post, 30min-post, 1h-post, 2h-post, and 6h-post infusion) to capture any transcriptional changes (RNAseq) related to VTR-297 treatment. In the current analysis, samples were collected and analyzed in respective batches (15min / 30min / 1h / 2h / 6h) and compared with combined baseline samples (pre-infusion). Using Deseq2 to ascertain transcriptionally affected genes (pval<0.05, up/down relative fold-change 1.5x), we detected 136 differentially expressed genes across at least one of the time point analyzed. Among the detected genes, we found novel and previously described genes related to the core pathophysiology of myeloid and lymphoid disease (e.g., iron metabolism, vascular metastasis, and tyrosine kinase activity). In conclusion, these preliminary signatures offer early biomarker information related to a specific transcriptional activity elicited by intravenously delivered VTR-297 in the clinical setting. In an ongoing clinical study, we will further monitor, validate, and expand on these findings. Further observations at higher, safe, and clinically meaningful doses will complement our current, early picture of VTR-297 activity and how it can be used to optimize TSA-based treatments.

Therapeutic Effect of Bortezomib Combined with Dag Regimen in Hyperleukocytic Acute Myeloid Leukemia

AbstractIntroduction: Hyperleukocytic acute myeloid leukemia(HAML) is a high-risk type of acute myeloid leukemia (AML), with white blood cell counts exceeding 100 x 10 ^ 9/L in peripheral blood, accounting for approximately 5%-20% of AML.Bortezomib is the first proteasome inhibitor approved by the US FDA for clinical use.The efficacy of either single agent or in combination with other agents for acute myeloid leukemia is inconclusive. DAG is commonly used as a classical chemotherapy regimen for acute myeloid leukemia.We have found that bortezomib has a therapeutic effect on acute myeloid leukemia in clinical empirical medication, so we investigated the therapeutic effect of bortezomib combined with DAG regimen on HAML. Methods:Primary hyperleukocytic leukemia cells were isolated from bone marrow of hyperleukocytic acute myeloid leukemia patients using ficoll liquid, then the primary hyperleukocytic leukemia cells were treated with bortezomib (0 nm, 5 nm, 10 nm, 20 nm, 50 nm), DAG, and bortezomib combined with DAG regimens at different concentration gradients.Cell viability was detected by flow cytometry. The HAML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of bortezomib combined with DAG regimen using the same dosing regimen as the clinical medication regimen: bortezomib 1.3 mg/m2, subcutaneous injection, 4 times a course, d1, 4, 8, and 11; doxorubicin liposome injection 5 mg/m2, intravenous drip, every other day, 5 times in total; cytarabine 10 mg/m2, subcutaneous injection, d1-14 every 12 h; and G-CSF 200 μg/m2 per day, subcutaneous injection, d1-14 days. Results: With the increase of concentration gradient, the apoptosis of HAML leukemia cells induced by bortezomib alone and DAG alone was gradually enhanced, while the viable cell count of bortezomib combined with DAG was much lower than that of bortezomib alone or DAG alone. In animal experiments, flow cytometry showed that the ratio of human leukaemia cells in bone marrow blood decreased revealed the most significant decrease in the bortezomib combined with DAG group, absolute counts of CD45 cells in the bone marrow cells of mice in each group also revealed the most significant decrease in the bortezomib combined with DAG group. Morphological examination of myelocyte smears revealed significantly fewer myeloblasts in the bortezomib combined with DAG group than in the other groups. The survival rate in the bortezomib combined with DAG group was better than in the bortezomib alone or DAG alonefor the HAML PDX model. Conclusion:Bortezomib combined with DAG regimen has synergistic killing effect on HAML and may serve as a certain clinical prospect in the treatment of hyperleukocytic acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

CSIG-13. CLINICAL IMPACT OF CDKN2A/B DELETIONS IN IDH-MUTANT ASTROCYTOMAS

Abstract BACKGROUND IDH-mutant astrocytomas with CDKN2A/B homozygous deletions (HD) are now categorized as grade 4 astrocytomas. It is unclear how these HD astrocytomas should be treated. We aimed to compare 3-year outcomes for HD versus heterozygous deleted (HeD) IDH-mutant astrocytomas, describe the prognostic impact of deletions relative to histologic grade and describe differences in outcomes based on treatment regimen. METHODS Molecular and clinical data concerning IDH-mutant glioma patients +/-CDKN2A/B deletions were retrieved across four neuro-oncology centers and two tumor banks from 01/2016-07/2021. RESULTS 48 patients with HD or HeD were identified. Median follow-up time was 4.0 years, median age 33 (range 20-74) years. Sixteen astrocytomas were histologic grade 4, remainder were grade 2 (n= 9) and grade 3 (n= 23). HD were detected in 16 patients. Survival data were unavailable in n= 1 HD and n= 2 HeD patients. 3-year OS for CDKN2A/B HD and HeD groups were 47% versus 67% (log-rank p= 0.004). For grades 2, 3 and 4, 3-year OS for HD were 100% (n= 1), 57% (n= 7) and 29% (n= 7) respectively, 3-year OS for HeD were 100% (n= 7), 56% (n= 16) and 57% (n= 7) respectively. In HD patients, six were treated with concurrent temozolomide-radiotherapy (3-year OS 50%) and five with radiotherapy and sequential temozolomide only (3-year OS 80%, log-rank p= 0.38). Treatment data were unavailable in two patients and three were treated with “other” regimens. Sequential regimens were preferentially used in histologic grade 2 and 3 cases. CONCLUSION Preliminary data are in keeping with current literature and are one of the first to describe outcomes based on clinical regimen. There was insufficient evidence of OS differences between concurrent and sequential therapy, though conclusions are limited by sample size and data maturity. Additional follow-up data are required to further define optimal treatment for these patients.

Effect of Nystatin on Candida albicans - Streptococcus mutans duo-species biofilms

ObjectiveTo assess the effect of Nystatin on Candida albicans and Streptococcus mutans duo-species biofilms using an in vitro cariogenic biofilm model. DesignBiofilms were formed on saliva-coated hydroxyapatite discs under high sugar challenge (1 % sucrose and 1 % glucose), with inoculation of 105CFU/ml S. mutans and 103CFU/ml C. albicans. Between 20 and 68 h, biofilms were treated with 28,000 IU Nystatin solution, 5 min/application, 4 times/day, to mimic the clinical application. Biofilm's three-dimensional structure was assessed using multi-photon confocal microscopy. The expression of C. albicans and S. mutans virulence genes was assessed via real-time PCR. Duplicate discs were used in 3 independent repeats. t-test and Mann-Whitney U test were used to compare outcomes between treatment and control group. ResultsNystatin treatment eliminated C. albicans in biofilms at 44 h. Nystatin-treated group had a significant reduction of biofilm dry-weight and reduced S. mutans abundance by 0.5 log CFU/ml at 44 and 68 h (p < 0.05). Worth noting that biomass distribution across the vertical layout was altered by Nystatin treatment, resulting in less volume on the substrate layers in Nystatin-treated biofilms compared to the control. Reduction of microcolonies size and volume was also observed in Nystatin-treated biofilms (p < 0.05). Nystatin-treated biofilms formed unique halo-shaped microcolonies with reduced core EPS coverage. Furthermore, Nystatin-treated biofilms had significant down-regulations of S. mutans gtfD and atpD genes (p < 0.05). ConclusionsNystatin application altered the formation and characteristics of C. albicans and S. mutans duo-species biofilms. Therefore, developing clinical regimens for preventing or treating dental caries from an antifungal perspective is warranted.