Administration Of Therapy Research Articles

Intraperitoneal administration of dual immune checkpoint inhibitor therapy in recurrent gynecologic malignancies: Updated results of a phase 1b study

Intraperitoneal administration of dual immune checkpoint inhibitor therapy in recurrent gynecologic malignancies: Updated results of a phase 1b study

Outcomes following off-site remote systemic cancer therapy administration.

The Veterans Affairs Nebraska Western Iowa Health Care System (VA-NWIHCS) uses teleoncology and remote systemic cancer therapy services to expand care to veterans in rural Nebraska via remote sites in Lincoln and Grand Island. This study compares clinical outcomes in patients receiving care at these remote sites to those at the primary site in Omaha. Data were retrospectively reviewed for 151 patients who received first-line systemic therapy at VA sites in Omaha, Lincoln, or Grand Island between January 1, 2018, and December 31, 2020. This included patient demographics, malignancy type and stage, survival, systemic therapy received, treatment intent and toxicities, missed or delayed cycles, and frequency of hospitalizations or emergency department visits. SAS version 9.4 was used for analysis. The study population included 108 patients who received their systemic therapy in Omaha, whereas 43 received therapy at the remote sites. The demographic of both populations was predominantly male with a median age of 69 years and Eastern Cooperative Oncology Group Performance Status of 0 to 1. The two groups were comparable in terms of comorbidities. Both populations had a similar distribution of cancer types, proportion of patients with stage IV disease, and treatment with curative intent. There was no difference in 1- and 2-year survival, systemic therapy-related toxicity classification and prevalence, number of delayed/missed cycles, and hospitalization/emergency department visits. Evaluated outcomes in patients treated in Omaha versus remote sites via teleoncology under the same providers were similar. Effective oncology care, including systemic therapy, can be provided via teleoncology, and this model can help mitigate issues with access to care.

Estimating the Prevalence of Primary Hypothyroidism in Karbala City, and Modulation of Clinical Manifestations Among Patients Receiving Levothyroxine; A Single Center Study

Background: Hypothyroidism has a wide range of clinical manifestations and general symptoms, including but not limited to obesity, tiredness, poor concentration, depression, widespread muscle soreness, menstruation abnormalities, and constipation. The administration of a daily dosage of levothyroxine is sufficient for the successful management of hypothyroidism, as it facilitates the restoration of serum thyroid stimulating hormone (TSH) levels to their normal range. Several factors can influence the absorption of levothyroxine in the human body, including age, weight, the presence of other medical problems, and dietary intake. The aim of this study was to assess the prevalence of primary hypothyroidism and alteration in clinical presentation associated with replacement therapy. Methods: This was a cross-sectional, observational study conducted over at Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) in Karbala city. The study team created a questionnaire, and data was collected from face-to-face patient interviews, which included various sociodemographic variables, TSH and ferritin levels, drug interactions, as well as signs and symptoms exhibited both prior to and following treatment. Additionally, the patient treatment regimen and the specific doses of levothyroxine administered are also recorded. Results: the total number of cases visited Al Hassan Metabolism, Endocrine, and Diabetes Center (HMEDC) during the study period was (10800). The prevalence of thyroid diseases was 300 (2.8%). The rate of primary hypothyroidism out of the total number of hypothyroid cases was 85.1%. (61%) of the patients had normal levels of TSH whereas (42%) of the patients were found to be undertreatment. A total of (84%) of the patients exhibited normal levels of ferritin. The patients exhibited a reduction in their signs and symptoms following the administration of therapy. Conclusion: treatment with levothyroxine improved sluggish speech, constipation, lack of appetite, cold sensitivity, weight gain, and weariness. There is no observed correlation between the dosage of levothyroxine and the manifestation of signs and symptoms.

Current application and results of the combined use of intravascular lithotripsy and rotational atherectomy for the treatment of calcified coronary lesions

Abstract Background Intravascular lithotripsy (IVL) and rotational atherectomy (RA) might be used simultaneously (Rotatripsy) to treat calcified lesions during percutaneous coronary intervention (PCI), though data on the effectiveness and sequence of their use is limited. Purpose To identify indicators for the use of Rotatripsy and to assess its safety and success rates, both acutely as at one-year follow-up. Methods Patients undergoing PCI with IVL and RA across six centers in two European countries from May 2019 to December 2023 were included. Demographic, clinical, procedural and follow-up data were collected. Angiographic and intracoronary imaging (ICI) data were analyzed centrally. Efficacy endpoints included device success (delivery of the RA-burr and IVL-balloon across the target lesion and administration of therapy without related complications), technical success (TIMI 3 flow and residual stenosis <30% by quantitative coronary analysis) and procedural success (composite of technical success with absence of in-hospital major adverse cardiovascular events (MACE: cardiac death, myocardial infarction or target vessel revascularization). Safety endpoints comprised rotatripsy-related complications and MACE at one-year follow-up. Results A total of 114 patients (75±9 years, 78% male) underwent rotatripsy for 120 lesions. Patients presented with an ACS in 58(51%) cases and chronic coronary syndrome in 56(49%). The left anterior descending artery(n=66, 55%) was the most frequently treated target vessel, with diverse lesions being addressed, including bifurcations(30%), ostial(18%), CTO(7%) and in-stent(12%) lesions. The mean burr size was 1.5±0.2mm with a maximum rotational speed of 171±15k rpm and burr/vessel ratio of 0.46±0.2. IVL involved an average of 68±25 pulses and a balloon size of 3.5±0.5mm. The predominant used sequence of rotatripsy was RA followed by IVL(n=106, 88%). Among these cases, IVL was electively combined with RA in 68(57%) lesions, and used for balloon underexpansion(n=37, 31%) and stent crossing failure after RA(n=1, 1%). Additionally, IVL served as bail-out strategy after RA and stenting in 10(8%) and preceded RA in 4(3%) lesions, particularly when balloon/stent delivery failed after IVL. After rotatripsy, stents were implanted in 116(97%) lesions and drug-eluting balloon used in 3(3%). ICI was utilized in 69(58%) target lesions. Device, technical and procedural success were 97%, 94% and 93%, respectively. Therapy-related complications occurred in 4 patients(4%), and included two(2%) coronary perforations, one(1%) dissection and one(1%) burr entrapment. At one-year follow-up (present in 77(67%)), MACE was observed in 7(6%). Conclusions Rotatripsy demonstrated efficacy across diverse clinical and anatomical settings, with the majority of procedures electively employing RA before IVL. High success rates and low complication rates were observed, with few patients experiencing MACE at one-year follow-up.

MONITORING OF A SEVERE COVID-19 PATIENT WITH PNEUMOTHORAX COMPLICATIONS THROUGH RADIOLOGICAL AND LABORATORY DIAGNOSIS

Introduction: Monitoring and treatment of severely ill patients with the coronavirus disease who are on mechanical ventilation due to the severity of the disease with the development of many complications remains a challenge. The increased incidence of pneumothorax in Covid-19 patients on mechanical ventilation may be due to a combination of infection-induced parenchymal injury and infl ammatory response with additional positive pressure ventilation. Materials and methods: In our study, we report a case of a severe Covid-19 patient with a pneumothorax complication through radiological and laboratory diagnostics. The performed radiogram of the lungs was taken each time in the AP projection in a semi-sitting position. A digital mobile X-ray device was used for imaging. All laboratory parameters that were monitored in the patient are performed in the panel of standard routine controls for patients with Covid-19. Results: The radiogram was better as the administration of therapy and chest drain were eff ective. Biochemical and hematological parameters are performed, which indicate a decrease in the number in blood count and biochemistry. The patient spent a total of 80 days in the hospital. Conclusion: Survival of a severe form of Covid-19 infection with the complication of pneumothorax is very rare, but still possible, as shown in our case. A chest radiograph with laboratory monitoring of the condition is of great importance in establishing the diagnosis of Covid-19 infection, and in the fi nal assessment of the patient's condition upon discharge from the hospital. Keywords: Covid-19, mechanical ventilation, pneumothorax, radiological diagnostics, laboratory diagnostics.

Intraarterial Administration of Peptide Receptor Radionuclide Therapy in Patients with Advanced Meningioma: Initial Safety and Efficacy.

Peptide receptor radionuclide therapy (PRRT) is a treatment option for patients with advanced meningioma. Recently, intraarterial application of the radiolabeled somatostatin receptor agonists has been introduced as an alternative to standard intravenous administration. In this study, we assessed the safety and efficacy of intraarterial PRRT in patients with advanced, progressive meningioma. Methods: Patients with advanced, progressive meningioma underwent intraarterial PRRT with [177Lu]Lu-HA-DOTATATE. The safety of PRRT was evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment response was assessed according to the proposed Response Assessment in Neuro-Oncology criteria for meningiomas and somatostatin receptor-directed PET/CT. Results: Thirteen patients (8 women, 5 men; mean age, 65 ± 13 y) with advanced meningioma underwent 1-4 cycles (median, 4 cycles) of intraarterial PRRT with [177Lu]Lu-HA-DOTATATE (mean activity per cycle, 7,428 ± 237 MBq; range, 6,000-7,700 MBq). Treatment was well tolerated with mainly grade 1-2 hematologic toxicity. Ten of 13 patients showed radiologic disease control at follow-up after therapy (1/10 complete remission, 1/10 partial remission, 8/10 stable disease), and 9 of 13 patients showed good control of clinical symptoms. Conclusion: Intraarterial PRRT in patients with advanced meningioma is feasible and safe. It may result in improved radiologic and clinical disease control compared with intravenous PRRT. Further research to validate these initial findings and to investigate long-term outcomes is highly warranted.

A case of complete response to radiotherapy combined with durvalumab and tremelimumab in a patient with unknown primary hepatocellular carcinoma arising in the lumbar spine.

A 58-year-old man visited an orthopedic clinic complaining of pain in his right lower back and numbness in his lower limbs for one month. Imaging tests revealed a tumorous lesion from the left side of the second lumbar vertebra to the paraspinal muscles. CT-guided biopsy of the tumor was performed, and immunostaining results diagnosed hepatocellular carcinoma (HCC). Although the liver showed signs of chronic liver damage, no primary tumor was found within the liver or in other organs. Blood tests showed negative hepatitis virus markers for both HBV and HCV. The tumor markers AFP, AFP-L3, and DCP were high. Because he developed spinal cord compression syndrome due to a lumbar tumor, radiation therapy and denosumab administration were performed. Subsequently, systemic therapy with durvalumab plus tremelimumab was started. In the year following the start of treatment, the tumor has shrunk, and no new lesions have been observed. Tumor markers have also decreased. We have experienced a case of HCC in the lumbar spine without a primary tumor in the liver. This is a very rare case, and the combination therapy with durvalumab and tremelimumab resulted in a complete response, which we consider to be a valuable case.

Distance to CAR-T Treatment Center Does Not Impede Delivery.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in relapsed or refractory large B cell lymphoma, but real-world evidence is needed to confirm safety and efficacy when facing the unique challenges of a wide geographical catchment area. We reviewed patients treated with commercially available CAR-T at a medium-sized single center in Canada (The Ottawa Hospital) between December 2020 and July 2022 (Canadian implementation started in 2020). Fifty-one patients (59% male, median age 62) traveled a median distance of 655 km (range 3-3659) for treatment. Median time from apheresis to CAR-T infusion was 36 days (range 26-81). With a median follow-up of 383 days (95% CI: 333-480), median progression-free survival (PFS) and overall survival (OS) were 257 days (95% CI: 92-NE) and 422 days (95% CI: 106-NE), respectively. The median PFS for out-of-province patients was 115 days (95% CI: 91-NE) versus 280 days for in-province patients (95% CI: 142-NE), p = 0.12. Multivariate analysis demonstrated that distance from treatment center (p = 0.05) and refractory disease status (p = 0.003) were independently associated with shorter PFS. The time from the last disease progression to CAR-T referral was longer for out-of-province patients, but there was no difference in the time of referral to CAR-T consult, apheresis, or CAR-T infusion between in-province and out-of-province patients. Our results confirm that despite the complexity of CAR-T therapy administration, Ottawa can effectively provide commercial CAR-T therapy in a timely fashion for patients from across the country.

Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.

Renal Cell Carcinoma with Venous Tumor Thrombus: 15 Years of Experience in an Oncology Center.

Background: The purpose of this study is to report the experience of a single Portuguese oncology center in the management of patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT). Methods: This is a retrospective analysis of all patients with RCC and VTT surgically treated in our center between 2008 and 2023. Only patients with VTT up to level III (Mayo Clinic classification) were included. Patient, tumor characteristics and peri-operative outcome data were registered. Administration of systemic therapy was performed upon progression. Survival analysis was conducted with the collected data. Results: A total of 64 patients (n = 16 women) were included in this study. The mean age at diagnosis was 66.3 ± 10.7 years old. The VTT level was 0, I, II and III in 40 (62.5%), 12 (18.7%), 6 (9.4%) and 6 (9.4%) patients, respectively. Nine patients (14.1%) had distant metastasis at diagnosis. No peri-operative deaths occurred, and the major complication rate was 3.1%. Histology revealed 98.4% of clear cell RCC, with sarcomatoid differentiation present in 12.5% of the cases. A negative margin status was achieved in 54 (84.4%) patients. Systemic therapy was administered in 24 (37.5%) patients during follow-up. The median progression-free (PFS), cancer-specific (CSS) and overall (OS) survival were 23, 60 and 48 months, respectively. In multivariable analysis, significant predictors of CSS were tumor size, sarcomatoid differentiation and collecting system invasion. Conclusions: Radical nephrectomy with VTT excision up to level III is a feasible and safe procedure. Patients with large tumor size, sarcomatoid differentiation and collecting system invasion are at the highest risk and should be closely monitored.

Febuxostat in patients with hyperuricemia and gout: is the nephroprotective effect real?

Hyperuricemia (HU) and gout are independent risk factors for chronic kidney disease (CKD). Worldwide, the increasing prevalence of CKD leads to a deterioration in the quality and duration of life of patients and an increase in mortality. If HU plays a significant role in the development of renal failure, then lowering high uric acid (UA) levels should theoretically contribute to the improvement of kidney function. The main method of lowering UA levels is administration of a urate-lowering therapy – xanthine oxidase (XO) inhibitors. The nephroprotective effect of one of the XO inhibitors, febuxostat has been demonstrated in animal models.The article analyzes the currently available data on the use of febuxostat in patients with HU and gout and different levels of renal function impairment and discusses the possible mechanisms of the drug's nephroprotective effect.

Strategies for Perioperative Anticoagulant Reversal in Orthopedic Surgery: A Review.

The administration of anticoagulation therapy during major orthopedic surgeries is a clinical challenge due to the risk of thrombotic events and bleeding complications. This review aims to evaluate the current strategies and emerging developments in perioperative anticoagulation reversal. We conducted a literature review on the management of perioperative anticoagulant therapy, which included the current status of anticoagulant reversal agents, as well as personalized medicine, pharmacogenomics, artificial intelligence (AI), and novel drug delivery systems. The review indicates that reversal agents such as idarucizumab and andexanet alfa are crucial in managing bleeding associated with direct oral anticoagulants (DOACs). Personalized medicine, guided by pharmacogenomics, allows for tailored anticoagulation regimens. AI and machine learning (ML) algorithms can enhance the predictive capabilities for bleeding and thrombotic risks. Additionally, nanotechnology and biomarkers offer innovative approaches to drug delivery and personalized treatment. Integrating evidence-based guidelines with innovative reversal agents, personalized medicine, AI and nanotechnology opens a new era in perioperative anticoagulation management. These advancements can ensure patient safety, minimize bleeding risks, and improve surgical outcomes. Future research should focus on the clinical validation of these strategies to ensure their effectiveness across diverse patient populations.

Differences Between Intravenous and Subcutaneous Modes of Administration in Oncology from the Patient, Healthcare Provider, and Healthcare System Perspectives: A Systematic Review.

While patients with cancer have traditionally received oncology treatments through intravenous (IV) administration, some therapies are becoming available via alternative modes of administration, such as subcutaneous (SC). This study aimed to evaluate IV versus SC therapy administration from the perspectives of the patient, healthcare provider (HCP), and healthcare system. A systematic review was conducted, searching MEDLINE and Embase databases from 2000 to 2022. This was supplemented with grey literature searches of additional sources such as conference proceedings. Observational studies and clinical trials were included if they assessed adult patients with any cancer type who were treated with pharmacologic therapies administered via IV or SC and included patient- or HCP-reported outcomes or healthcare system perspectives on the mode of administration. Records identified by the literature search were screened by two independent reviewers. Included studies were data extracted by a single reviewer and validated by a second reviewer and synthesized using a narrative approach. After screening, 33 unique studies were included in the systematic review. Patients and HCPs reported substantially more favorable preference rates for SC over IV treatment. Additionally, from the patient perspective there were reductions in treatment time and economic burden for SC compared with IV therapy. From the HCP's perspective, treatment time was consistently reduced by SC compared with IV treatment administration. Although information on the impact of SC and IV treatments for oncology on healthcare systems was limited, the use of SC formulations showed consistent cost savings (direct costs) and time savings from this perspective considering various uptake scenarios compared with IV administration. Compared with IV administration, SC oncology treatment is a preferred option by patients and HCPs, increasing optionality and reducing treatment time while simultaneously increasing capacity and reducing the financial burden on healthcare systems.

Abstract B046: Enhanced immune cell engineering utilizing a novel, effective intracellular delivery method for introduction of diverse cargo types

Abstract Engineered immune cell therapies have great potential to revolutionize cancer therapeutics and progress has been made in developing both engineering and manufacturing methodologies. However, limitations remain in some areas including long manufacturing times, potential for cell exhaustion, and limited access to the disease site as in the case for solid tumors. In addition, some immune cell types such as monocytes, B cells, and gamma delta T cells have remained difficult to engineer.Portal has developed a novel implementation of mechanoporation technology using a silicon membrane with pores which enables deformation of the cell and poration of the cell membrane, allowing for diffusion of any cargo, charged or uncharged, into the cell. Mechanoporation is a gentle intracellular delivery technique which preserves cell viability and function in cells (DiTommaso, et al PNAS 2018) and has the potential to shorten manufacturing time as well as allow for introduction of key therapy enhancing factors via transient modifications shortly before therapy administration. Portal has established methodology for cytoplasmic introduction of many diverse cargo including mRNA, circular RNA, siRNA, proteins, peptides, and CRISPR RNPs to primary immune cells, including both unstimulated and activated T cells, B cells, NK cells, monocytes and iPSCs. The Portal technology is easily scalable, enabling both research scale (1e6 - 5e7 cells) and process scale (over 1e9 cells) deliveries. Editing and RNA expression efficiencies are above 80% with viability maintained at 70% or above. We have demonstrated sustained expression of circular RNA, and have successfully delivered an mRNA CAR. Cargo can easily be multiplexed with equivalent delivery efficiencies across cargo classes. Portal’s methodology is gentle and effective enough to be utilized multiple times within a therapeutic workflow. For example, we have demonstrated high editing efficiencies in unstimulated T cells, followed by rapid expansion for 7 days and subsequent mRNA delivery at clinical scale - yielding over 50% knockout and 90% mRNA expression. Portal’s technology and approach has the potential to further advance immune cell therapy developments, particularly in multiplexed engineering approaches involving simultaneous delivery of multiple cargos. Coupled with Portal’s compatibility with diverse immune cell types and next generation cargos, such as circRNA, we believe this simple approach to intracellular delivery can dramatically reduce manufacturing time and cost, easily integrate into existing clinical equipment and enable unique enhancements that underpin a new generation of therapeutics. Citation Format: Zhihui Song, Eleni Rogers, Sophia Hirsch, Andrew Larocque, Darby Kreienberg, Rachel Conover, Jacquelyn Hanson, Alec Barclay, Mathias Pawlak, Armon Sharei. Enhanced immune cell engineering utilizing a novel, effective intracellular delivery method for introduction of diverse cargo types [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B046.

Oral Lichenoid lesions induced by programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4 bispecific antibody: a case report

BackgroundCadonilimab is the first approved dual immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), currently utilized for the treatment of various solid tumors. Oral mucosal adverse reactions, such as oral lichenoid lesions, represent one of the most prevalent immune-related adverse events associated with immune checkpoint antibodies. However, reports detailing oral side effects specifically linked to Cadonilimab are lacking. Documenting these side effects is essential to alert oncologists and stomatologists, facilitating timely intervention for affected patients.Case PresentationWe present a case involving a 35-year-old male patient diagnosed with hepatocellular carcinoma who received Cadonilimab following hepatectomy and subsequently developed extensive oral lichenoid lesions along with mucosal erosion at 13–14 weeks post-treatment initiation. A biopsy was conducted revealing immunohistochemical findings of CD3+, CD4+, CD8+, CD20 + lymphocytes, CD68 + macrophages, and α-SMA + myofibroblasts infiltrating the tissue of the oral lichenoid lesions. The patient’s oral lesions improved after administration of systemic and local glucocorticoid therapy alongside cessation of Cadonilimab treatment.ConclusionThis report marks the first documented instance of an oral adverse effect associated with Cadonilimab use. It underscores that administration of this agent may lead to significant lichenoid lesions and erosions within the oral cavity—an issue warranting increased vigilance from both oncologists and stomatologists.

Targeted non-invasive Metformin-Curcumin co-loaded nanohyaluosomes halt osteoarthritis progression and improve articular cartilage structure: A preclinical study

Osteoarthritis (OA) is a degenerative disease that affects the quality of life in elderly and young populations. Current therapies using corticosteroids and non-steroidal anti-inflammatory drugs via parenteral or oral routes show limited ability to retard progression of the disease and achieve long term effectiveness and safety. Herein, the potential of MT-Cur combinatorial nano-formulations in OA management was explored for the first time. MT-Cur loaded nanohyaluosomes (MT-Cur-HL1) were designed for topical administration of the combined therapy in OA. The optimized MT-Cur-HL1 showed particle size 247.7 ± 3.7 nm, zeta potential −37.3 ± 0.4 mV; and entrapment efficiency (%EE) 70.22 %±0.303 and 76.7 %±0.077 for MT and Cur, respectively. MT-Cur-HL1 exhibited sustained drug release over 24 h and were stable over 3 months at 4 °C in terms of P.S., ZP and %EE. A detailed preclinical study, using MIA-induced osteoarthritis rat model, revealed the most significant anti-arthritic effect and halted OA progression of MT-Cur-HL1. This was proved to be mainly through the potentiation of p-AMPK signaling that ultimately led to suppression of its downstream TLR4/ NF-κB signaling pathway with subsequent reduction in MMP13 and ADAMTS5 induced chondrocytes degeneration. This study proved that this trajectory effectively promotes a significant improvement in the articular cartilage structure and reinforcement of joint mobility with an efficient antinociceptive effect. In conclusion, the novel MT-Cur coloaded nanohyaluosomes offer a promising non-invasive approach for the local management of OA.

Cost-effectiveness of pembrolizumab as an adjuvant treatment of renal cell carcinoma post-nephrectomy in Switzerland

Aims Pembrolizumab has demonstrated significantly prolonged disease-free survival and overall survival (OS) among adult patients post-nephrectomy who have an intermediate-high risk, high-risk, or M1 stage with no evidence of disease (M1 NED) renal cell carcinoma (RCC) with clear cell component. The aim of this study was to evaluate the cost-effectiveness of pembrolizumab for patients with RCC post-nephrectomy versus observation in Switzerland. Materials and methods A previously published Markov model was adapted for the Swiss setting to estimate the cost-effectiveness of adjuvant pembrolizumab versus observation from the Swiss statutory health insurance perspective. Transition probabilities between model states were estimated using survival curves from KEYNOTE-564 (data cut-off: June 14, 2021). Outcomes included costs (2022 Swiss francs [CHF]), quality-adjusted life-years (QALYs), and life-years (LYs), measured over a lifetime horizon. Costs included drug acquisition and administration for adjuvant and subsequent therapy. Both costs and effectiveness were discounted at 3.0% annually. Cost-effectiveness was evaluated at a hypothetical willingness-to-pay (WTP) threshold of CHF 100,000 Sensitivity was assessed through scenario analyses as well as deterministic and probabilistic sensitivity analyses. Results Over a lifetime horizon, the total incremental cost for pembrolizumab versus observation was CHF 59,089, providing incremental gains of 0.90 QALYs (1.07 LYs); the incremental cost-effectiveness ratio was CHF 65,299/QALY. Pembrolizumab was deemed cost-effective versus observation, with a 69.9% probability of cost-effectiveness. Limitations A more recent interim analysis data cut from KEYNOTE-564 with median follow up of 57.2 months has since been published; however, these were not available at the time of analysis. It would likely have minimal impact on transition probabilities from disease-free, and the current approach remains conservative for predicting OS for pembrolizumab. Conclusions As an adjuvant treatment of RCC post-nephrectomy, pembrolizumab was found to be cost-effective versus observation in Switzerland at a WTP threshold of CHF 100,000/QALY. Policy makers should consider pembrolizumab as an adjuvant treatment for patients with RCC post-nephrectomy when making decisions regarding resource allocation.

Alteration of treatment choices and the visual prognosis for diabetic macular edema in the era of anti-VEGF drugs: Analysis of the STREAT-DME 2 study.

To assess the real-world outcome of best-corrected visual acuity (BCVA) following 2-year intervention for treatment-naïve diabetic macular edema (DME) since the approval of anti-vascular endothelial growth factor (VEGF) therapy. A total of 1,780 treatment-naïve eyes with DME for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final BCVA, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated. Over a 2-year period, BCVA improved annually, finally reaching 7 letters. The proportion of eyes in which good vision was maintained (BCVA >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%. Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for DME. These findings reflect the evolution of DME treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time.

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DEFECTS

Patients with pulmonary arterial hypertension, associated with congenital heart disease (PAH-CHD) are a heterogeneous population with a varied course of PH. Improvements in pediatric cardiac surgery have changed the epidemiology and survival rate of patients with CHD, of which 90% reach adulthood. Progress in terms of prognosis has also been observed among patients with PAH-CHD. Better survival was observed in ES compared with PAH after defect correction. Advances in surgical treatment of CHD and an increase in life expectancy have led to the study of PAH-CHD and the need to create recommendations for drug treatment of this category of patients. In most of studies, the evaluation of drug treatment of group 1 PAH was carried out without identifying its subgroups. And thus, according to existing recommendations, treatment algorhithms for patients with PAH-CHD are similar to approaches to other forms of PAH. However, various clinical, functional, physical and hemodynamic characteristics of patients with PAH-CHD call into question of correct risk stratification approaches development. Multicenter randomized clinical trials included predominantly a small number of patients with corrected defects, which does not allow the results to be interpreted for the entire population of patients with PAH-CHD. Data from single-center observational studies, expert opinion, and several randomized trials primarily involving patients with Eisenmenger syndrome (ES) indicate the effectiveness and safety of PAH-specific therapy in patients with PAH-CHD. In this literature review, we examined and showed the results of studies involving patients with PAH-CHD and their response to specific therapy. The results obtained significantly expanded the possibilities of using bosentan, sildenafil, epoprostenol, riociguat, ralinepag, sotatercept as they lead to improvement of functional capacity and hemodynamic parameters in patients with PAH-CHD, and only epoprostenol demonstrated an effect on prognosis. Combination PAH-specific therapy, initial or sequential administration of two or more drugs with different mechanisms of action, is an important treatment strategy for patients with PAH. The role of such therapy has increased in recent years. Based on the results of the AMBITION, SERAPHIN, GRIPHON, COMPASS-2 studies, initial or sequential oral combination PAH-specific therapy is recommended for patients with WHO FC II or III. At the same time, there is little evidence to support the effectiveness of this approach in ES patients. The use of anticoagulants in PAH-CHD remains controversial. Low-flow oxygen therapy should be considered individually and continued when there is a significant predominance of subjective or objective benefit. Iron deficiency is associated with poor survival in ES. It is important to note that microcytosis is rare in patients with iron deficiency cyanosis and a normal mean red cell volume does not indicate the absence of anemia. In cases of intolerance to oral iron, intravenous drugs should be used. Currently, based on existing guidelines, most centers follow a consistent symptom-based approach in the treatment of patients with PAH-CHD. Therapy begins with oral ERAs or PDE-5 inhibitors and is escalated if symptoms persist or clinical worsening occurs. If there is no effect of oral PAH-specific therapy, it is recommended to consider parenteral drugs.

Short-term Outpatient Parenteral Antimicrobial Therapy Administration in the Pediatric Emergency Department: Feasibility, Safety, and Outcome.

The practice of administration of intravenous (IV) antimicrobial therapy in outpatient settings (OPAT) is a low-cost alternative to in-patient admission and treatment. There is, however, limited evidence supporting OPAT management protocols for children. The primary objective of this study was to describe the use of pediatric emergency-based OPAT, as well as the safety of this practice. The study was a prospective, observational study conducted in pediatric emergency department of a tertiary care hospital. Children younger than 14 years who required pediatric emergency department-based OPAT were included in the study. Three hundred and ninety-two children were included in the study. The mean duration of OPAT was 3.5 days. Ceftriaxone was the most frequently used antimicrobial. Chest infection was the commonest indication, followed by sickle cell disease with fever and soft tissue infections. There were no major intravenous line-related complications over course of treatment. Most of the patients (89.5%) completed the OPAT course successfully. Only 10.4% patients required subsequent hospital admission, with failure to improve on the OPAT protocol being the main reason patients for admission. None of the admitted patients required intensive care settings or faced unexpected morbidity. Our results affirm that pediatric emergency-based OPAT is a safe yet effective practice in children with good clinical outcome. We believe that a reduction in admissions translates to better hospital resource utilization.