Dual Drug Therapy Research Articles

Dual Drug Therapy Versus Single Drug Therapy in Prevention of Pinna Keloid Recurrence.

Keloids are fibroproliferative disorders caused due to injury to skin. The recurrence rate has been found to be as high as 100% even after surgical excision. The high recurrence rate has led to the need for various adjuvant therapies as a single approach alone has not been found to be efficient in preventing recurrence. This attributes to the need for a multimodal approach. Steroids are found to be useful in preventing recurrence. To evaluate the efficacy of the combination of hyaluronidase with corticosteroid injection compared to corticosteroid injection alone in the prevention of recurrence of keloid after surgical excision. This randomized controlled study was conducted in the Department of Otorhinolaryngology among 50 patients with ear keloids who underwent surgical excision. Patients were divided into two groups. One group was given Triamcinolone injection alone and the other was given Triamcinolone with Hyaluronidase on postoperative weeks 1, 2, and 3. Patients were followed up for 6 months and recurrence was noted and compared. Statistical analysis was done and the results were considered significant with a p-value of less than 0.05. Of the total 50 patients, there were a total of eight male and 39 female patients. In a single therapy group, recurrence was noted in one patient after 3 months and in three more patients after 6 months. In the group with combination therapy, there was no recurrence after 3 months but three patients had recurrence after 6 months. Triamcinolone and hyaluronidase injection protected from recurrence for about 3 to 5 months after which patients had recurrence. Further studies are recommended with prolonged duration of hyaluronidase injection.

Effects of Dual and Triple Drug Therapy in Chronic Obstructive Pulmonary Disease Management: An Overview

Effects of Dual and Triple Drug Therapy in Chronic Obstructive Pulmonary Disease Management: An Overview

Development of Poly(vinyl alcohol)-Chitosan Composite Nanofibers for Dual Drug Therapy of Wounds.

Current trends in localized drug delivery are emphasizing the development of dual drug-loaded electrospun nanofibers (NFs) for an improved therapeutic effect on wounds, especially infected skin wounds. The objective of this study was to formulate a new healing therapy for an infected skin wound. To achieve this goal, this study involved the development and characterization of poly(vinyl alcohol) (PVA)/chitosan nanofibers loaded with ciprofloxacin and rutin hydrate. Polymers and drugs were used in different ratios. Nanofiber morphology was studied by scanning electron microscopy, thermal stability by thermogravimetric analysis, structural determination by the X-ray diffraction method, and integrity by Fourier transform infrared spectroscopy. Dissolution studies were performed to check the drug release behavior of the formulations. Antibacterial studies were performed against Staphylococcus aureus and Pseudomonas aeruginosa. The wound healing efficiency of dual drug-loaded nanofibers was measured by a full-thickness excisional wound model of rabbits. The fabricated nanofibers were smooth in morphology. According to FTIR findings, the drugs remained intact in the nanofibers. The results of swelling ratio and porosity revealed that the pore size was increased as the amount of chitosan was increased up to 30% but a further increase in chitosan concentration reduced the swelling ratio and porosity. Drug release studies of nanofibers depicted an initial burst effect and afterward controlled drug release behavior. Drug-loaded nanofibers showed better activity against S. aureus than P. aeruginosa. The antibacterial efficacy of rutin hydrate with ciprofloxacin was improved compared to that of the formulation having rutin hydrate only, likely due to the additive effect in activity. Based on wound healing studies, nanofibrous membranes acted as a promising wound dressing material as compared to the commercial wound healing formulation. Drug-loaded polymeric nanofibers were successfully fabricated by using an electrospinning method. These nanofibers showed an efficient ability to deliver drugs and treat infected wounds.

Decellularized plant-derived vasculature-on-a-chip interacting with breast cancer spheroids to evaluate a dual-drug therapy

Breast cancer progression is a complex process involving the primary tumor and its microenvironment supported by a vascular network. Multicellular spheroids closely mimic in vivo-like tumor conditions, paving the way for effective treatments. Although spheroid formation by simulated microgravity emerges as a promising technique for cancer spheroids, the lack of a perfusable vascular network still limits the evaluation of tumor progression. Recently, decellularized plant structures with hierarchically formed vasculatures similar to the human vascular system gained interest as engineered vascular networks. In this study, breast cancer spheroids co-cultured with endothelial cells were grown both under unit-gravity and simulated microgravity conditions, whereas vasculature was formed by the decellularization of spinach leaf. The optimized spheroids and plant-derived vasculature populated with endothelial cells were integrated into a microplatform, where fibroblasts were embedded into the extracellular matrix (ECM) to mimic the tumor microenvironment (TME). The vasculature-on-a-chip was used to assess the response of breast cancer spheroids to a combinatorial dose of Doxorubicin (DOX) and Bevacizumab (BMAB) treatment administered to circulating flow emulating intravenous administration. The developed platform offers a biomimetic model to recapitulate key aspects of breast cancer progression and evaluate the responses of both the tumor and the vasculature to chemotherapeutic drugs.

Dual Antiplatelet Therapy Regimens and Duration for Intracranial Stenting Procedures: Literature Review

Objectives of the study. Our aim was to analyse different antithrombotic drug regimens and duration in intracranial stenting procedures (stent assisted coiling, flow diverter) for unruptured aneurysms and based on the literature review from 2017–2023 to implement dual antiplatelet therapy algorithm for neuro-interventional procedures in Lithuania. Research methods and methodology. A comprehensive literature search of PubMed, BioMed Central, BMJ Journals, EBSCO Publishing, SAGE Journals Online, ScienceDirect, SpringerLink was conducted by two independent readers (MP, GŠ) for studies published from January 2017 to April 2023. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. 23 studies: 6 retrospective cohort, 11 retrospective case-control, 1 prospective cohort, 1 prospective randomized-control, 1 systemic literature review, 3 metanalysis observational studies were identified. Results and conclusions. We found widespread variation in practices even among the same country centres, lending credence to the importance of a future prospective studies of dual antiplatelet drug therapy (DAPT) regimens and duration for the purpose of deriving optimal methods and streamlining tactics. Our suggested algorithm for DAPT in neuro-interventional procedures in Lithuania is provided in Graph 1.

Recurrence after resolution of symptomatic atrioventricular block and correction of transient causes, should we keep an eye on everyone?

Abstract Introduction Atrioventricular block (AVB) can be associated with secondary causes, some of which are potentially reversible. Permanent Pacemaker (PPM) implantation is not recommended in transient causes that can be corrected and prevented. However there is a high rate of recurrence which eventually warrant PPM implantation. Purpose Our aim was to characterize the population which had recurrence of symptomatic AVB after having recovered from an index event and having corrected secondary causes. Methods We performed a retrospective analysis between February 2011 and November 2022 of all patients admitted with symptomatic second degree AVB (including 2:1 and high-grade), third degree AVB and atrial fibrillation with AVB who had a reversible cause capable of being corrected and had a recovery of rhythm without PPM implantation, in a single expert centre. AVB secondary to Acute Coronary Syndromes and patients who required PPM to tolerate bradycardia inducing drugs were excluded from analysis. Medical records were analysed for demographics, clinical data and outcomes. Results Of the 135 patients analysed, 25 fulfilled all inclusion criteria and were analysed. The mean age at analysis was 77±8 years with a male preponderance (52%). The rhythm of presentation had been complete AVB for most of the cohort (68%). A prior ECG was obtained for most patients (92%), with atrioventricular (AV) conduction abnormalities identified in 28% of patients and intraventricular (IV) conduction abnormalities identified in 56% of patients. At index admission, bradycardic drug therapy was the most identified reversible cause (92%) and significant hyperkalaemia (categorized as above 5,5 mmol/L) was identified in 40% of patients. In 20 patients (80%) there was recurrence of symptomatic AVB during follow-up (median time to recurrence of 11,5 months, minimum less than a month and maximum 130 months) which warranted a PPM implantation. The independent predictors of recurrence were the presence of hyperkalaemia as a causal factor at index admission and of non-recurrence the dual therapy with bradycardic drugs at index admission (Qui square test for both p<0,05). The age, sex, prior of chronic kidney disease (with or without dialysis) prior AV or IV conduction abnormality, high dose bradycardic drug therapy at index admission, association between hyperkalaemia and bradycardic drug therapy and presentation rhythm different from complete AVB were non-significant. Conclusions Patients with a transient cause for symptomatic AVB which recovers with its correction have a high rate of recurrence in follow-up, particularly if the transient cause was hyperkalaemia , and only the initial presence of dual bradycardic drug therapy which was suspended predicted sustained recovery.

Abstract 15318: A Dene- and Drug-Eluting Peripheral Stent Using a Baculovirus-Eluting PVA Hydrogel Coating

Introduction: Over 20 % of people over 60 have peripheral artery disease (PAD), the narrowing of peripheral arteries due to atherosclerosis. More recent data suggests a surge in PAD in younger people (affecting up to 4 % of people). Atherosclerosis is complex, initially involving fat deposition and endothelial cell dysfunction, leading to inflammation, hyperproliferation of cells, plaque development, and calcification. This can lead to significant pain, discomfort, limb ischemia, stroke, and increases the risk of major cardiovascular events such as myocardial infarction and coronary artery disease. Often a bare-metal or drug-eluting stent will force the artery open. These stents are highly effective but come with complications such as restenosis, thrombosis, and enhanced endothelial dysfunction leading to patency as low as 60 % one-year post-implantation. Hypothesis: A gene- and drug-eluting hydrogel stent coating can promote endothelial recovery while the long-term drug elution prevents restenosis and inflammation, improving the clinical outcome of PAD (Figure 1). Methods & results: The gene encoding nitric oxide had been cloned into a baculovirus, a highly efficient and safe gene delivery vector to arterial cells. Nitric oxide inhibits smooth muscle cell proliferation, promotes endothelial cell proliferation, promotes angiogenesis, and prevents reactive oxygen species production within the diseased artery. The 10-day gene elution has the potential to leave behind a healthy endothelial lining, and the 100-day Everolimus drug elution can prevent restenosis and inflammation. Moreover, the gene- and drug-eluting stent is stable during crimping and expansion, has a high tensile strength, is non-cytotoxic, and is anti-thrombotic by preventing platelet adhesion. Conclusion: Overall, the novel stent exhibits beneficial mechanical and cellular properties with the potential to mitigate current stenting complications using dual gene and drug therapy.

A Prospective Observational Study on Single Vs Dual Antiplatelet Drug Therapy in Patients with Ischemic Stroke in a Tertiary Care Hospital

From the study, we conclude that patients aged 60–69 are prone to stroke, and the patients who are receiving DAPT have a higher rate of recovery with fewer major bleeding risks when compared with SAPT, but reoccurrence is seen more in SAPT.

HGG-02. METABOLIC TARGETING OF HIGH-GRADE GLIOMAS WITH MTAP LOSS

Abstract Malignant transformation of pediatric glioma is often associated with homozygous deletion of CDKN2A. With CDKN2A loss, MTAP which is in the same chromosomal location, 9p21, is homozygously deleted in a majority of HGGs and some LGGs. The MTAP gene codes for methylthioadenosine phosphorylase (MTAP) protein which plays an important role in methionine salvage pathway. Absence of MTAP results in accumulation of 5’-methylthioadenosine (MTA), de novo purine synthesis, and tumor cell dependency on protein arginine methyltransferase 5 (PRMT5) and its substrate provider, methionine adenosyltransferase II alpha (MAT2A). We hypothesize that drugs targeting PRMT5, MAT2A, and de novo purine synthesis, in combination with drugs targeting hyper-activated RAS/MAPK pathway, will be effective in inhibiting MTAP-null glioma growth. Patient-derived glioma cells were validated for MTAP loss using genome sequencing, RNA sequencing and western blot. MTA accumulation caused by MTAP loss was validated through high-performance liquid chromatography. Cells were subjected to monotherapy and combination drug therapy with PRMT5, MAT2A and de novo purine synthesis inhibitors, in addition to drugs targeting RAS/MAPK signaling pathway. Additionally, MTAP-null (MTAPnull) in vivo models are being developed.We show accumulation of MTA in MTAPnull cells compared to MTAP-wild type (MTAPWT) cells, caused by loss of MTAP that cleaves MTA to adenine and 5-methylthioribose-1-phosphate (MTR). Accumulation of MTA makes MTAPnull glioma cells more sensitive to MAT2A inhibitor AG-270 in comparison to MTAPWT cells. Additionally, dual-drug therapies involving MTA and AG-270 result in additive effect on MTAPnull cells and antagonistic effect on MTAPWT cells. De novo purine synthesis inhibitor and drugs targeting the RAS/MAPK pathways also exhibited cell growth inhibition of MTAPnull cells. Overall, metabolic targeting of HGGs bearing CDKN2A/MTAP loss is indispensable for targeted therapy and for minimizing toxicity towards surrounding normal cells lacking similar mutations.

An integrated therapeutic approach to sickle cell disease management beyond infancy.

Hydroxyurea, the first approved drug for sickle cell disease, decreases sickle hemoglobin polymerization by inducing fetal hemoglobin. Its effects in young children are excellent; responses in adults are variable and not curative. The goal of pharmacotherapy should not be disease "moderation" but reducing morbidity and mortality by diminishing both hemolytic anemia and vaso-occlusive events. This is best done by preventing sickle hemoglobin polymerization; if anti-polymerization treatment is insufficient, agents disrupting pathophysiologic pathways "downstream" of the sickle hemoglobin polymer should be added. We recommend that all patients should be started first on maximal doses of hydroxyurea. When the clinical and hematologic response to hydroxyurea is insufficient, as it is almost always in adults, we favor adding voxelotor, a hemoglobin-oxygen affinity-shifting agent that, likely in a pancellular distribution, decreases sickle hemoglobin polymerization. The P-selectin inhibitor crizanlizumab reduces sickle cell-endothelial interactions and can be used in patients with continued vaso-occlusive events. There is no physiologic reason that all three drugs could not be combined when the response to monotherapy or dual-drug therapy is poor. Drug therapy must be considered in the context of possibly "curative" cellular therapeutics and if needed, exchange transfusion programs.

Hypertension clinical care in the era of coronavirus disease 2019

Objective: The objective of this study was to seek the opinion of Indian health-care professionals (HCPs) about hypertension (HTN) care during coronavirus disease 2019 (COVID-19) era. Methods: HCPs' opinions (n = 2832) were recorded based on survey and round table meetings. Standard questionnaire consisting of nine questions pertaining to HTN care in COVID-19 was prepared, discussed, and evaluated by experts who treat patients with HTN during COVID-19 era. Results: Smoking/tobacco use, obesity, and comorbidities (diabetes/dyslipidemia) were ranked as the top three modifiable risk factors. A total of 37% and 33% of HCPs reported an increase in blood pressure (BP) during the lockdown period in 10%–20% and 20%–40% of hypertensive patients, respectively, who were on monotherapy. Around 35% of HCPs reported that 20%–30% of their patients with HTN showed uncontrolled BP (>150/100 mmHg). Dual-drug therapy in patients with uncontrolled BP was preferred by 56% of HCPs. Nearly 71% preferred dual combination for HTN management. In dual combination, 27% preferred angiotensin receptor blockers (ARBs) + diuretic, 26% preferred ARB + calcium channel blockers, and 18% preferred ARB + beta-blockers. The majority of HCPs (44%) consider that <30% of their patients with HTN check BP at home. A total of 47% of HCPs reported acute coronary syndrome as the most common HTN-related complication. The majority of HCPs (57%) considered that avoiding contamination during BP measurement is the challenging parameter. Around 32% considered self-BP monitoring (SBPM) as the best method to improve medication adherence. Conclusion: SBPM, combination therapies, and digital connect with patients are critical aspects of HTN management during COVID-19 pandemic.

BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

Time of Resumption of Antiplatelet Drugs After Upper Gastrointestinal Hemorrhage.

BackgroundThis study aimed to investigate the optimum time to reintroduce the original antiplatelet drugs after upper gastrointestinal hemorrhage in patients as secondary prevention for cardiovascular and cerebrovascular diseases.Material/MethodsAfter the upper gastrointestinal bleeding stopped, patients were randomly divided according to the oral antiplatelet drugs administered. The aspirin group was further divided into 3-day and 7-day aspirin groups. The patients who took aspirin and clopidogrel were randomly divided into 3 groups: 0-day aspirin+3-day clopidogrel; 0-day aspirin+7-day clopidogrel; and 3-day aspirin+7-day clopidogrel. The recovery time, rebleeding rate, incidence of cardiovascular and cerebrovascular events, and death were observed.ResultsThe 3-day aspirin group had more rebleeding, reduced risk of cardiovascular and cerebrovascular events, and a similar mortality rate compared to the other groups. In the aspirin+clopidogrel group, the 0-day aspirin+3-day clopidogrel group had the highest rebleeding rate and the lowest risk of cardiovascular and cerebrovascular events. The 3-day aspirin+7-day clopidogrel group had the highest risk of cardiovascular and cerebrovascular events and increased hospitalization time. The risk of rebleeding and cardiovascular and cerebrovascular events was lower in the 0-day aspirin+7-day clopidogrel group, and the overall mortality rate was the lowest in this group.ConclusionsIn patients receiving only aspirin, this drug should be reintroduced as soon as possible after peptic ulcer hemorrhage. Aspirin and clopidogrel are dual antiplatelet drugs used for the secondary prevention of cardiovascular diseases. In patients under dual-drug therapy, aspirin should not be stopped, while clopidogrel should be restarted in about 7 days.

Evaluation of Prescribing Pattern, Therapeutic Adherence and Occurrence of Adverse Drug Reactions in Patients with Type 2 Diabetes Mellitus

Background: Persistent hyperglycemia in diabetes mellitus (DM) is considered the leading cause of morbidity and mortality associated with both microvascular and macrovascular complications, having a greater economic impact. This study aimed to assess the impact of socioeconomic status, prescribing patterns, and patient compliance in type 2 diabetes mellitus patients. Method: This study was carried out at the Department of Medicine and Diabetic Clinic of Hakeem Abdul Hameed (HAH) Centenary Hospital at Hamdard University, New Delhi, India. We conducted a prospective observational study on prescribing patterns and monitoring adverse drug reactions (ADRs) in patients with type 2 DM (T2DM) under standard care. We enrolled 150 confirmed cases, and data was obtained from pre-validated questionnaires and then coded and analyzed to observe the association between variables. Results: The glycosylated haemoglobin level in 56% of the cases was between 6.4 to 8.0, and cardiovascular complications were observed as the major comorbidities. 45.33 % of the cases were on mono drug therapy, and metformin (23. 52 %) was the drug of choice, followed by glimepiride (23.52 %). Among the dual drug therapies, sitagliptin with metformin and triple-drug therapy, glimepiride concurrent with metformin and voglibose was the most preferred drug in the treatment of T2DM. Sitagliptin was observed to be a major patient burden (46.213 USD). In only 7.33 % of the cases, we observed definite ADR in T2DM patients. Underprivileged awareness, mainly due to low literacy, was a major concern in the development of new cases of T2DM. Conclusion: We observed better patient compliance; however, a disease awareness program must be implemented. The use of oral hypoglycaemic drugs is still dominant in clinical practice and cardiovascular disorders as comorbidities emerge as a greater challenge in terms of patient outcome and cost burden.

Comparison of platinum monotherapy with concurrent chemoradiation therapy versus platinum-based dual drug therapy with concurrent chemoradiation therapy for locally advanced cervical cancer: a systematic review and meta-analysis

ObjectiveTo compare the survival outcomes and adverse events of patients with locally advanced cervical cancer (LACC) who received platinum monotherapy with concurrent chemoradiation therapy (CCRT) versus platinum-based dual drug therapy with CCRT.MethodAll relevant literature was screened form the PubMed, EMBASE, Web of Science, The Cochrane Library and other databases from their establishment to October 2020. The main endpoint indicators included overall survival (OS) and progression-free survival (PFS). Grade 3 and above adverse events induced by chemotherapy were also compared.ResultsThis study involved 17 literature and 4,106 patients. There were 2,066 patients treated with CCRT with platinum-based dual drug therapy and 2,040 patients received CCRT with platinum monotherapy. Meta-analysis results showed that, compared to CCRT with platinum monotherapy, OS (HR = 0.68, 95% CI 0.58–0.79) and PFS (HR = 0.67, 95% CI 0.58–0.77) of LACC patients were significantly improved by CCRT with platinum-based dual drug therapy. In addition, CCRT with platinum-based dual drug therapy led to more adverse reactions such as neutropenia (OR = 4.92, 95% CI 3.55–6.84), anemia (OR = 1.99, 95% CI 1.17–3.39), diarrhea (OR = 1.70, 95% CI 1.30–2.22), leukopenia (OR = 2.42, 95%CI 1.84–3.17), thrombocytopenia (OR = 2.87, 95%CI 1.44–5.72), etc.ConclusionCCRT with platinum-based dual drug therapy improved OS and PFS of LACC patients relative to the CCRT with platinum monotherapy. But it also increased the adverse reactions caused by multiple chemotherapy drugs. Thus, it is crucial to select a proper chemotherapy regimen based on the actual tolerance of patients in clinical practice.

Polymerization-Induced Self-Assembly (PISA) for in situ drug encapsulation or drug conjugation in cancer application

HypothesisWe describe the possibility of using the same block copolymer carriers prepared by PISA for in situ drug encapsulation or drug conjugation. ExperimentsBlock copolymers containing poly((ethylene glycol) methacrylate)–co-poly(pentafluorophenyl methacrylate)-b-poly(hydroxypropyl methacrylate) (P((PEGMA-co-PFBMA)-b-PHPMA)) were synthesized at 10 wt% using PISA. The first approach involved in situ Doxorubicin (DOX) loading during PISA, while the second exhibited surface functionalization of PISA-made vesicles with dual drug therapies, N-acetyl cysteine (NAC) and DOX using para-fluoro-thiol reaction (PFTR) and carbodiimide chemistry, respectively. Cytotoxicity, cell uptake, and cell apoptosis were assessed on MDA-MB-231 cell lines. FindingsP((PEGMA-co-PFBMA)-b-PHPMA) nanocarriers were prepared, showing size and shape transformations from spheres, cylinders to raspberry-forming vesicles. DOX was readily loaded into NPs during PISA with relatively high encapsulation efficiency of 70 %, whereas the plain PISA-made vesicles could be functionalized with NAC and DOX at high yields. DOX-free NPs showed biocompatibility, whilst DOX-conjugated NPs imparted a concentration-dependent cytotoxicity, as well as an enhanced cell uptake compared to free DOX. The results demonstrated that the same PISA-derived self-assemblies enabled either in situ drug encapsulation, or post-polymerization surface engineering with useful functionalities upon tuning the macro-CTA block, thus holding promises for future drug delivery and biomedical applications.

Bacterial infections in cancer: A bilateral relationship.

Bacteria share a long commensal relationship with the human body. New findings, however, continue to unravel many complexities associated with this old alliance. In the past decades, the dysbiosis of human microbiome has been linked to tumorigenesis, and more recently to spontaneous colonization of existing tumors. The topic, however, remains open for debate as the claims for causative-prevailing dual characteristics of bacteria are mostly based on epidemiological evidence rather than robust mechanistic models. There are also no reviews linking the collective impact of bacteria in tumor microenvironments to the efficacy of cancer drugs, mechanisms of pathogen-initiated cancer and bacterial colonization, personalized nanomedicine, nanotechnology, and antimicrobial resistance. In this review, we provide a holistic overview of the bilateral relationship between cancer and bacteria covering all these aspects. Our collated evidence from the literature does not merely categorize bacteria as cancer causative or prevailing agents, but also critically highlights the gaps in the literature where more detailed studies may be required to reach such a conclusion. Arguments are made in favor of dual drug therapies that can simultaneously co-target bacteria and cancer cells to overcome drug resistance. Also discussed are the opportunities for leveraging the natural colonization and remission power of bacteria for cancer treatment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Mucormycosis and diabetes in the times of COVID-19: A Mumbai-based observational study.

There is a significant increase in the number of mucormycosis cases in the setting of the coronavirus disease 2019 (COVID-19) pandemic. This study was undertaken to understand the clinical profile of such patients and the risk factors associated with increased mortality of this already deadly infection. A retrospective observational study was conducted by including microbiologically confirmed cases of mucormycosis with the background of COVID-19 infection (COVID-19-associated mucormycosis [CAM]). Data was segregated into those of survivors versus non-survivors and the two groups were analyzed for various risk factors. Early and late CAM were also compared. The case fatality rate was 21.73% (5/23 patients). Case fatality in early CAM was 33.3% versus 9.1% in late CAM. Rhino-orbital-cerebral mucormycosis (P = 0.01) and cranial nerve involvement (P = 0.0482) were associated with increased mortality. Diabetes and poor glycemic control were the common factors in all patients. Early CAM patients were more likely to have orbital or cerebral involvement (P = 0.0065). Patients having chronic liver disease had a higher risk of mortality (P = 0.0395). Sequential treatment or concurrent dual drug therapy with a combination of antifungal drugs was independently associated with better survival (P = 0.0395). The average duration of treatment with amphotericin-b required for cure by survivors was 29.05 ± 17.05 days. The average duration of treatment with isavuconazole/posaconazole for survivors was 50.32 ± 25.23 days. Early CAM had a higher case fatality rate. Patients had better recovery rates with sequential or dual antifungal treatment. The raised incidence and mortality in the COVID-19 pandemic is probably related to the COVID-19-induced immunosuppression with associated diabetes and excessive use of steroids.

CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

First Reported Case Series of Concomitant Ruxolitinib and Ibrutinib for Graft-Versus-Host Disease (GVHD)

Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD.Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172.Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved.Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option. DisclosuresCairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.