Determination of valsartan and pitavastatin using synchronous spectrofluorimetry and augmented least squares chemometric models: A comparative study with greenness and blueness assessment.

Hypertension and hyperlipidemia are two common conditions that require effective management to reduce the risk of cardiovascular diseases. Among the medications commonly used for the treatment of these conditions, valsartan and pitavastatin have shown significant efficacy in lowering blood pressure and cholesterol levels, respectively. In this study, synchronous spectrofluorimetry coupled to chemometric analysis tools, specifically concentration residual augmented classical least squares (CRACLS) and spectral residual augmented classical least squares (SRACLS), was employed for the determination of valsartan and pitavastatin simultaneously. The developed models exhibited excellent predictive performance with relative root mean square error of prediction (RRMSEP) of 2.253 and 2.1381 for valsartan and pitavastatin, respectively. Hence, these models were successfully applied to the analysis of synthetic samples and commercial formulations as well as plasma samples with high accuracy and precision. Besides, the greenness and blueness profiles of the determined samples were also evaluated to assess their environmental impact and analytical practicability. The results demonstrated excellent greenness and blueness scores with AGREE score of 0.7 and BAGI score of 75 posing the proposed method as reliable and sensitive approach for the determination of valsartan and pitavastatin with potential applications in pharmaceutical quality control, bioanalytical studies, and therapeutic drug monitoring.

International disparities in diagnosis and treatment access for cystic fibrosis.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment. However, previous research has demonstrated profound global disparities in diagnosis and treatment access. If unaddressed, these threaten to widen existing health inequities. Therefore, in this analysis we aimed to reappraise gaps and evaluate progress in diagnosis and treatment equity in high-income (HIC) versus low- and middle-income countries (LMICs). METHODS: Estimates of the global CF population were made in 158 countries using patient registries, systematic literature searches, and an international survey of 14 CF experts. Estimates of the global burden of undiagnosed CF were made using epidemiological studies identified in literature searches and registry coverage data. The proportion of people receiving ETI was estimated using publicly available revenue data and a survey of 23 national drug pricing databases. RESULTS: 188,336 (163,421-209,204) people are estimated to have CF in 96 countries. Of these, 111,767 (59%) were diagnosed and 51,322 (27%) received ETI. The undiagnosed patient burden is estimated to be 76,569 people, with 82% in LMICs. ETI is reimbursed in 35 HICs, but only one LMIC. Four years after approval, there are 13,723 people diagnosed with CF who live in a country where ETI is inaccessible. This increases to 76,199 when including the estimated undiagnosed population. CONCLUSIONS: Equitable access to CFTR modulators must become a top priority for the international CF community. ETI costs up to $322,000 per year but could be manufactured for $5000 to allow access under a voluntary license. Given the extent of disparities, other mechanisms to improve access that circumvent the manufacturer should also be considered.

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Cost sharing for oral lenvatinib among commercially insured patients.

OBJECTIVE: To use a nationwide pharmaceutical claims database to evaluate cost-sharing trends for commercially insured patients with cancer who were prescribed lenvatinib (Lenvima). STUDY DESIGN: IBM MarketScan databases were used to evaluate lenvatinib costs for patients with employer-based commercial insurance, and for patients 65 years and older, Medicare claims for fee-for-service plans. METHODS: Patients were included if they had least 1 outpatient pharmaceutical claim for lenvatinib paid on a noncapitated basis from 2015 to 2019. Median and IQR costs were estimated and inflation adjusted to 2019 US$ for 30-day supplies and reported as total, insurance liability, coordination of benefits, and out-of-pocket costs. RESULTS: A total of 685 patients had at least 1 pharmaceutical claim for lenvatinib, which included patients with thyroid (n = 251; 36.6%), renal cell (n = 202; 29.5%), hepatocellular (n = 160; 23.4%), and endometrial (n = 48; 7.0%) cancer. The median (IQR) number of prescriptions per patient was 3 (2-7), and the median (IQR) total days of supply was 90 (45-210) days. The median (IQR) 30-day cost of lenvatinib was $17,253 ($15,597-$18,120). Median (IQR) 30-day insurance liability was $16,847 ($15,000-$17,981). Median (IQR) 30-day coordination of benefits was $0 ($0-$0). Median (IQR) 30-day patient out-of-pocket cost was $32 ($0-$100). However, the maximum 30-day out-of-pocket cost in our patient cohort was $12,538. CONCLUSIONS: In this cohort, insurance was liable for the majority of total lenvatinib drug costs, and 75% of patients paid $100 or less per month out of pocket. This information can be used by care teams to counsel insured patients. Health systems and drug manufacturers must identify patients with high out-of-pocket costs and provide convenient access to financial assistance programs so that patients are not forced to forgo the benefits of these drugs due to financial barriers. Value-based payment models and drug pricing reform are also needed to address underlying drivers of high drug costs.

Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.

Cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy for treating previously treated advanced endometrial cancer in Sweden.

OBJECTIVE: Pembrolizumab plus lenvatinib was recently approved for the treatment of advanced or recurrent endometrial carcinoma in women with disease progression on or following prior treatment with a platinum­containing therapy in any setting, and who are not candidates for curative surgery or radiation (KEYNOTE-775/Study-309; NCT03517449). The objective was to assess the cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy from a Swedish healthcare perspective. MATERIALS AND METHODS: A lifetime partitioned-survival model with three health states (progression free, progressed disease, death) was constructed. Chemotherapy was represented by paclitaxel or doxorubicin. Overall survival, progression-free survival, time on treatment, and utility data were obtained from KEYNOTE-775 (database lock: March 1, 2022). Costs (in 2020 Swedish Krona [SEK]) included drug acquisition and administration, health state, end of life, adverse event management, subsequent treatment, and societal (scenario analysis). Outcomes were calculated as quality-adjusted life-years (QALY) and life-years. Model results were presented as incremental cost-effectiveness ratios for all-comers, patients with proficient mismatch repair tumors, and deficient mismatch repair tumors. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Pembrolizumab plus lenvatinib is a cost-effective treatment when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios of SEK 795,712 and 819,757 per QALY gained. Pembrolizumab plus lenvatinib was associated with a large incremental QALY and life-year gain per person versus chemotherapy over the model time horizon (1.49 and 1.76). LIMITATIONS: Time-to-event data were incomplete and semiparametric and parametric curves were utilized for lifetime extrapolation. Willingness-to-pay thresholds, costs, and utility weights vary by country, which would vary the treatment's cost effectiveness in different countries. CONCLUSIONS: This partitioned survival analysis suggests that pembrolizumab plus lenvatinib is cost effective compared with chemotherapy in Sweden for women with advanced or recurrent endometrial carcinoma following previous systemic therapy. Results were robust to mismatch repair status and to changes in parameters/assumptions.

Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.

Cost-effectiveness of lenvatinib plus pembrolizumab versus chemotherapy for recurrent mismatch repair-proficient endometrial cancer after platinum-based therapy.

OBJECTIVE: The recent Study 309-KEYNOTE-775 showed improved survival for lenvatinib plus pembrolizumab compared to chemotherapy in patients with recurrent endometrial cancer. We created a decision model to compare the cost-effectiveness of lenvatinib plus pembrolizumab in patients with recurrent mismatch repair-proficient (pMMR) endometrial cancer who had progressed after first-line chemotherapy. METHODS: A Markov model was created to simulate the clinical trajectory of 10,000 patients with recurrent pMMR endometrial cancer. The initial decision point in the model was treatment with ether lenvatinib plus pembrolizumab or chemotherapy (doxorubicin or dose-dense paclitaxel). Model probabilities, utility values and costs were derived with assumptions drawn from published literature. A cycle length of 3 months and a time horizon of 2 years was used. The effectiveness was calculated in terms of average quality adjusted life years (QALYs) gained. The primary outcome was incremental cost-effectiveness ratios (ICERs), expressed in 2020 US dollars/QALYs. One-way, two-way and probabilistic sensitivity analyses were performed. RESULTS: Chemotherapy was the least costly strategy at $66,693 followed by lenvatinib plus pembrolizumab ($193,590). Lenvatinib plus pembrolizumab resulted in more patients being alive at 2 years (lenvatinib plus pembrolizumab: 367, chemotherapy: 109). Chemotherapy was cost-effective compared with lenvatinib plus pembrolizumab (ICER: $164,493/QALYs). Lenvatinib plus pembrolizumab became cost-effective when its cost was reduced by $1553 per month (7.8% reduction). CONCLUSION: For patients with recurrent pMMR endometrial cancer Lenvatinib plus pembrolizumab is associated with greater survival but is more costly than chemotherapy. The cost of lenvatinib and pembrolizumab would have to be reduced by approximately 7% to be considered cost-effective.

Development and validation of cost-effective SYBR Green-based RT-qPCR and its evaluation in a sample pooling strategy for detecting SARS-CoV-2 infection in the Indonesian setting.

A low-cost SYBR Green-based RT-qPCR method to detect SARS-CoV-2 were developed and validated. Primers targeting a conserved and vital region of the N genes of SARS-CoV-2 were designed. In-silico study was performed to analyse the compatibility of the selected primer pair with Indonesian SARS-CoV-2 genome sequences available from the GISAID database. We determined the linearity of our new assay using serial dilution of SARS-CoV-2 RNA from clinical samples with known virus concentration. The assay was then evaluated using clinically relevant samples in comparison to a commercial TaqMan-based test kit. Finally, we applied the assay in sample pooling strategies for SARS-CoV-2 detection. The SYBR Green-based RT-qPCR method was successfully developed with sufficient sensitivity. There is a very low prevalence of genome variation in the selected N primer binding regions, indicating their high conservation. The validation of the assay using clinical samples demonstrated similar performance to the TaqMan method suggesting the SYBR methods is reliable. The pooling strategy by combining 5 RNA samples for SARS-CoV-2 detection using the SYBR RT-qPCR methods is feasible and provides a high diagnostic yield. However, when dealing with samples having a very low viral load, it may increase the risk of missing positive cases.

68Ga-FAPI PET/CT Interobserver Agreement on Tumor Assessment: An International Multicenter Prospective Study.

68Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [n = 10], colorectal cancer [n = 10], pancreatic adenocarcinoma [n = 10], genitourinary cancer [n = 10], and other types of cancer [n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers.

Noninvasive Assessment of Renal Fibrosis of Chronic Kidney Disease in Rats by [68Ga]Ga-FAPI-04 Small Animal PET/CT and Biomarkers.

Renal fibrosis is the most common pathological feature and common pathway of progression in chronic kidney disease (CKD). We evaluated [68Ga]Ga-FAPI-04 small animal positron emission tomography/computed tomography (PET/CT) and biomarkers as noninvasive assessments of renal fibrosis (RF) in CKD rats to generate new ideas for clinical diagnosis. A rat model of renal fibrosis was administered adenine by gavage (n = 28), and the control group was given 0.9% NaCl by gavage (n = 20). At different time points (weeks 1, 2, 4, and 6), five rats were randomly selected from the two groups for [68Ga]Ga-FAPI-04 small animal PET/CT imaging. At the same time, the expression of Fibroblast activation protein (FAP) in renal tissue and the expression levels of type III procollagen N-terminal peptide (PIIINP), transforming growth factor (TGF-ß1), Klotho, and sex-determining region Y-box protein 9 (SOX9) in blood and urine were determined. FAP was highly expressed in the renal tissue of rats in the CKD group and expression increased with the progression of renal fibrosis. [68Ga]Ga-FAPI-04 small animal PET/CT examination showed that the uptake of radioactive tracers in the CKD group was higher than that in the control group, and SUVmax (r = 0.9405) and target-to-background ratio (TBR) (r = 0.9392) were positively correlated with renal fibrosis. The serum levels of PIIINP, TGF-ß1, and SOX9 in CKD rats were significantly higher than those in the control group and were positively correlated with RF (r = 0.8234, r = 0.7733, and r = 0.7135, respectively) and SUVmax (r = 0.8412, r = 0.7763, and r = 0.6814, respectively). Compared with the control group, the level of serum Klotho decreased and was negatively correlated with RF (r = -0.6925) and SUVmax (r = -0.6322). Compared with the control group, the levels of PIIINP and TGF-ß1 in urine were positively correlated with RF (r = 0.8127 and r = 0.8077, respectively) and SUVmax (r = 0.8400 and r = 0.8177, respectively). Urine Klotho decreased compared with the control group and was negatively correlated with RF (r = -0.5919) and SUVmax (r = -0.5995). The change in urine SOX9 was not statistically significant. In conclusion, compared with renal biopsy, [68Ga]Ga-FAPI-04 small animal PET/CT shows renal fibrosis quickly and noninvasively. PIIINP, TGF-ß1, and Klotho in serum and urine may be used as biomarkers of RF, and serum SOX9 is expected to become a new diagnostic biomarker of RF.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Quinoline-based heterocyclic hydrazones: Design, synthesis, anti-plasmodial assessment, and mechanistic insights.

A library of quinoline-based hydrazones bearing 1H-1,2,3-triazole core was designed, synthesized, and evaluated for their antiplasmodial activity against the drug-resistant Plasmodium falciparum W2 strain. The inclusion of pyrazine-2-carboxylic acid with a flexible propyl spacer afforded the most active scaffold with an IC50 value of 0.26 µM. Mechanistically, the compound inhibited heme to hemozoin formation, as demonstrated by UV-vis and mass spectral studies.

Tumor-to-blood ratio for assessment of fibroblast activation protein receptor density in pancreatic cancer using [68Ga]Ga-FAPI-04.

PURPOSE: [68Ga]Ga-FAPI PET/CT has been widely used in clinical diagnosis and radiopharmaceutical therapy. In this study, tumor-to-blood ratio (TBR) was evaluated as a powerful tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as an effective index for tumors with high FAP expression in theranostics. METHODS: Nine patients with pancreatic cancer underwent a 60-min dynamic PET/CT scan by total-body PET/CT (with a long AFOV of 194 cm) after injection of [68Ga]Ga-FAPI-04. After dynamic PET/CT scan, three patients received chemotherapy and underwent the second dynamic scan to evaluate treatment response. Time-activity curves (TACs) were obtained by drawing regions of interest for primary pancreatic lesions and metastatic lesions. The lesion TACs were fitted using four compartment models by the software PMOD PKIN kinetic modeling. The preferred pharmacokinetic model for [68Ga]Ga-FAPI-04 was evaluated based on the Akaike information criterion. The correlations between simplified methods for quantification of [68Ga]Ga-FAPI-04 (SUVs; tumor-to-blood ratios [TBRs]) and the total distribution volume (Vt) estimates obtained from pharmacokinetic analysis were calculated. RESULTS: In total, 9 primary lesions and 25 metastatic lesions were evaluated. The reversible two-tissue compartment model (2TCM) was the most appropriate model among the four compartment models. The total distribution volume Vt values derived from 2TCM varied significantly in pathological lesions and background regions. A strong positive correlation was observed between TBRmean and Vt from the 2TCM model in pathological lesions (R2=0.92, P<0.001). The relative difference range for TBRmean was 2.1% compared to the reduction rate of Vt in the patients who were treated with chemotherapy. CONCLUSIONS: A strong positive correlation was observed between TBRmean and Vt for [68Ga]Ga-FAPI-04. TBRmean reflects FAP receptor density better than SUVmean and SUVmax, and would be the preferred measurement tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as a means for evaluating treatment response.

Head­to­head assessment of [68Ga]Ga-DOTA-FAPI-04 PET/CT vs [18F]FDG PET/CT in fibroblastic tumors.

OBJECTIVES: We aimed to evaluate [68Ga]Ga-DOTA-FAPI-04 versus [18F]FDG PET/CT in the application of fibroblastic tumors. METHODS: Twenty participants with 6 subtypes of fibroblastic tumors prospectively underwent 18F-FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT examinations to evaluate the lesions. PET/CT findings were confirmed by surgical pathology of fifteen participants, puncture biopsy of two participants, or imaging follow-up of three participants. Two independent sample t tests were used to compare the uptake of [18F]FDG vs [68Ga]Ga-DOTA-FAPI-04 in primary, recurrent and metastatic lesions. One-way ANOVA was used to compare the uptake of [18F]FDG or [68Ga]Ga-DOTA-FAPI-04 among primary, recurrent, and metastatic lesions. The uptake of [68Ga]Ga-DOTA-FAPI-04 vs [18F]FDG in different histopathological lesions was compared by two independent sample t tests. RESULTS: Twenty participants were confirmed to have 38 lesions. Although there was no significant difference in the detection of lesions between [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT (38 vs 36, p = 0.493), the uptake of [68Ga]Ga-DOTA-FAPI-04 in lesions was significantly higher than that of [18F]FDG (p < 0.001), including primary (p < 0.001), recurrent (p = 0.018) and metastatic (p < 0.001) lesions. The SUVmax of [68Ga]Ga-DOTA-FAPI-04 in primary and recurrent lesions was higher than that in metastasis (p = 0.034 and p = 0.015, respectively). The SUVmax of [68Ga]Ga-DOTA-FAPI-04 in primary and recurrent malignant lesions was significantly higher than that of the intermediate (p < 0.001). The SUVmax of [68Ga]Ga-DOTA-FAPI-04 in one participant of recurrent SFT with 5 lesions was significantly lower after treatment than before treatment (p = 0.016). CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 outperformed [18F]FDG PET/CT in displaying the primary, recurrent and metastatic lesions of fibroblastic tumors.

Pembrolizumab plus lenvatinib as first-line therapy for patients with mismatch repair-proficient advanced endometrial cancer: A United States-based cost-effectiveness analysis.

OBJECTIVE: In 2022, the KEYNOTE-775 (NCT03517449) study showed that pembrolizumab plus lenvatinib (PL) has more benefits than traditional chemotherapy as a first-line regimen to treat patients with mismatch repair-proficient (pMMR) advanced endometrial cancer (aEC). However, given the high cost of immuno-targeted therapy, the widespread use among patients remains uncertain. Therefore, we conducted a cost-effectiveness comparison between PL and chemotherapy. METHODS: We evaluated the cost-effectiveness of PL versus chemotherapy over 7 years by developing a comprehensive Markov model, included 697 patients, that calculated total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of $150,000 per QALY. The robustness of the model was evaluated by one-way, two-way, and probabilistic sensitivity analyses. In addition, we also performed subgroup analyses. RESULTS: Chemotherapy yielded a mean survival of 0.705 QALYs (0.901 LYs) per patient and was associated with a mean cost of $163,777. PL was associated with an incremental cost of $38,582 and an additional 0.349 QALYs, leading to an ICER of $110,401 per QALY as compared to chemotherapy. The cost of pembrolizumab had a significant impact on ICER. At the assumed WTP threshold of $150,000 per QALY, approximately 79.2% of simulations show cost-effectiveness occurs in PL. Results of the subgroup analysis showed that PL was the most cost-effective regimen for patients who had previously received 1-line of therapy. CONCLUSION: For patients with pMMR aEC, the PL strategy may be the most cost-effective strategy at a WTP of $150,000 from the economic perspective of the United States.

Lenvatinib Plus Pembrolizumab vs. Chemotherapy in Pretreated Patients With Advanced Endometrial Cancer: A Cost-Effectiveness Analysis.

Background: In the international, randomized, open-label, phase 3 study 309-KEYNOTE-775 trial, lenvatinib plus pembrolizumab (LP) showed improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in pretreated patients with advanced endometrial cancer. This study aimed to investigate whether LP is cost-effective compared with chemotherapy. Materials and Methods: The clinical data for this model was derived from the 309-KEYNOTE-775 trial. Costs and utilities were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced endometrial cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether LP is cost-effective in patients with mismatch repair-proficient (pMMR) disease. Results: Lenvatinib plus pembrolizumab provided an incremental 0.64 quality-adjusted life years (QALYs) with an incremental cost of $241,278.18, compared with chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $378,251.44/QALY, which exceeded the willingness to pay (WTP) threshold. While in the pMMR subgroup, the ICER increased to $413,256.68/QALY. The variance of the utility of PFS state, the cost of LP, and the utility of the progressive disease state were the most influential factors in the sensitivity analysis. Conclusion: Under the current WTP threshold, LP is not cost-effective compared with chemotherapy in pretreated patients with advanced endometrial cancer.

Cost-effectiveness analysis of donafenib versus lenvatinib for first-line treatment of unresectable or metastatic hepatocellular carcinoma.

BACKGROUND: Donafenib and lenvatinib are approved by China National Medical Products Administration and recommended as first-line treatment of Metastatic Hepatocellular Carcinoma (HCC). The aim of this study was to assess the cost-effectiveness of donafenib compared with lenvatinib for first-line treatment of advanced HCC in China. METHODS: A partitioned survival model consisting with three health states was developed to simulate lifetime development of advanced HCC from China healthcare payer's perspective. The lifetime costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER) were calculated. The efficacy data were obtained from ZGDH3 and REFLECT trials. The cost and health outcomes were discounted at a rate of 5%. Sensitivity and scenario analyses were carried out to explore the variation of model results. RESULTS: Compared with lenvatinib, donafenib incurred more costs of $1500.86 and had 0.139 QALYs gained, resulting in an ICER of $10,790.18/QALY. The probability of being cost-effective was 84.9% at a willingness-to-pay threshold of gross domestic product per capita in 2020 in China ($31,499.2/QALY). Sensitive and scenario analysis results were in line with base-case analysis. CONCLUSIONS: Donafenib appears to be a cost-effective strategy compared with lenvatinib for the first-line treatment of patients with unresectable or metastatic HCC in China.

Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells.

Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.