A potential therapeutic strategy of an innovative probiotic formulation toward topical treatment of diabetic ulcer: an in vivo study.

BACKGROUND: The probiotic potential of Lacticacid bacteria has been studied in various medical complications, from gastrointestinal diseases to antibiotic resistance infections recently. Moreover, diabetic ulcer (DU) is known as one of the most significant global healthcare concerns, which comprehensively impacts the quality of life for these patients. Given that the conventional treatments of DUs have failed to prevent later complications completely, developing alternative therapies seems to be crucial. METHODS: We designed the stable oleogel-based formulation of viable probiotic cells, including Lactobacillus rhamnosus (L. rhamnosus), Lactobacillus casei (L. casei), Lactobacillus fermentum (L. fermentum), and Lactobacillus acidophilus (L. acidophilus) individually to investigate their effect on wound healing process as an in vivo study. The wound repair process was closely monitored regarding morphology, biochemical, and histopathological changes over two weeks and compared it with the effects of topical tetracycline as an antibiotic approach. Furthermore, the antibiofilm activity of probiotic bacteria was assessed against some common pathogens. RESULTS: The findings indicated that all tested lactobacillus groups (excluded L. casei) included in the oleogel-based formulation revealed a high potential for repairing damaged skin due to the considerably more levels of hydroxyproline content of tissue samples along with the higher numerical density of mature fibroblasts cell and volume density of hair follicles, collagen fibrils, and neovascularization in comparison with antibiotic and control groups. L. acidophilus and L. rhamnosus showed the best potential of wound healing among all lactobacillus species, groups treated by tetracycline and control groups. Besides, L. rhamnosus showed a significant biofilm inhibition activity against tested pathogens. CONCLUSIONS: This experiment demonstrated that the designed formulations containing probiotics, particularly L. acidophilus and L. rhamnosus, play a central role in manipulating diabetic wound healing. It could be suggested as an encouraging nominee for diabetic wound-healing alternative approaches, though further studies in detailed clinical trials are needed.

Corticosteroid-loaded chitosan-based in-situ forming gel combined with microneedle technology for improvement of burn eschar wound healing.

Burn is one of the most common skin injuries and accounts for 300,000 deaths annually. Debridement and antibiotic therapy are major burn treatments, however, as debridement is not always possible and many drugs have poor penetration into necrotic tissue, permeation enhancement is acquired. Another challenge is the short duration of topically applied drugs. This study aims to address both problems by combining in-situ forming gels and microneedles. A chitosan-based in-situ forming gel of hydrocortisone was applied to human burn eschar using microneedles. The formulation was optimized using Design-Expert software. Formulation characterization was done in terms of gelling time and temperature, thermal analysis, release phenomenon, rheology, texture analysis, and stability. Finally, animal studies on mice burn wound treatment were conducted. Results showed that optimized formulation controlled the drug release, and wherever microneedle was used, drug permeation and flux increased (P-value < 0.05). In all ex-vivo and in-vivo stages, gel plus microneedle (length of 1.5 mm and application mode of 2) produced the best results concerning increased flux and faster recovery of burn eschar. In conclusion, the in-situ forming gel with appropriate texture, quality, and stability in combination with microneedle can be a good candidate for the controlled release of drugs in third-degree burn eschars.

A thermoresponsive chitosan-based in situ gel formulation incorporated with 5-FU loaded nanoerythrosomes for fibrosarcoma local chemotherapy.

Local administration of drugs at tumor sites over an extended period of time shows potential as a promising approach for cancer treatment. In the present study, the temperature-induced phase transition of chitosan and poloxamer 407 is used to construct an injectable hydrogel encapsulating 5-FU-loaded nanoerythrosome (5-FU-NER-gel). The 5-FU-NERs were found to be spherical, measuring approximately 115 ± 20 nm in diameter and having a surface potential of -7.06 ± 0.4. The drug loading efficiency was approximately 40 %. In situ gel formation took place within 15 s when the gel was exposed to body temperature or subcutaneous injection. A sustained release profile was observed at pH 7.4 and 6.8, with a total 5-FU release of 76.57 ± 4.4 and 98.07 ± 6.31 in 24 h, respectively. MTT, Live/dead, and migration assays confirmed the cytocompatibility of the drug carrier and its effectiveness as a chemotherapeutic formulation. After in vivo antitumor assessment in a subcutaneous autograft model, it was demonstrated that tumor growth inhibition in 14 days was 90 %. Therefore, the obtained injectable chitosan-based hydrogel containing 5-FU-loaded nanoerythrosomes illustrated promising potential as a candidate for local and enhanced delivery of chemotherapeutics at the tumor site.

Design of a sustainable supply chain network of biomass renewable energy in the case of disruption.

Non-renewable energy sources, including fossil fuels, are a type of energy whose consumption rate far exceeds its natural production rate. Therefore, non-renewable resources will be exhausted if alternative energy is not fully developed, leading to an energy crisis in the near future. In this paper, a mathematical model has been proposed for the design of the biomass supply chain of field residues that includes several fields where residue is transferred to hubs after collecting the residue in the hub, the residue is transferred to reactors. In reactors, the residue is converted into gas, which is transferred to condenser and transformers, converted into electricity and sent to demand points through the network. In this paper, the criteria of stability and disturbance were considered, which have been less discussed in related research, and the purpose of the proposed model was to maximize the profit from the sale of energy, including the selling price minus the costs. Genetic algorithm (GA) and simulated annealing (SA) algorithm have been used to solve the model. Then, to prove the complexity of the problem, different and random examples have been presented in different dimensions of the problem. Also, the efficiency of the algorithm in small and large dimensions was proved by comparing GA and SA due to the low deviation of the solutions and the methods used have provided acceptable results suitable for all decision-makers. Also, the effectiveness of the algorithm in small and large dimensions is proven by comparing the genetic algorithm and simulated annealing, and the genetic algorithm's values are better, considering the deviation of 2.9%.and have provided solution methods suitable for all decision makers.

Mixed-Micelle in Situ Gel as a Candidate for Oral Inflammatory Ulcerative Diseases.

The current treatment for oral inflammatory ulcerative diseases has limitations. In situ forming hydrogels have shown great potential to deliver therapeutic substances for drug delivery to the buccal cavity. This study aimed to prepare and characterize lipid- and surfactant-based mixed micelle in situ gel (MIG) and evaluate whether it can offer more favorable properties than the in situ gel for effective treatment of the disease. Dexamethasone was incorporated into the MIGs particles, based on Poloxamer 407 and chitosan. The lower gelation time at 37 ℃ was considered a criterion to select superior formulations among the different lipid- and surfactant-based candidates. Further characterization was performed to evaluate the opted formulations regarding morphology, physical stability, rheology, texture, and release profile. All formulations were thermoresponsive and had a shorter gelation time as the temperature increased. Dexamethasone was released in a highly controlled manner, and morphological evaluation revealed that the mixed micelle in situ gels had spherical nanoparticles. Thixotropic behavior was observed in all MIGs, indicating a prolonged retention time of the formulation after oral administration. This study has shown that among different MIGs, the one with oleic acid is a more promising candidate than the in situ gel and other MIGs for drug delivery to the buccal cavity.

A Sustainable Multi-Objective Model for Capacitated-Electric-Vehicle-Routing-Problem Considering Hard and Soft Time Windows as Well as Partial Recharging.

Due to the high pollution of the transportation sector, nowadays the role of electric vehicles has been noticed more and more by governments, organizations, and environmentally friendly people. On the other hand, the problem of electric vehicle routing (EVRP) has been widely studied in recent years. This paper deals with an extended version of EVRP, in which electric vehicles (EVs) deliver goods to customers. The limited battery capacity of EVs causes their operational domains to be less than those of gasoline vehicles. For this purpose, several charging stations are considered in this study for EVs. In addition, depending on the operational domain, a full charge may not be needed, which reduces the operation time. Therefore, partial recharging is also taken into account in the present research. This problem is formulated as a multi-objective integer linear programming model, whose objective functions include economic, environmental, and social aspects. Then, the preemptive fuzzy goal programming method (PFGP) is exploited as an exact method to solve small-sized problems. Also, two hybrid meta-heuristic algorithms inspired by nature, including MOSA, MOGWO, MOPSO, and NSGAII_TLBO, are utilized to solve large-sized problems. The results obtained from solving the numerous test problems demonstrate that the hybrid meta-heuristic algorithm can provide efficient solutions in terms of quality and non-dominated solutions in all test problems. In addition, the performance of the algorithms was compared in terms of four indexes: time, MID, MOCV, and HV. Moreover, statistical analysis is performed to investigate whether there is a significant difference between the performance of the algorithms. The results indicate that the MOSA algorithm performs better in terms of the time index. On the other hand, the NSGA-II-TLBO algorithm outperforms in terms of the MID, MOCV, and HV indexes.

A photocrosslinkable and hemostatic bilayer wound dressing based on gelatin methacrylate hydrogel and polyvinyl alcohol foam for skin regeneration.

The enormous potential of multifunctional bilayer wound dressings in various medical interventions for wound healing has led to decades of exploration into this field of medicine. However, it is usually difficult to synthesize a single hydrogel with all the required capabilities simultaneously. This paper proposes a bilayer model with an outer layer intended for hydrogel wound treatment. By adding gelatin methacrylate (GelMA) and tannic acid (TA) to the hydrogel composition and using polyvinyl alcohol-carboxymethyl chitosan (PVA-CMCs) foam layer as supports, a photocrosslinkable hydrogel with an optimal formulation was created. The hydrogels were then examined using a range of analytical procedures, including mechanical testing, rheology, chemical characterization, and in vitro and in vivo tests. The resulting bilayer wound dressing has many desirable properties, namely uniform adhesion and quick crosslinking by UV light. When used against Gram-positive and Gram-negative bacterial strains, bilayer wound dressings demonstrated broad antibacterial efficacy. In bilayer wound dressings with GelMA and TA, better wound healing was observed. Those without these elements showed less effectiveness in healing wounds. Additionally, encouraging collagen production and reducing wound infection has a major therapeutic impact on wounds. The results of this study could have a significant impact on the development of better-performing wound dressings.

Recent Biomaterial-Assisted Approaches for Immunotherapeutic Inhibition of Cancer Recurrence.

Biomaterials possess distinctive properties, notably their ability to encapsulate active biological products while providing biocompatible support. The immune system plays a vital role in preventing cancer recurrence, and there is considerable demand for an effective strategy to prevent cancer recurrence, necessitating effective strategies to address this concern. This review elucidates crucial cellular signaling pathways in cancer recurrence. Furthermore, it underscores the potential of biomaterial-based tools in averting or inhibiting cancer recurrence by modulating the immune system. Diverse biomaterials, including hydrogels, particles, films, microneedles, etc., exhibit promising capabilities in mitigating cancer recurrence. These materials are compelling candidates for cancer immunotherapy, offering in situ immunostimulatory activity through transdermal, implantable, and injectable devices. They function by reshaping the tumor microenvironment and impeding tumor growth by reducing immunosuppression. Biomaterials facilitate alterations in biodistribution, release kinetics, and colocalization of immunostimulatory agents, enhancing the safety and efficacy of therapy. Additionally, how the method addresses the limitations of other therapeutic approaches is discussed.

Preparation and characterization of a nanohydroxyapatite and sodium fluoride loaded chitosan-based in situ forming gel for enamel biomineralization.

The development of remineralizing smart biomaterials is a contemporary approach to caries prevention. The present study aimed at formulation preparation and characterization of a thermoresponsive oral gel based on poloxamer and chitosan loaded with sodium fluoride (NaF) and nanohydroxyapatite (nHA) to treat demineralization. The chemical structure and morphology of the formulation were characterized using FTIR and FESEM-EDS tests. Hydrogel texture, rheology, and stability were also examined. The hydrogel was in a sol state at room temperature and became gel after being placed at 37 °C with no significance different in gelation time with the formulation without nHA and NaF as observed by t-test. The FTIR spectrum of nHA/NaF/chitosan-based hydrogel indicated the formation of physical crosslinking without any chemical interactions between the hydrogel components. The FESEM-EDS results demonstrated the uniform distribution of each element within the hydrogel matrix, confirming the successful incorporation of nHA and NaF in the prepared gel. The hardness, hydrogel's adhesiveness, and cohesiveness were 0.9 mJ, 1.7 mJ, and 0.37, respectively, indicating gel stability and the acceptable retention time of hydrogels. The formulation exhibited a non-Newtonian shear-thinning pseudoplastic and thixotropic behavior with absolute physical stability. Within the limitation of in vitro studies, nHA/NaF/chitosan-based in situ forming gel demonstrated favorable properties, which could be trasnsorm into a gel state in oral cavity due to poloxamer and chitosan and can prevent dental caries due to nHA and NaF. We propose this formulation as a promising dental material in tooth surface remineralization.

Simvastatin-Loaded Nanostructured Lipid Carriers as Topical Drug Delivery System for Wound Healing Purposes: Preparation, Characterization, and In Vivo Histopathological Studies.

Purpose: Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a commonly used drug to reduce total cholesterol and low-density lipoprotein (LDL) levels. Furthermore, several mechanisms showed the wound-healing potential of statins, especially simvastatin. Simvastatin is a lipophilic drug, therefore, it has low water solubility with limited skin permeability potential. In this regard, nanostructured lipid carriers (NLCs) were recruited as novel topical drug delivery systems to enhance skin adhesion and film formation, maintain skin integrity, sustain the release of simvastatin, and prolong simvastatin skin deposition to help pressure ulcers healing and regeneration. Methods: NLCs were fabricated using the solvent diffusion evaporation technique. Drug loading, in vitro drug release, and morphological assessment on the optimized formulation were considered. Furthermore, in vivo effect of simvastatin-loaded NLCs gel on pressure ulcer healing was assessed using a rat skin model. Histopathological assessments were compared with conventional simvastatin gel and drug-free NLCs gel. Results: Simvastatin-loaded NLC with an average diameter of 100 nm was considered as the optimum formulation. According to the results entrapment efficiency of simvastatin within the NLCs was about 99.4%. Drug release studies revealed sustained drug release from NLCs in which about 87% of the drug was slowly released during 48 hours. Animal study results confirmed that simvastatin-loaded NLCs gel has better efficacy on pressure ulcers and could significantly reduce inflammation, and promote skin regeneration compared to both drug-free NLCs and conventional simvastatin gels. Conclusion: Simvastatin-loaded NLCs with an average particle size of 100 nm would be a promising novel topical drug delivery system with sustained drug release potential for pressure ulcer treatment.

Pharmacotechnical aspects of a stable probiotic formulation toward multidrug-resistance antibacterial activity: design and quality control.

As a well-known group of the probiotic family, the Lactobacillus has increasingly contributed to hindering the growth of pathogens, particularly resistant species, in the last decades. Since antibiotic resistance has become a severe problem in global healthcare systems and considerably increased the mortality and morbidity rate in infectious diseases, we aimed to obtain a new stable formulation of Lactobacillus to overcome resistant infections. For this purpose, we designed various gel formulations containing Lactobacillus rhamnosus (L. rhamnosus) as an active pharmaceutical ingredient (API) in a water base and oil base gel, evaluated the probiotic stability in formulation to obtain an optimum formulation, and finally, investigated the antibacterial activities of that against two common hospital-associated multidrug-resistant pathogens, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Furthermore, the pharmaceutical aspects of the optimum formulation, including stability, homogeneity, spreadability, pH value, conductivity, and rheological behavior, were assessed.The results indicated that the optimum formulation based on glycerol exhibited desirable pharmaceutical properties, including long-term stability, a perfect level of homogeneity, an acceptable range of spreadability with pseudo-plastic thixotropic behavior, and a promising antibacterial potential against MRSA and VRE. Our findings indicate that this novel probiotic formulation could be an excellent candidate to cope with antibiotic-resistant species, representing a hopeful treatment potential for topical applications, particularly in incurable infections. However, further in vivo studies seem warranted to evaluate their bactericidal activity against multi-drug resistant microorganisms.

Metformin-loaded nanoerythrosomes: An erythrocyte-based drug delivery system as a therapeutic tool for glioma.

Glioma is an intra-cranial malignancy with the origin of neural stem cells or precursor cells, the most prevalent brain tumor worldwide. Glioblastoma, the fourth-grade glioma, is a common brain tumor whose incidence rate is 5-7 people per 100,000 populations annually. Despite their high mortality rate, all efforts for treatment have yet to achieve any desirable clinical outcome. The Wnt signaling pathway is a conserved pathway among species that seems to be a candidate for cancer therapy by its inhibition. Metformin is a known inhibitor of the Wnt signaling pathway. Its effects on glioma treatment have been observed in cellular, animal, and clinical experiments. Nanoerythrosomes are drug carriers obtained from the cellular membrane of red blood cells in nano size which can offer several characteristics to deliver metformin to brain tumors. They are good at loading and carrying hydrophilic drugs, they can protect metformin from its metabolizing enzymes, which are present in the blood-brain barrier, and they can extend the period of metformin presence in circulation. In this study, nanoerythrosomes were prepared by using the hypotonic buffer. They had particle sizes in the range of 97.1 ± 34.2 nm, and their loading efficiency and loading capacity were 72.6% and 1.66%, respectively. Nanoerythrosomes could reserve metformin in their structure for a long time, and only 50% of metformin was released after 30 h. Moreover, they released metformin at a low and approximately constant rate. Besides, nanoerythrosomes could tolerate various kinds of stress and maintain most of the drug in their structure. Altogether, nanoerythrosome can be a suitable drug delivery system to deliver therapeutic amounts of metformin to various tissues.

Knowledge Gaps in Generating Cell-Based Drug Delivery Systems and a Possible Meeting with Artificial Intelligence.

Cell-based drug delivery systems are new strategies in targeted delivery in which cells or cell-membrane-derived systems are used as carriers and release their cargo in a controlled manner. Recently, great attention has been directed to cells as carrier systems for treating several diseases. There are various challenges in the development of cell-based drug delivery systems. The prediction of the properties of these platforms is a prerequisite step in their development to reduce undesirable effects. Integrating nanotechnology and artificial intelligence leads to more innovative technologies. Artificial intelligence quickly mines data and makes decisions more quickly and accurately. Machine learning as a subset of the broader artificial intelligence has been used in nanomedicine to design safer nanomaterials. Here, how challenges of developing cell-based drug delivery systems can be solved with potential predictive models of artificial intelligence and machine learning is portrayed. The most famous cell-based drug delivery systems and their challenges are described. Last but not least, artificial intelligence and most of its types used in nanomedicine are highlighted. The present Review has shown the challenges of developing cells or their derivatives as carriers and how they can be used with potential predictive models of artificial intelligence and machine learning.

Platelets and platelet-derived vesicles as an innovative cellular and subcellular platform for managing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that involves young individuals. The drug delivery systems now are available for this disease have chronic and non-targeted effects on the patients. Because of the presence of BBB (blood-brain-barrier), their concentration in the CNS (central nervous system) is low. Because of this flaw, it is critical to use innovative active targeted drug delivery methods. RESULT: Platelets are blood cells that circulate freely and play an important role in blood hemostasis. In this review, we emphasize the various roles of activated platelets in the inflammatory condition to recruit other cells to the injured area and limit inflammation. Besides, the activated platelets in the different stages of the MS disease play a significant role in limiting the progression of inflammation in the peripheral area and CNS. DISCUSSION: This evidence indicates that a platelet-based drug delivery system can be an efficient biomimetic candidate for drug targeting to the CNS and limiting the inflammation in the peripheral and central areas for MS therapy.

Ultrasound-responsive hyaluronic acid hydrogel of hydrocortisone to treat osteoarthritis.

One of the practical ways to manage the disease flares of arthritis is using an intra-articular depot formulation of glucocorticoids. Hydrogels, as controllable drug delivery systems, are hydrophilic polymers with distinctive properties, such as remarkable water capacity and biocompatibility. This study aimed to design an injectable thermo-ultrasound-triggered drug carrier based on Pluronic® F-127, hyaluronic acid, and gelatin. The in situ hydrogel loaded by hydrocortison was developed and D-optimal design was used to formulate the process. The optimized hydrogel was combined with four different surfactants to better regulate the release rate. In situ gels composed of the hydrocortisone-loaded hydrogel and hydrocortisone-loaded mixed-micelle hydrogel were characterized. The hydrocortisone-loaded hydrogel and selected hydrocortisone-loaded mixed-micelle hydrogel showed a spherical shape and were nano-sized with a unique thermo-responsive nature able to prolong drug release. The ultrasound-triggered release study showed that drug release was time-dependent. By inducing osteoarthritis in a rat model, behavioral tests and histopathological analyses were carried out on the hydrocortisone-loaded hydrogel and a particular hydrocortisone-loaded mixed-micelle hydrogel. In vivo results showed that the selected hydrocortisone-loaded mixed-micelle hydrogel improved the status of the disease. Results highlighted the potential of ultrasound-responsive in situ-forming hydrogels as hopeful formulas for efficient treatment of arthritis.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results: Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion: We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Enhancing Methotrexate Delivery in the Brain by Mesoporous Silica Nanoparticles Functionalized with Cell-Penetrating Peptide using in Vivo and ex Vivo Monitoring.

The blood-brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by "a lipophilic gate" as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N2 adsorption-desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug's blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

Larotrectinib in NTRK Fusion-Positive High-Grade Glioneuronal Tumor: A Case Report.

Glioneuronal tumors are rare central nervous system tumors with heterogeneous histological and molecular features. While the majority are low grade, a small percentage can behave aggressively. Due to the rarity of these tumors, there is no consensus on how to treat high-grade glioneuronal tumors, and they are often managed similarly to glial tumors. With the advent of molecular profiling, management decisions are increasingly determined by molecular alterations in the tumor rather than the tumor type, which can be a useful approach for tumor types that do not have robust supportive clinical trial data due to low prevalence. We present a case of an 18-year-old patient with a high-grade glioneuronal neoplasm initially treated with craniospinal irradiation, vincristine, and cyclophosphamide. He presented eight years later with a recurrent tumor and was found to be positive for MEF2D-NTRK1 fusion. He was treated with surgical resection and postoperative intensity-modulated radiation therapy (IMRT; 55.8 Gy) with concurrent temozolomide, followed by the NTRK inhibitor larotrectinib. He achieved a radiographic response, with a decrease in residual enhancement and radiographic improvement over the course of treatment. He remained in clinical and radiographic remission for six months. This demonstrates the successful treatment of a high-grade glioneuronal NTRK fusion-positive tumor with larotrectinib, which has only been previously reported once in the literature.

Pharmacokinetic assessment of vancomycin in critically ill patients and nephrotoxicity prediction using individualized pharmacokinetic parameters.

Introduction: Therapeutic drug monitoring (TDM) and pharmacokinetic assessments of vancomycin would be essential to avoid vancomycin-associated nephrotoxicity and obtain optimal therapeutic and clinical responses. Different pharmacokinetic parameters, including trough concentration and area under the curve (AUC), have been proposed to assess the safety and efficacy of vancomycin administration. Methods: Critically ill patients receiving vancomycin at Nemazee Hospital were included in this prospective study. Four blood samples at various time intervals were taken from each participated patient. Vancomycin was extracted from plasma samples and analyzed using a validated HPLC method. Results: Fifty-three critically ill patients with a total of 212 blood samples from June 2019 to June 2021 were included in this study. There was a significant correlation between baseline GFR, baseline serum creatinine, trough and peak concentrations, AUCτ, AUC24h, Cl, and Vd values with vancomycin-induced AKI. Based on trough concentration values, 66% of patients were under-dosed (trough concentration <15 µg/ml) and 18.9% were over-dosed (trough concentration ≥20 µg/ml). Also, based on AUC24h values, about 52.2% were under-dosed (AUC24h < 400 µg h/ml), and 21.7% were over-dosed (AUC24h > 600 µg h/ml) that emphasizes on the superiority of AUC-based monitoring approach for TDM purposes to avoid nephrotoxicity occurrence. Conclusion: The AUC-based monitoring approach would be superior in terms of nephrotoxicity prediction. Also, to avoid vancomycin-induced AKI, trough concentration and AUCτ values should be maintained below the cut-off points.

Ketogenic Metabolic Therapy for Glioma.

PURPOSE: This study describes a retrospective case series of patients with glioma who received ketogenic metabolic therapy through dietary adherence and intermittent fasting. METHODS: A retrospective chart review of a single surgeon's clinic records was performed to identify patients who maintained nutritional ketosis for at least four months between January 2015 and October 2020. RESULTS: Sixteen patients who met the inclusion criteria constituted a heterogeneous population of patients with diagnoses including eight World Health Organization (WHO) grade IV gliomas (seven glioblastoma, one gliosarcoma), seven WHO grade III gliomas (three oligodendroglioma, four astrocytoma), and one WHO grade II oligodendroglioma. IDH1 mutation status was present for 12 patients, and MGMT methylation status was present for eight patients. The mean (standard deviation [SD]) duration of ketogenic metabolic therapy was 20.6 (13.8) months. The Response Assessment in Neuro-oncology Criteria was applied during the ketogenic metabolic therapy interval, indicating a complete response in eight patients and partial response in eight patients. The mean (SD) progression-free survival while patients maintained ketogenic metabolic therapy was 20.0 (14.4) months. CONCLUSION: Ketogenic metabolic therapy appears to convey a survival advantage within this patient series, which highlights the possibility that this therapy, when strictly applied, can augment the standard of care. Further exploration of this modality in a prospective series is warranted to formally explore this therapy.