Failure Of Therapy Research Articles

Skin Clearance is Associated with Reduced Treatment Failure in Patients with Psoriasis: Real-World Evidence from the CorEvitas Psoriasis Registry.

Complete and near-complete skin clearance have become achievable treatment goals for patients with psoriasis receiving systemic biologic therapies. However, there is limited real-world evidence regarding the impact of the degree of skin clearance on biologic treatment patterns among these patients. This longitudinal cohort study assessed the relationship between degree of skin clearance following initiation of a systemic biologic therapy and treatment failure among patients from the CorEvitas Psoriasis Registry (April 2015-August 2021). Patients had Psoriasis Area and Severity Index (PASI) score > 5 at systemic biologic therapy initiation and ≥ 1 follow-up visit(s) within 15months of initiation. Treatment failure (discontinuation due to poor response/adverse event; addition of non-biologic therapy) and degree of skin clearance (measured by PASI) were assessed following biologic initiation. Proportional hazards regression was used to estimate the association between PASI response level and treatment failure over follow-up. This study included 2701 patient initiations from 2516 unique patients with 3846 total visits over follow-up. Over half of the patient initiations (n = 1412; 52.3%) were among patients with PASI >10. Treatment failure occurred in 1.3% of visits at which PASI100 was achieved, while those achieving PASI90 - < 100 and PASI75 - < 90 had treatment failure rates of 3.4% and 3.5%, respectively. After adjustment for confounders, the risk of treatment failure was two to three times higher in the PASI90- < 100 (hazard ratio [HR] = 2.61; 95% confidence interval [CI] 1.35, 5.02; p = 0.004) and PASI75 < 90 (HR = 2.97; CI 1.58, 5.58; p = 0.001) groups compared to the PASI100 group. The risk of treatment failure was more than 20 times higher in the < PASI75 group versus the PASI100 group (HR = 22.26; CI 13.32, 37.21; p < 0.001). The results suggest that patients are more likely to remain on a systemic biologic therapy if they achieve near-complete or complete skin clearance, supporting the continued need to target skin clearance as a treatment goal in psoriasis. ClinicalTrials.gov identifier, NCT02707341.

B-242 Fast and Cost-effective RNA Extraction in Onco-hematology Laboratories

Abstract Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of a BCR-ABL1 rearrangement; its detection and quantification by real-time quantitative PCR (RQ-PCR) plays a central role in CML diagnosis, therapy monitoring, and sequencing to identify resistance mutations in case of therapy failure. To evaluate the molecular response of CML, BCR-ABL1 quantification must be calculated on the international scale (IS%) for which RQ-PCR has the necessary sensitivity (up to 10−5). Currently, BCR-ABL1 quantifications are ubiquitous in onco-hematology laboratories (OHLs; ∼70% of tests performed in our OHL), whereby quality, cost, and turn-around-time are of critical importance. Today, the majority of OHLs in Brazil rely on laborious manual RNA-extraction methods (e.g., Trizol) that usually require 8 mL of peripheral blood (PB) to monitor CML. Here, we report a strategy that requires only 2 mL of PB in combination with the automated magnetic DNA/RNA-extraction kit Extracta-MPTA (Loccus do Brasil) for CML diagnosis and monitoring. Methods: BCR:ABL1 was quantified and its IS% determined using our developed kit, which was calibrated using ERM-AD263 and UK-NEQAS (external quality assessment). Total RNA was extracted from 40 PB samples, after erythrocyte lysis using two different methods: 1) Leukocytes from 8 mL of PB were extracted manually using Trizol; 2) leukocytes from 2 mL of PB were automatically extracted using Extracta-MPTA (Loccus do Brasil). BCR-ABL1 quantification, BCR-ABL1 IS%, and BCR quantification (internal control) were compared statistically (paired t-test). The reproducibility was evaluated by analyzing 20 replicates; the low limit of the leucocyte number to BCR:ABL1 quantification using Extracta-MPTA were also evaluated. Median and moving means of 135 unpaired samples were used to monitor BCR-ABL1 IS% between Trizol, Extracta-MPTA, while EQA from UK-NEQAS was also evaluated using both methods. In parallel, RNA was extracted by both methods from 20 samples for the diagnosis of acute lymphoblastic leukemia (ALL) (BCR-ABL p190 transcript) and acute promyelocytic leukemia (APL) (PML-RARA transcript). Results A comparison of BRC-ABL1, BCR, and %IS in 40 paired samples showed that the results obtained from Trizol or Extracta-MPTA are comparable (paired t-test: P = 0.4222, P = 0.9263, and P = 0.071, respectively). The reproducibility was evaluated by BCR quantification (24%). A comparison of the medians from 135 unpaired samples extracted using Trizol and Extracta-MPTA revealed that BCR-ABL1 IS% distribution among our patients is stable over time (P = 0.7704; Mann Whitney: r2 = 0.0012). EQA was extracted using both methods and the results were identical. A comparison between Trizol and EXTRACTA_MPTA for ALL and APL was 100% identical (Fischer; P = 1.000). Conclusion Both RNA extraction methods are suitable for OHLs for PML-RARA and BCR-ABL (p190 and p210) detection and CML diagnosis/monitoring by BCR-ABL1 detection/quantification. By using Extracta-MPTA the amount of PB used to obtain RNA can be reduced by 75%, test results can be obtained within 4 h, and direct reagent costs are reduced by 25% with a minimum of hands-on time.

The Lipid Metabolism as Target and Modulator of BOLD-100 Anticancer Activity: Crosstalk with Histone Acetylation.

The leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure.

Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis.

High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes. A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed. A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack. The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

The relationship between the role of the family and the use of control card with the level of compliance with medication in elderly patients at UPTD Puskesmas Wonokromo

Introduction: Non-compliance is the cause of therapy failure, which has an impact on the worsening of the patient's condition because of complications and damage to organs. Family support plays an important role for the elderly because the family is a support system, which requires the presence of the family to assist in daily activities, for example in terms of reminding you to take medication regularly and so on. The purpose of this study was to analyze the relationship between the role of the family and the use of control cards with the level of adherence to medication in elderly patients. Methods: This research is an analytic correlation with a cross-section approach. The population in this study was all elderly in the UPTD Puskesmas Wonokromo, with a total of 993 elderly. The number of samples studied amounted to 285 respondents. The data collection technique used non-probability sampling purposive sampling, the instrument used was a family role questionnaire, a Morisky Medication Adherence Scale (MMAS) medication adherence quasi-satire, and a drug control card sheet. Data analysis using a rank- spearman statistic test with a significant value of p &lt; = 0.05. Results: The results showed that of the 285 respondents, almost half (49.1%) had good family roles, most (55.4%) had routine control cards and most (55.4%) medication adherence was obedient. Based on the Spearman rank test found that the significance level &lt; = 0.05, so there is a relationship between family roles and the use of control cards with the level of adherence to taking medication for elderly patients. Conclusion: There is a relationship between the role of the family and the use of control cards with the level of adherence to taking medication in elderly patients.

Upfront tofacitinib in patients with biological-naïve ulcerative colitis - An Indian multicentric experience.

Tofacitinib is a Janus Kinase inhibitor used for treating moderate to severe ulcerative colitis (UC), mainly after the failure of biological therapy. There is a paucity of data on the outcome of tofacitinib in biological-naïve UC patients. The present study wasaimed at analyzing the safety and efficacy of tofacitinib in biological-naïve Indian patients with UC. The present study retrospectively evaluated consecutive patients with biological-naïve moderate-to-severe active UC from six tertiary care centers in India receiving tofacitinib from September 2020 to September 2022. Clinical remission or response assessment was based on partial Mayo score (PMS) calculated at baseline and weeks eight, 16 and 24. Total 47 cases (57.4% male, median age: 32years) were included. After eightweeks of therapy, 33 (70.2%) achieved clinical remission and eight (17.0%) had a primary failure. The baseline serum albumin at treatment initiation was the only independent predictor of remission at eightweeks (Odds ratio: 11.560, 95%CI: 1.478 - 90.404), but not at 16weeks. By 24weeks, 59.6% (28/47) of the patients were in remission and 29.8% (14/47) had stopped tofacitinib either due to failure (27.6%) or adverse events (AEs) (2.1%). Among the 47 patients, 10 (21.2%) cases developed AEs during follow-up, including two tuberculosis (4.2%), one cytomegalovirus (CMV) colitis (2.1%) and one herpes zoster (2.1%). Four patients with infection required temporary drug discontinuations. One required permanent discontinuation (mania). Upfront tofacitinib is effective in biologic-naïve Indian patients with moderate-severe UC. Further randomized studies are required to validate the study findings.

Some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives overcome imatinib resistance by induction of apoptosis and reduction of P-glycoprotein activity.

Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) introduced for the chronic myeloid leukemia (CML) therapy. Emergence of IMA resistance leads to the relapse and failure in CML therapy. Benzimidazole is a heterocyclic organic compound which is widely investigated for the development of anticancer drugs. In this study, we aimed to explore the anticancer effects of some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives on K562S (IMA-sensitive) and K562R (IMA-resistant) cells. To analyze the cytotoxic and apoptotic effects of the compounds, K562S, K562R, and L929 cells were exposed to increasing concentrations of the derivatives. Cytotoxic effects of compounds on cell viability were analyzed with MTT assay. Apoptosis induction, caspase3/7 activity were investigated with flow cytometry and BAX, BIM, and BAD genes expression levels were analyzed with qRT-PCR. Rhodamine123 (Rho-123) staining assays were carried out to evaluate the effect of compounds on P-glycoprotein (P-gp) activity. The hit compounds were screened using molecular docking, and the binding preference of each compounds to BCR-ABL protein was evaluated. Our results indicated that compounds triggered cytotoxicity, caspase3/7 activation in K562S and K562R cells. Rho-123 staining showed that compounds inhibited P-gp activity in K562R cells. Overall, our results reveal some benzimidazole derivatives as potential anticancer agents to overcome IMA resistance in CML.

Self-pay insurance status is associated with failure of medical therapy in patients with acute uncomplicated type B aortic dissection

BackgroundTraditionally, acute uncomplicated type B aortic dissections are managed medically, and acute complicated dissections are managed surgically. Self-pay patients with medically managed acute uncomplicated type B aortic dissections may fare worse than their insured counterparts. MethodsIn this single-center, retrospective cohort study, demographics, follow-up, and outcomes of patients with acute type B aortic dissections from 2011 to 2020 were analyzed. ResultsIn total, 159 patients presented with acute type B aortic dissections; 102 were complicated and managed with thoracic endovascular aortic repair, and 57 were uncomplicated and managed medically. A total of 32% (n = 51) were self-pay. Self-pay patients were from areas with worse area deprivation indices (71% vs 63%, P = .024). They more often reported alcohol abuse (28% vs 7%, P < .001), cocaine/methamphetamine use (16% vs 5%, P = .028), and nonadherence to home antihypertensives (35% vs 11%, P < .001). Self-pay patients less often had a primary care physician (65% vs 7%, P < .001) or took antihypertensives before admission (31% vs 58%, P = .003). Self-pay patients frequently required financial assistance at discharge (63%), most often using charity funds (46%). Few patients (7%) qualified for our hospital’s financial assistance program, and most (78%) remained uninsured at the first follow-up. Self-pay acute uncomplicated type B aortic dissections patients had the lowest rate of follow-up (31% vs 66%, P < .001) and were more likely to represent emergently (75% vs 0%, P = .033) compared to insured acute uncomplicated type B aortic dissections patients. Self-pay patients were more likely to follow up after thoracic endovascular aortic repair for acute complicated type B aortic dissections (82% vs 31%, P < .001). ConclusionSelf-pay patients have multiple, interconnected, complex socioeconomic factors that likely influence preadmission risk for dissection and post-discharge adherence to optimal medical management. Further research is needed to clarify treatment strategies in this high-risk group.

Spinach protein-capped silver nanoparticles with low hemolytic activity inhibit methicillin-resistant Staphylococcus aureus biofilm formation as a new therapeutic approach

BackgroundThe methicillin-resistant Staphylococcus aureus (MRSA) was designated as a high-priority pathogen by the World Health Organization. Cardiovascular and thoracic surgery complications frequently involve MRSA infection. Treatment of newly emerging resistant S. aureus strains is clinically challenging due to the natural tendency of MRSA survival through biofilm formation. The failure of traditional antibiotic therapy necessitates development of next-generation therapeutic molecules. ObjectivesSilver nanoparticles were investigated to treat MRSA in order to overcome the challenges of antibiotic therapy. MethodsSpinach protein functionalized silver nanoparticles (SPAgNPs) were synthesized by reducing with sodium borohydride. The resazurin microtiter assay was used to determine the minimum inhibitory concentration (MIC) of SPAgNPs against MRSA. The antibiofilm activity was investigated using a crystal violet assay at sub-MIC levels and validated using scanning electron microscopy. To demonstrate the mechanism of action of SPAgNPs, the virulence factors involved in MRSA biofilm formation were examined. SEM was used to evaluate the hemocompatibility of human red blood cells. Results and conclusionThe synthesized SPAgNPs showed characteristic yellow colour with surface Plasmon resonance maximum at 418 nm. Powder X-ray diffraction and transmission electron microscopy analysis confirmed that the particles are crystalline with a size range from 14 to 40 nm. SPAgNPs have antibacterial activity at a minimum inhibitory concentration (MIC) of 1.25 mM, killing MRSA via disrupting membrane integrity and producing excess reactive oxygen species. Strikingly, SPAgNPs inhibit MRSA biofilm formation at sub-MIC (0.625 mM). Scanning electron microscopy study reveals that SPAgNPs trigger biofilm inhibition without causing cell damage. Hence the NPs are very effective in preventing pathogens from triggering stress responses. SPAgNPs suppress exopolysaccharide production, cell surface hydrophobicity, and staphyloxanthin biosynthesis. Testing SPAgNPs against human red blood cells reveals that NPs do not harm human cells, suggesting that the SPAgNPs are biocompatible. The findings show that SPAgNPs could be explored as next-generation materials for treating MDR pathogenic infection linked with biofilms.

Overall signature of acquired KRAS gene changes in advanced non-small cell lung cancer patient with EGFR-TKI resistance.

Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited. We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our analysis specifically focused on the acquired changes to the KRAS gene. Among the 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations who experienced resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy, 14 individuals (4.3%) developed resistance due to acquired KRAS alterations. Of these 14 patients, 10 cases (71.4%) were due to KRAS missense mutations, 1 case (7.2%) was due to KRAS gene fusion and 3 cases (21.4%) were due to KRAS amplification. Notably, we identified one newly demonstrated KRAS gene fusion (KRAS and LMNTD1), one KRAS G13D and one KRAS K117N. The emergence of acquired KRAS alterations was often accompanied by novel mutations and high tumor mutation burden, with TP53, CNKN2A, PIK3CA, MYC, STK11, CDK4, BRCA2 and ERBB2 being the most frequently observed concurrent mutations. The median progression-free survival and overall survival for the 14 patients were 5.2 and 7.3months, respectively. Acquired KRAS missense variants were associated with significantly worse progression-free survival compared with other KRAS variant subtypes (P<0.028). This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Outcome after chimeric antigen receptor (CAR) T-cell therapy failure in large B-cell lymphomas.

This study retrospectively evaluated the outcome of salvage therapy in 51 patients who failed axicabtagene ciloleucel or tisagenlecleucel for relapsed/refractory large B-cell lymphomas. Of these patients, 22 (43%) were enrolled in clinical trials (glofitamab or loncastuximab tesirine + ibrutinib), whereas 29 received standard therapies (lenalidomide [Len], checkpoint inhibitors [CPIs], ibrutinib [I], chemoimmunotherapy and radiotherapy) or supportive care. Overall, 26 of 39 (67%) treated patients received a treatment based on immunotherapy (glofitamab, CPI, Len) that was mainly represented by bispecific antibody (n = 18). In this subgroup, plasma samples were collected and analysed for circulating tumour DNA (ctDNA) using cancer-personalized profiling by deep sequencing (CAPP-seq). The study found that patients with high ctDNA had poor outcomes. At a median follow-up of 11.7 months, the estimated 12-month overall survival (OS) was 35%. Factors adversely affecting the prognosis in the multivariable model were the absence of response to CAR T-cell therapy (HR: 3.08; p = 0.0109) and a diagnosis other than PMBCL and t-FL (HR: 4.54; p = 0.0069). The outcome of patients failing CAR T cells is poor and requires further investigation.

Validation of imatinib therapy failure score (IMTF) in chronic phase chronic myeloid leukemia in real life practice

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival. Aim of our study was to validate this index in a large cohort of patients treated with imatinib.

Impact of media compositions and culture systems on the immunophenotypes of patient-derived breast cancer cells

BackgroundHeterogeneous tumor cells are thought to be a significant factor in the failure of endocrine therapy in estrogen receptor-positive (ER+) cancers. Culturing patient-derived breast cancer cells (PDBCCs) provides an invaluable tool in pre-clinical and translational research for the heterogeneity of cancer cells. This study aimed to investigate the effects of different media components and culture methods on the BCSC-associated immunophenotypes and gene expression in ER + PDBCCs.MethodsTen patients with ER + breast cancer were employed in this study, six of whom had neoadjuvant chemotherapy and four of whom did not. PDBCCs were isolated by enzymatic methods using collagen I and hyaluronidase. PDBCCs were grown as monolayers in mediums with different compositions and as multicellular spheroid in a suspended condition. Collagen I-coated plate and ultralow attachment plate coated with polymer-X were used for monolayer and spheroid culture. Flow cytometry, immunofluorescent staining, RT-PCR, and RNA-sequencing were employed to examine the immunophenotype and genetic profile of PDBCCs.ResultsMore than 95% of PDBCCs sustain EpCAM high/+/fibroblast marker- phenotypes in monolayer conditions by subculturing 3–4 times. A83-01 removal induced senescent cells with high β-galactosidase activity. PDBCCs grown as monolayers were characterized by the majority of cells having an EpCAM+/CD49f + phenotype. Compared to full media in monolayer culture, EGF removal increased EpCAM+/CD49f − phenotype (13.8-fold, p = 0.028), whereas R-spondin removal reduced it (0.8-fold, p = 0.02). A83-01 removal increased EpCAM+/CD24 + phenotype (1.82-fold, p = 0.023) and decreased EpCAM low/-/CD44+/CD24- phenotype (0.45-fold, p = 0.026). Compared to monolayer, spheroid resulted in a significant increase in the population with EpCAM-/CD49+ (14.6-fold, p = 0.006) and EpCAM low/-/CD44+/CD24- phenotypes (4.16-fold, p = 0.022) and ALDH high activity (9.66-fold, p = 0.037). ALDH1A and EMT-related genes were upregulated. In RNA-sequencing analysis between spheroids and monolayers, a total of 561 differentially expressed genes (2-fold change, p < 0.05) were enriched in 27 KEGG pathways including signaling pathways regulating pluripotency of stem cells. In a recurrence-free survival analysis based on the Kaplan-Meier Plotter database of the up-and down-regulated genes identified in spheroids, 15 up-, and 14 down-regulated genes were associated with poor prognosis of breast cancer patients.ConclusionThe media composition and spheroid culture method change in the BCSCs and EMT markers of PDBCCs, implying the importance of defining the media composition and culture method for studying PDBCCs in vitro.

Annual trends of cystectomy complications: A contemporary analysis of the NSQIP database.

Despite significant morbidity, radical cystectomy (RC) is standard of care for muscle invasive bladder cancer, certain high-risk nonmuscle invasive tumors and after failure of intravesical or trimodal therapy. Modern efforts have hastened the recovery after this surgery without impact on overall complication rates. Our primary aim was to examine changes in complication rates of RC over time. The National Surgical Quality Improvement Program database included 11,351 RC from 2006 to 2018 for nondisseminated bladder cancer. Baseline characteristics and complication rates were studied across time periods: 2006 to 2011, 2012 to 2014, and 2015 to 2018. Thirty-day complications, readmissions, and mortality were identified. Overall complication rates decreased over time (56.5%, 57.4%, 50.6%, P < 0.01). Infectious complications were stable, including UTIs (10.1%, 8.8%, 8.3% respectively, P = 0.11) and sepsis (10.4%, 8.8%, 8.7% respectively, P = 0.20). On multivariable analysis, ASA≥3 (OR 1.399, 95% CI 1.279-1.530) was associated with increased complications, while procedures in 2015 to 2018 (OR 0.825, 95% CI 0.722-0.942), laparoscopic/robotic approach (OR 0.555, 95%CI 0.494-0.622), and ileal conduit (OR 0.796, 95% CI 0.719-0.882) were associated with decreased complication rates. Other outcomes of interest included mean length of stay (LOS), which decreased over time (10.5, 9.8, 8.6 days, respectively, P < 0.01) and readmission (20.0%, 21.3%, 21.0%, respectively, P = 0.84) and mortality rates were stable (2.7%, 1.7%, 2.0%, respectively, P = 0.13). Decreased early complications and LOS after RC over time may reflect beneficial effects of recent advances in bladder cancer treatment such as enhanced recovery after surgery protocols and minimally invasive techniques. Further opportunities to improve long term outcomes, readmissions and infection rates are needed.

Risk factor for the failure of first-line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic oncology research investigators coLLborAtion study (GORILLA-3004) (1152)

Risk factor for the failure of first-line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic oncology research investigators coLLborAtion study (GORILLA-3004) (1152)

Sulfonated Polyether Ketone Membranes Embedded with Nalidixic Acid-An Emerging Controlled Drug Releaser.

The effective administration of medication has advanced over decades, but the medical community still faces significant demand. Burst release and inadequate assimilation are major drawbacks that affect wound healing efficiency, leading to therapy failure. The widespread application of polymers in biomedical research is significant. The polyether ether ketone (PEEK) family is known for its biocompatibility, inertness, and semi-crystalline thermoplastic properties. In our present studies, we have chosen a member of this family, polyether ketone (PEK), to explore its role as a drug carrier. The PEK backbone was subjected to sulfonation to increase its hydrophilicity. The response surface methodology (RSM) was used to optimize the sulfonation process based on the time, degree of sulfonation, and temperature. The PEK polymer was sulfonated using sulfuric acid at 150 °C for 6 h; back titration was performed to quantify the degree of sulfonation, with 69% representing the maximum sulfonation. SPEK and nalidixic sodium salt were dissolved in dichloroacetic acid to create a thin membrane. The physiological and morphological properties were assessed for the SPEK membrane. The studies on drug release in distilled water and a simulated body fluid over the course of 24 h revealed a controlled, gradual increase in the release rate, correlating with a mathematical model and demonstrating the zero-order nature of the drug release. Hemolysis on the SPEK membrane revealed lower toxicity. The SPEK membrane's biocompatibility was established using in vitro cytotoxicity tests on the Vero (IC50: 137.85 g/mL) cell lines. These results confirm that the SPEK membranes are suitable for sustained drug release.

Combining Olaparib and Ascorbic Acid on Nanoparticles to Enhance the Drug Toxic Effects in Pancreatic Cancer.

Pancreatic cancer (PC) shows a very poor response to current treatments. Development of drug resistance is one of the causes of the therapy failure, being PARP1 (poly ADP-ribose polymerase 1) a relevant protein in the resistance mechanism. In this work, we have functionalized calcium phosphate-based nanoparticles (NPs) with Olaparib (OLA, a PARP-1 inhibitor) in combination with ascorbic acid (AA), a pro-oxidative agent, to enhance their individual effects. Amorphous Calcium Phosphate (ACP) NPs were synthesized through a biomimetic approach and then functionalized with OLA and AA (NP-ACP-OLA-AA). After evaluation of the loading capacity and release kinetic, cytotoxicity, cell migration, immunofluorescence, and gene expression assays were performed using pancreatic tumor cell lines. In vivo studies were carried out on tumors derived from the PANC-1 line in NOD SCID gamma (NSG) mice. NP-ACP-OLA-AA was loaded with 13%wt of OLA (75% loading efficiency) and 1% of AA, respectively. The resulting dual nanosystem exhibited a gradual release of OLA and AA, being the latter protected from degradation in solution. This ensured the simultaneous availability of OLA and AA for a longer period, at least, during the entire time of in vitro cell experiments (72 hours). In vitro studies indicated that NP-ACP-OLA-AA showed the best cytotoxic effect outperforming that of the free OLA and a higher genotoxicity and apoptosis-mediated cytotoxic effect in human pancreatic ductal adenocarcinoma cell line. Interestingly, the in vivo assays using immunosuppressed mice with PANC-1-induced tumors revealed that NP-ACP-OLA-AA produced a higher tumor volume reduction (59.1%) compared to free OLA (28.3%) and increased the mice survival. Calcium phosphate NPs, a highly biocompatible and biodegradable system, were an ideal vector for the OLA and AA co-treatment in PC, inducing significant therapeutic benefits relative to free OLA, including cytotoxicity, induction of apoptosis, inhibition of cell migration, tumor growth, and survival.

Multiple sclerosis with comorbidity depression and its association with vitamin D deficiency in a narrative review of the current literature

Over the past decade, knowledge of the pathophysiology and immunology of multiple sclerosis (MS) and depression, and the complex links to vitamin D (VitD) balance, has increased rapidly. Both diseases are characterized by an imbalance of proinflammatory and antiinflammatory cytokines, increased serum neurofilament light chains (sNfLs), disruption of the blood-brain barrier (BBB), abolition of the physiological function of the various types of microglia (MG), decreased calcidiol-serum levels, and disorders of the gut microbiome in combination with hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis/microbiome-gut-brain-axis characterized. In depression, stress initiates cellular and molecular changes in the brain via increased cortisol release in the HPA-axis. Microglial activation and neuronal damage as well as dysregulation of neuroplastic and neurotrophic factors complete the spectrum of pathological damage. It is shown that gut dysbiosis leads to increased gut permeability, which favors endotoxemia and ultimately paves the way to systemic inflammation. A VitD supplementation could restore the balance of microorganisms in the intestine and reduce the inflammatory processes at various levels. VitD promotes regulatory T cell (Treg) proliferation, inhibits the expression of T helper 1 (Th1) cells and Th17 immune cells, and inhibits proinflammatory interleukin-17 (IL-17). 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] reduces also the secretion of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Increased calcitriol levels lead to a reduction in MG activation, oxidative stress, and lower BBB permeability. An early, permanent, daily sufficient VitD supplementation as an add-on therapy under control of the serum 25-hydroxyvitamin D [s25(OH)D] levels is an essential therapeutic tool to slow down the disability caused by MS and thereby primarily prevent or reduce the stress and subsequently the manifestation of depression. Through the future continuous measurement of the biomarkers serum neurofilament ligth chains and glial fibrillary acidic proteins as well as the s25(OH)D level in MS and comorbidity depression, future therapy successes or failures can be avoided.

The Role of P-Glycoprotein (P-gp) in Cancer Multidrug Resistance (MDR): Challenges for Inhibiting P-gp in the Context of Overcoming MDR

Multidrug resistance (MDR), as is well known, is regarded as the primary factor in cancer therapy failure. A common mechanism of MDR in anticancer drugs is the expression of P-glycoprotein (P-gp), a class of ATP-dependent membrane transport efflux pumps called adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It pumps xenobiotics outside the cell and plays part in typical physiological detoxification and host defense activities. This transporter is distributed in gastrointestinal mucosa epithelial cell surfaces, blood-tissue barriers, hepatic biliary epithelium, proximal tubules of the kidney, and the adrenal cortex. P-gp is known to be responsible for MDR because of its over-expression in malignant cells. It functions as an efflux pump lowering the concentration of drugs intracellularly, thus decreasing the effectiveness of cancer chemotherapy. Although using multiple anticancer medications is a good strategy, Cancerous cells are able to develop MDR. A number of chemically synthesized P-gp inhibitors were investigated to overcome MDR in clinical studies. Additionally, certain natural compounds have been observed to modulate P-gp. Numerous investigations on strategies to modulate MDR have been conducted as a result of the significant impact of chemotherapeutic drug resistance. This review discusses the role of P-gp in cancer MDR and challenges for inhibiting P-gp in the context of overcoming MDR mediated by P-gp. It is concluded that the discovery of selective, safe, and potent inhibitors of P-gp remains necessary.

Efficacy and Tolerability of Enfortumab Vedotin for Metastatic Urothelial Carcinoma: Early Experience in the Real World.

This study retrospectively investigated the impact of enfortumab vedotin (EV) monotherapy on the oncological outcome, safety profile, and health-related quality of life (HRQoL) in patients with metastatic urothelial carcinoma. We assessed 26 consecutive patients who had received EV monotherapy after failure of platinum-based chemotherapy and immune checkpoint blockade therapy at our single institution from December 2021 to January 2023. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and EORTC QLQ-C30 as an HRQoL instrument were evaluated. The ORR and DCR were 57.7% and 80.8%, respectively. EV was effective regardless of the patient and tumor characteristics, including the efficacy of previous systemic therapy, performance status, number of Bellmunt risk factors, and presence of variant histology. With a median follow-up time of 7.5 months, the median durations of PFS and OS were 5.4 months and 10.3 months, respectively. Grade ≥3 AEs included neutropenia (15.4%), fatigue (7.7%), appetite loss (7.7%), rash (3.8%), febrile neutropenia (3.8%), hyperglycemia (3.8%), and interstitial pneumonia (3.8%). AEs resulting in withdrawal of EV, interruption of EV, and dose reduction occurred in two (7.7%), nine (34.6%), and 13 patients (50.0%), respectively. The EORTC QLQ-C30 scores from baseline to post-EV introduction remained stable. EV monotherapy demonstrated promising anti-tumor activity and tolerability in patients with metastatic urothelial carcinoma.