Line Agents Research Articles

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Therapy Landscape.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are rare, chronic cholestatic diseases that can progress to liver failure. The goals of treatment are to halt the progression of liver disease to cirrhosis and/or liver failure, and alleviate symptoms associated with these diseases. Ursodeoxycholic acid (UDCA) has historically been the first-line treatment for PBC, with obeticholic acid (OCA) and fibrates used as second-line or adjunctive therapies. However, the treatment landscape is rapidly expanding. Recently, two new second line agents gained FDA approval for the treatment of PBC, and several other therapies remain under investigation with promising results. While significant progress has been made in development of therapies for PBC, there are no current approved treatments for PSC other than liver transplantation although several emerging therapies have shown encouraging results. This review outlines the current and upcoming treatments for PBC and PSC.

Double Encapsulation of Resveratrol and Doxorubicin in Composite Nanogel—An Opportunity to Reduce Cardio- and Neurotoxicity of Doxorubicin

The simultaneous encapsulation of drugs into nanosized delivery systems could be beneficial for cancer therapies since it could alleviate adverse reactions as well as provide synergistic effects. However, the encapsulation of hydrophobic drugs into hydrophilic nanoparticles, such as nanogels, could be challenging. Therefore, innovative technological approaches are needed. In this research, a composite nanogel system was prepared from chitosan, albumin, and hydroxypropyl-β-cyclodextrin for co-delivery of the hydrophilic anticancer drug doxorubicin and hydrophobic antioxidant resveratrol. The nanoparticles were characterized using dynamic light scattering and found to have a hydrodynamic diameter of approx. 31 nm, narrow size distribution (PDI = 0.188), positive ƺ-potential (+51.23 mV), and pH-dependent release of the loaded drugs. FTIR and X-ray analyses proved the successful development of the composite nanogel. Moreover, the double-loaded system showed that the loading of resveratrol exerted protection against doxorubicin-induced toxicity in cardioblast H9c2 and neuroblast SH-SY5Y cells. The simultaneous loading did not influence the cytostatic effect of the antitumor agent in lymphoma L5178Y and L5178MDR cell lines.

Synergistic Action of Thymol-citral is Associated with Cell Cycle Arrest and Intracellular ROS Generation in A549 Cells

Objective: NSCLC is the predominant form of lung cancer, often exhibiting resistance to chemotherapy. Thymol and citral have shown promise as anticancer agents in different cancer cell lines but have not been evaluated in combination against NSCLC. Hence, we planned to investigate the anticancer effect of thymol-citral combination and explore its mechanisms of action against A549 cells. Methods: A549 cells were exposed to varying concentrations of thymol and citral, alone and in combination. Cell proliferation, plasma membrane integrity, apoptotic markers, reactive oxygen species (ROS) levels, cell cycle distribution, senescence induction, and migration potential were assessed. Additionally, in vitro safety was evaluated in human bronchial epithelial cells (HBECs) and human red blood cells (RBCs). Results: Thymol and citral showed synergistic action against A549 cells, with a CI value of 0.75. After 24 h, they induced apoptosis, caused G0/G1 phase arrest, and increased ROS levels, suggesting oxidative stress as the mechanism. This combination also induced cell senescence, significantly inhibited A549 cell migration, and was non-toxic to human RBCs and HBECs. Conclusion: Overall, the thymol-citral synergistic combination was found to be a safe and effective therapy option for non-small cell lung cancer.

Elimination of Reactive Oxygen Species Formed by Chemotherapeutic Agent in Imatinib Resistant K562r Cell Line by Sweetgum Oil

Elimination of Reactive Oxygen Species Formed by Chemotherapeutic Agent in Imatinib Resistant K562r Cell Line by Sweetgum Oil

Expect the unexpected: fulminant myocardial cytotoxic Injury from Trabectedin

BackgroundTrabectedin (Tbt) is an alkylating agent prescribed for soft tissue sarcomas after treatment failure of first line agents. While cardiomyopathy can occur with Tbt treatment after anthracycline exposure, Tbt-induced fulminant myocardial cytotoxic injury in the setting of other systemic cytotoxicity associated with Tbt has not been reported.Case presentation51-year-old female with hypertension, hyperlipidemia, metastatic leiomyosarcoma with progression of disease despite several lines of chemotherapy including doxorubicin-based therapy was started on Trabectedin (Tbt) 5 days prior to presentation with symptoms of fever, myalgias, arthralgias, and palpitations. She was admitted for management of rhabdomyolysis, acute kidney and liver injuries which were reportedly known to be associated with Tbt treatment. A baseline electrocardiogram (ECG) revealed sinus tachycardia with non-specific T-wave changes, and a transthoracic echocardiogram (TTE) was unremarkable. However, on day 3 of hospitalization, an episode of asymptomatic sustained monomorphic ventricular tachycardia with a heart rate of 150 beats per minute was captured on telemetry. A 12-lead ECG revealed new septal T-wave inversions. Labs revealed rising hs-TnI levels (peak at 37,933ng/L) and serum markers suggested multi-organ failure. Steroids were initiated given its role in treating multi-organ Tbt-induced toxicity. A cardiac MRI to rule out myocarditis and left heart catheterization to rule out obstructive coronary artery disease were forgone due to acute renal failure. A right heart catheterization with an endomyocardial biopsy was performed revealing normal cardiac filling pressures and indices. Pathology showed cytoplasmic vacuoles indicating drug-induced myocardial cytotoxicity. Serial echocardiograms revealed preserved biventricular function. The patient’s clinical condition deteriorated with multi-organ failure despite maximal supportive care in the intensive care unit. She ultimately passed away, and an autopsy was declined.ConclusionThis is the first reported case of fulminant myocardial injury after initiation of Tbt with histologic evidence of drug-induced myocardial cytotoxicity. While it is unclear if anthracyclines potentiate Tbt cytotoxic injury as in this case, it is plausible; and that Tbt-induced cardiotoxicity ranges from subclinical to fulminant. Given increasing use of Tbt in refractory high-grade sarcomas, raising awareness of its toxicity profile will improve early detection and outcomes.

Alternative treatment methods for bovine mastitis: prospects and limitations (review)

Mastitis remains the most common problem of dairy industry despite the preventive measures and treatment schemes being developed. Antibacterial drugs remain first line agents for therapy of the mammary gland inflammatory diseases in animals. Taking into account the risks associated with antibiotic therapy, such as decreased drug effectiveness due to occurrence of bacterial resistant strains, food safety issues, environmental impact and restrictions on the use of antibacterial drugs in veterinary medicine, an increasing number of scientific studies are addressing new therapeutic agents that can serve as an alternative to conventional therapy. The aim of this review is to give an idea of currently available literature data on alternative methods for the prevention and treatment of mastitis in cattle that are not associated with antibiotics. In general, a significant number of in vitro studies aimed at finding new effective and safe drugs are yielding promising results. This review describes the following alternative remedies: probiotics, bacteriocins, bacteriophages, phage enzymes (endolysins), nanoparticles, plant extracts, essential oils and immunobiological agents (vaccines). Understanding the mechanisms of their action will allow recommending the best treatment option for mastitis in each specific case. These treatment methods can potentially reduce use of antibiotics and increase animal productivity, however more in vivo studies are needed to prove the effectiveness of antibiotics used directly in the conditions of farm settings.

Effects of oral steroid sparing immunosuppressive drugs in long term maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials.

Reassessing the management of uncomplicated urinary tract infection: A retrospective analysis using machine learning causal inference.

Uncomplicated urinary tract infection (UTI) is a common indication for outpatient antimicrobial therapy. National guidelines for the management of uncomplicated UTI were published by the Infectious Diseases Society of America in 2011, however it is not fully known the extent to which they align with current practices, patient diversity, and pathogen biology, all of which have evolved significantly in the time since their publication. We aimed to re-evaluate efficacy and adverse events for first-line antibiotics (nitrofurantoin, and trimethoprim-sulfamethoxazole), versus second-line antibiotics (fluoroquinolones) and versus alternative agents (oral β-lactams) for uncomplicated UTI in contemporary clinical practice by applying machine learning algorithms to a large claims database formatted into the Observational Medical Outcomes Partnership (OMOP) common data model. Our primary outcome was a composite endpoint for treatment failure, defined as outpatient or inpatient re-visit within 30 days for UTI, pyelonephritis or sepsis. Secondary outcomes were the risk of 4 common antibiotic-associated adverse events: gastrointestinal symptoms, rash, kidney injury and C. difficile infection. We adjusted for covariate-dependent censoring and treatment indication using a broad set of domain-expert derived features. Sensitivity analyses were conducted using OMOP-learn, an automated feature engineering package for OMOP datasets. Our study included 57,585 episodes of UTI from 49,037 patients. First-line antibiotics were prescribed in 35,018 (61%) episodes, second-line antibiotics were prescribed in 21,140 (37%) episodes and alternative antibiotics were prescribed in 1,427 (2%) episodes. After adjustment, patients receiving first-line therapies had an absolute risk difference of -2.1% [95% CI -2.9% to -1.6%] for having a revisit for UTI within 30 days of diagnosis relative to second-line antibiotics. First-line therapies had an absolute risk difference of -6.6% [95% CI -9.4% to -3.8%] for 30-day revisit compared to alternative β-lactam antibiotics. Differences in adverse events were clinically similar between first and second line agents, but lower for first-line agents relative to alternative antibiotics (-3.5% [95% CI -5.9% to -1.2%]). Results were similar for models built with OMOPlearn. Our study provides support for the continued use of first-line antibiotics for the management of uncomplicated UTI. Our results also provide proof-of-principle that automated feature extraction methods for OMOP formatted data can emulate manually curated models, thereby promoting reproducibility and generalizability.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention - part 4: propranolol

ObjectiveThe aim of this paper is to critically re-appraise the published trials assessing propranolol for migraine prophylaxis.MethodsWe report methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared propranolol with placebo for migraine prophylaxis in adults. The outcomes of interest were informed by the Core outcome set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in monthly migraine days, the reduction of monthly migraine days, and the number of adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB (risk of bias) 2.0 tool and the certainty of evidence by using the GRADE approach.ResultsOur search yielded twenty trials (n = 1291 patients) eligible for data synthesis and analysis. The analysis revealed a moderate certainty evidence that propranolol leads to a reduction in monthly migraine days versus placebo (-1.27; 95% CI: -2.25 to -0.3). We found moderate certainty evidence that propranolol increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo with a relative risk of 1.65 (95% CI 1.41 to 1.93); absolute risk difference: 179 more per 1,000 (95% CI 113 to 256). We found high certainty evidence that propranolol increases the proportion of patients who discontinue due to adverse events compared to placebo with a risk difference of 0.02 (95% CI 0.00 to 0.03); absolute risk difference: 20 more per 1,000 (95% CI 0 to 30).ConclusionsThe present meta-analysis shows that propranolol has a prophylactic role in migraine, with an overall acceptable tolerability profile. Combining these results with its long-standing use and its global availability at a low cost confirms its role as a first line agent in the prophylaxis of migraine.

Formulation of 1% α-mangostin in orabase gel induces apoptosis in oral squamous cell carcinoma

BackgroundPlant-derived compounds have chemopreventive properties to be used as alternative medicine. Pericarp of Mangosteen (Garcinia mangostana Linn.), a tropical fruit in Southeast Asia contains a phytochemical α-mangostin (α-MG) that demonstrates potent anticancer effects against various types of cancer. α-MG has been reported to be the most effective agent in human cancer cell lines. The objectives of this study were to develop oral gel formulations containing α-MG and determine their (1) anticancer activity, (2) anti-HPV-16 and antimicrobial activities, (3) nitric oxide (NO) inhibitory activity, and (4) wound healing effect.MethodsFormulations of oral gel containing α-MG were developed. Anticancer activity on SCC-25 was assessed. Apoptotic induction was determined using flow cytometry technique. Antiviral activity against HPV-16 pseudovirus and antimicrobial activity against S. mutans, P. gingivalis and C. albicans were investigated. NO inhibition was carried out. Fibroblast cell migration was determined by in vitro scratch assay.ResultsThe formulation of 1% α-MG in orabase gel demonstrated anticancer activity by promoting apoptosis in SCC-25. The induction of apoptotic activity was dose dependent with pronounced effect in late apoptosis. The formulation appeared to reduce cell viability of oral keratinocytes (OKC). At CC50 it showed an inhibition against HPV-16 pseudovirus infection. The formulation had no antimicrobial activity against S. mutans, P. gingivalis and C. albicans. No significant NO inhibitory activity and wound healing effects were found.Conclusions1% α-MG in orabase gel exhibited anticancer activity by inducing apoptosis although low level of cytotoxicity observed in OKC was present. The appropriate carrier for novel nano-particles targeting cancer cells should be further investigated.

Evaluation of the merit of ethanolic extract of Annona reticulata as an anti-cancer agent in human colon cancer cell lines (HCT-116)

Background Colon cancer is the third most common cancer type worldwide. Novel alternative therapeutic anti-cancer drugs against colon cancer with less toxicity are to be explored . This study was aimed to explore the anti-proliferative and anti-migratory activity of various fractions of Annona reticulata ethanolic leaf extract on human colon cancer cell lines (HCT-116) and to explore the potential molecular targets from the most potent plant extract fraction. Methods After obtaining ethical clearance from the institutional ethics committee, the extract and fractions were prepared and a preliminary analysis of the phytochemical was done qualitatively. Total phenolic and flavonoids were determined. Ethanolic leaf extract and its fractions were subjected to cytotoxicity analysis using the sulforhodamine B assay and the most promising fraction which showed the highest viability was selected to study anti-migratory activity. The anti-migratory effect was studied using a scratch wound healing assay. Gas chromatography-mass spectrometry (GC-MS) was done to identify the major phytocompounds present in the fraction. The major five phytocompounds identified from the GC-MS were subjected to bioinformatics analysis. Result Among the four fractions, the petroleum ether fraction exhibited the highest anti-proliferative activity. The migration of colon cancer cells was significantly inhibited by the extract and petroleum ether fraction. The major phytocompounds identified from GC-MS were phytol (13.03%), 2,6-bis (3,4-methylenedioxyphenyl)-3,7-dioxabicyclo (3.3.0) octane (11.95%), gamma.-sitosterol (10.45%), alpha.-tocopherol-beta.-D-mannoside (7.50%) and 3-amino-4-piperonyl-5-pyrazolone (5.84%). The bioinformatics analysis of these phytochemicals showed a high potential to affect the levels of key proteins driving colon cancer progression, inhibiting the enzymes and proteins overexpressed in cancer. Conclusion The outcome of this study endorses the potential of phytochemicals of the petroleum ether fraction of ethanolic leaf extract of Annona reticulata for the development of a new chemotherapeutic agent in the treatment of colon cancer.

Evaluation of Whole Genome Sequencing-Based Predictions of Antimicrobial Resistance to TB First Line Agents: A Lesson from 5 Years of Data.

Phenotypic susceptibility testing of the Mycobacterium tuberculosis complex (MTBC) isolate requires culture growth, which can delay rapid detection of resistant cases. Whole genome sequencing (WGS) and data analysis pipelines can assist in predicting resistance to antimicrobials used in the treatment of tuberculosis (TB). This study compared phenotypic susceptibility testing results and WGS-based predictions of antimicrobial resistance (AMR) to four first-line antimicrobials-isoniazid, rifampin, ethambutol, and pyrazinamide-for MTBC isolates tested between the years 2018-2022. For this 5-year retrospective analysis, the WGS sensitivity for predicting resistance for isoniazid, rifampin, ethambutol, and pyrazinamide using Mykrobe was 86.7%, 100.0%, 100.0%, and 47.8%, respectively, and the specificity was 99.4%, 99.5%, 98.7%, and 99.9%, respectively. The predictive values improved slightly using Mykrobe corrections applied using TB Profiler, i.e., the WGS sensitivity for isoniazid, rifampin, ethambutol, and pyrazinamide was 92.31%, 100%, 100%, and 57.78%, respectively, and the specificity was 99.63%. 99.45%, 98.93%, and 99.93%, respectively. The utilization of WGS-based testing addresses concerns regarding test turnaround time and enables analysis for MTBC member identification, antimicrobial resistance prediction, detection of mixed cultures, and strain genotyping, all through a single laboratory test. WGS enables rapid resistance detection compared to traditional phenotypic susceptibility testing methods using the WHO TB mutation catalog, providing an insight into lesser-known mutations, which should be added to prediction databases as high-confidence mutations are recognized. The WGS-based methods can support TB elimination efforts in Canada and globally by ensuring the early start of appropriate treatment, rapidly limiting the spread of TB outbreaks.

Quality of antibiotic prescribing for outpatient cystitis in adult females

Background: Urinary tract infections (UTI) are responsible for a significant portion of female, outpatient antibiotic prescriptions. Especially true in uncomplicated cases, where symptoms remain the cornerstone of diagnosis, ensuring the optimal choice of agent, dose, and duration may mitigate future bacterial resistance and lower the likelihood of adverse events and/or recurrence. This study is the first in Canada to examine the quality of antibiotic prescribing to females in the outpatient setting, for uncomplicated UTI–by agent, dose, and duration. Methods: All adult female residents of British Columbia with a physician record for cystitis from January 1, 2014, to December 31, 2018, were identified. Patients with a history of urologic abnormalities, spinal cord injury, catheter use, kidney transplant, as well as pregnant females, were excluded. Primary outcomes included the proportion of total episodes prescribed and the proportion of appropriate antibiotic use, examined using Poisson regression. Results: A total of 182,162 episodes of cystitis were examined, with 70% receiving an antibiotic prescription. The rate of cystitis-associated prescribing was 697 prescriptions per 1,000 population. Overall, 35% of prescriptions were appropriate by guideline adherence or clinical justification. Nitrofurantoin and trimethoprim-sulfamethoxazole, accounted for 71% of total antibiotic use. Seven days was the most commonly dispensed duration of therapy, followed by 5, then 10. Conclusions: Shortening length of therapy in line with clinical guidelines and encouraging the use of first line agents present clear, actionable targets for provincial stewardship efforts.

Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.

Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.

Biomass-derived carbon dots as fluorescent quantum probes to visualize and modulate inflammation

Quantum dots, which won the Nobel Prize in Chemistry, have recently gained significant attention in precision medicine due to their unique properties, such as size-tunable emission, high photostability, efficient light absorption, and vibrant luminescence. Consequently, there is a growing demand to identify new types of quantum dots from various sources and explore their potential applications as stimuli-responsive biosensors, biomolecular imaging probes, and targeted drug delivery agents. Biomass-waste-derived carbon quantum dots (CQDs) are an attractive alternative to conventional QDs, which often require expensive and toxic precursors, as they offer several merits in eco-friendly synthesis, preparation from renewable sources, and cost-effective production. In this study, we evaluated three CQDs derived from biomass waste for their potential application as non-toxic bioimaging agents in various cell lines, including human dermal fibroblasts, HeLa, cardiomyocytes, induced pluripotent stem cells, and an in-vivo medaka fish (Oryzias latipes) model. Confocal microscopic studies revealed that CQDs could assist in visualizing inflammatory processes in the cells, as they were taken up more by cells treated with tumor necrosis factor-α than untreated cells. In addition, our quantitative real-time PCR gene expression analysis has revealed that citric acid-based CQDs can potentially reduce inflammatory markers such as Interleukin-6. Our studies suggest that CQDs have potential as theragnostic agents, which can simultaneously identify and modulate inflammatory markers and may lead to targeted therapy for immune system-associated diseases.

Real-World Effectiveness of First Line Lenvatinib Therapy in Advanced Hepatocellular Carcinoma: Current Insights.

Lenvatinib received its initial approval in 2018 for the treatment of advanced hepatocellular carcinoma. It has since emerged as the preferred first line agent, supported by non-inferiority data from the REFLECT trial. Notably, lenvatinib exhibits a more favorable toxicity profile and a higher response rate compared to sorafenib. Despite the approval of immunotherapy in 2020, specifically the combination of atezolizumab and bevacizumab following the IMbrave150 trial, tyrosine kinase inhibitors remain an indispensable class of agents in the landscape of hepatocellular carcinoma treatment. This comprehensive review delves into various facets of lenvatinib utilization in hepatocellular carcinoma, shedding light on real-world data, addressing challenges, and providing insights into strategies to overcome these obstacles.

#2645 Clinical features and outcomes of steroid resistant focal sclerosing glomerulosclerosis (FSGS) in a single tertiary nephrology centre in Malaysia

Abstract Background and Aims Steroid resistant FSGS is defined as persistence of proteinuria with <50% reduction from baseline despite prednisolone 1 mg/kg/d for at least 16 weeks. We aim to study the clinical presentations, treatment, treatment response and kidney survival among steroid resistant FSGS patients. Method This retrospective study included all patients who had undergone renal biopsy in HSIS and had documented diagnosis of steroid resistant FSGS from January 2007 until December 2022. Data was collected and analysed using SPSS version 17. Results are expressed in mean ± standard deviation (SD) unless stated otherwise. Results A total of 74 patients had primary FSGS out of which 15 were identified as steroid resistant. Median age was 33 years old with 53% being female. Median weight at diagnosis was 73.7kg with BMI of 28kg/m2. One third had no co-morbid disease while 4 patients had underlying diagnosis of minimal change disease. Proteinuria on presentation was 7.6g with albumin levels of 16 g/L. No difference was seen between steroid resistant and steroid sensitive cohort with regards to age, proteinuria, GFR and laboratory parameters. Median duration of steroid was 38.8 months with duration of high dose steroids were 5 months and complications often set in by 2 months of therapy. Steroid toxicity occurred in 13 patients with most common complication seen was Cushingoid features (8/13) followed by acne (2/13) and diabetes mellitus (2/13). There were more steroid complications in steroid resistant cohort compared to the steroid sensitive. Second line was initiated in all patients but one with cyclosporin A being the most common choice (11/14) followed by Azathioprine (2/14) and cyclophosphamide (3/14). The median duration of second line agent was 22 months with CNI specifically being for 18 months. 3 patients developed CNI toxicity and was given cyclophosphamide while one patient developed CNI resistance and was given IV Rituximab. 4 (%) patients went on to achieve complete remission, 8 had partial remission while the rest did not achieve remission. 9 patients had normal renal function, while 3 developed chronic kidney disease. One patient went on to become end stage renal disease while 2 patients died. There was no difference in terms of renal or patient outcome between steroid resistant and steroid sensitive FSGS. Conclusion Steroid resistant FSGS is a challenging entity of FSGS that warrants close monitoring for complications and management. The outcomes were not different between steroid sensitive and steroid resistant FSGS however, the steroid complications were more common in steroid resistant FSGS.

#2659 Clinical characteristics of patients with minimal change disease (MCD) that evolved to focal sclerosing glomerulosclerosis (FSGS)

Abstract Background and Aims Minimal change disease (MCD) and focal sclerosing glomerulosclerosis (FSGS) are both podocytopathies and are possibly diseases that lie on a similar spectrum with FSGS being the severe form. We aim to describe the clinical and laboratory parameters along with treatment and outcomes of MCD that were found to be FSGS on repeated biopsy. Method All patients who had undergone renal biopsy in Hospital Serdang and had documented diagnosis of FSGS from January 2007 until December 2022 were identified. Data was collected and analysed using SPSS version 17. Results were expressed in mean ± standard deviation (SD) unless stated otherwise. Results Total minimal change disease were 70 patients. A total of 14 were identified as FSGS on repeated biopsy. At time of biopsy, all patients presented as relapse in nephrotic syndrome (NS). Mean age of diagnosis was 18 years for MCD while mean age of FSGS diagnosis was 23.8 years. 11 were males and two patients had positive family history of kidney disease while 10 had some form of haematuria. All patients were on steroids with 4 of them developing steroid resistance. 11 patients were on second line agents either due to steroid resistance or toxicity. Majority of patients were on azathioprine followed by cyclosporine and mycophenolate mofetil. Mean follow up was 5.7 years. Those with MCD had higher platelet (mean 462) and total cholesterol (mean 14.2) values at diagnosis of FSGS. Mean relapse after diagnosis of FSGS was 2.2 episodes. (Patients remain in remission for 31 months before relapsing) As of December 2022, 9(65%) patients had normal kidney function, 2 end stage renal disease on dialysis while 3 CKD V had passed away due to acute coronary syndrome. Conclusion Minimal change disease is part of a spectrum podocytopathies along with FSGS. Those with frequent relapses in MCD, older children with nephrotic syndrome and those with presence of haematuria may be warranted for a repeated biopsy to rule out evolution to FSGS.

A CASE OF PULMONARY HYPERTENSION ASSOCIATED WITH MYELOFIBROSIS: THERAPEUTICAL CHALLENGES FROM ACUTE TO CHRONIC SETTING

Abstract A 85–year–old female was transferred to our ICCU for acute heart failure from one of our spoke hospitals. The patient had a long history of chronic myelofibrosis, treated with fedratinib as a second–line agent after ruxolitinib failure. During a recent hospital admission, transthoracic echocardiography already showed signs of severe pulmonary hypertension (PH) with right ventricular (RV) dysfunction, so diuretic was started. On admission the patient presented showed consistent with acute on chronic kidney injury (serum Cr 3.2 mg/dl), stable anemia (Hb 9.2 mg/dl) and markedly elevated Nt–proBNP. A pulmonary CT–scan excluded acute pulmonary embolism and lung parenchymal alterations, with a clear dilation of main pulmonary artery. Transthoracic echocardiography (figure 1) confirmed precapillary PH phenotype diagnosis. Electrocardiogram (figure 2) showed sinus rhythm; incomplete RBBB, T wave inversion in V2 to V4. The patient was initially treated with high dose furosemide, low flow oxygen; but later she needed multiple cycles of inotropes, vasopressors and combined diuretic therapy (metolazone and acetazolamide) to stabilize the clinical setting. The patient also experienced episodes of paroxysmal high ventricular rate atrial flutter. After resolution of volume overload, a right heart catheterization was performed and findings were consistent with severe precapillary pulmonary hypertension: PA pressure 90/58/40 mmHg, normal PCWP, high PVR, mild cardiac index reduction. Due to critical clinical situation, Sildenafil 20 mg was started as an off–label therapy for PH (group 5). Subsequently, the patient experienced gradual but constant hemodynamic and clinical improvement and was discharged in NYHA class II. At 1 month control, patient was stable, echocardiogram revealed improvement in right ventricle dimension, systolic function and right atrial enlargement. At three months, patient is still in an intermediate risk class for PH, so we are evaluating a combination therapy (either endothelin receptor antagonist or prostanoids), taking into account anemia and thrombocytopenia. Take home message: PH can be a complication of hematological disorders as myelofibrosis, included in “mixed” forms (group 5) of PH. In our patient, after a challenging management for acute right heart failure, an off–label PDE–5 inhibitor stabilized the clinical scenario: more data are needed on PH drugs use in this setting where up to now therapeutic strategies are lacking.

CDK4/6 inhibitors: The Devil is in the Detail.

Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.