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Background: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. Methods: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with F-FES 1-5 days post administration of Z-endoxifen. Results: Statistically significant changes ( p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. Conclusion: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy. [ABSTRACT FROM AUTHOR]

Purpose: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate F-FLT-PET for response assessment. Methods: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m IV every 21 days. Before and after cycle 1, patients underwent PET imaging with F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. Results: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was −17.5 % ( n = 10 patients, lower, upper quartiles: −25.5, −4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUV was −20.9 % ( n = 29 lesions; lower, upper quartiles: −42.4, 2.0 %), and the median percentage change in SUV was also −20.9 % ( n = 29; lower, upper quartiles: −49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. Conclusions: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and F-FLT-PET imaging. [ABSTRACT FROM AUTHOR]

Background: ANG1005 (formerly GRN1005) is a novel drug conjugate consisting of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the blood brain barrier via endocytosis after binding the low-density lipoprotein (LDL) receptor-related protein (LRP). In development for taxane-sensitive brain metastases, a multi-center, single-arm study with the primary endpoint of intra-cranial overall response rate in patients with brain metastases from breast cancer is ongoing. Since MRI detection of brain metastases utilizes gadolinium leakage rather than actual tumor volume, new assessment methods are needed. A pilot study at the NCI enrolled patients to evaluate the utility of 18F-FLT (3’-fluoro-3’ deoxythymidine)-PET. Methods: Patients with measurable brain metastases from breast cancer were eligible. ANG1005 was administered IV at 550 mg/m2 q 21 days. MRI imaging with gadolinium was used to determine clinical response, and compared to 18F-FLT PET/ CT imaging performed before and after cycle 1. FLT incorporation reflects DNA synthesis. Dynamic scans were obtained over 30 min and a static whole body PET image at 1 hour. The % change in standard uptake value (SUV) before and after ANG1005 was determined, considering a significant change > 20%. Results: Eighteen metastatic brain lesions in eight patients were analyzed with FLT PET. The maximum (SUVmax) ranged from 0.8 to 4.0 at baseline, mean 1.8. Tumor to normal (T:N) ratios ranged from 2.9 to 22.3, mean 7.7. Twelve of the 18 lesions showed a >20% decrease post-therapy. The average % change in SUVmax was -24.8% (11 to -66.8%), and T:N ratios -7.7%. The FLT-PET response was frequently discordant with the MRI result. Two patients had confirmed partial responses with durations of response of 6 and 13 cycles. One patient had an unconfirmed PR, with progression after 6 cycles. Two patients had stable disease, receiving 6 and 8 cycles. Conclusion: Therapy for CNS metastases from breast cancer is an important unmet need, as is assessment of therapeutic outcome. ANG1005 is a paclitaxel conjugate with demonstrated activity designed to cross the blood-brain barrier. Pilot evaluations of FLT-PET imaging of brain metastases suggest it is a promising tool for detection and measurement of CNS disease. [ABSTRACT FROM AUTHOR]

The article presents the case of an athletic young woman with acute back pain while playing Ultimate Frisbee. The pain is midline, sharp, without radiation, and rates a 10 on a scale of 1 to 10. During the physical examination, localized edema and tenderness to palpation over L5 without warmth, erythema, or hematoma are noted. Once pain free, the patient can begin physical therapy and an exercise program that strengthens the abdominal and paraspinal muscles and stretches the hamstrings.

External Quality Assessment schemes (EQAS) are mandatory to ensure quality standards in diagnostic methods and achieve laboratory accreditation. As host institution for two German culture-based bacteriology EQAS (RV-A and RV-B), we investigated the obtained data of 590 up to 720 surveys per year in RV-A and 2,151 up to 2,929 in RV-B from 2006 to 2023. As educational instruments, they function to review applied methodology and are valuable to check for systemic- or method-dependent failures in microbiology diagnostics or guidelines. Especially, containment of multi-resistant bacteria in times of rising antibiotic resistance is one major point to assure public health. The correct identification and reporting of these strains is therefore of high importance to achieve this goal. Moreover, correct antimicrobial susceptibility testing (AST) per se is important for selecting appropriate therapy, to restrict broad-spectrum antibiotics and minimize resistance development. The reports of participating laboratories displayed a high level of correct identification results in both schemes with mostly consistent failure rates around 2.2% (RV-A) and 3.9% (RV-B) on average. In contrast, results in AST revealed increasing failure rates upon modification of AST requirements concerning adherence to standards and subsequent bacterial species-specific evaluation. Stratification on these periods revealed in RV-A a moderate increase from 1.3% to 4.5%, while in RV-B failure rates reached 14% coming from 4.3% on average. Although not mandatory, subsequent AST evaluation and consistent reporting are areas of improvement to benefit public health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lindenberg, Waldmann, Suerbaum, Schlüter and Ziesing.)

Introduction: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis., Methods: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed., Results: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most., Conclusion: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems., Competing Interests: Competing interests: THB: Bristol-Myers Squibb(speaker engagement). MD: Achiles Therapeutics (consulting), Astra Zeneca (teaching), Bristol-Myers Squibb (consulting and teaching), F. Hoffman-La Roche (speaker engagement), Genentech (consulting), Merck (speaker engagement), Novartis (speaker engagement). JH: Achilles Therapeutics (Scientific Advisory Board), Amgen (funding), Asher Bio (funding), Bayer (consulting), BioNtech US (Scientific Advisory Board, funding), Bristol-Myers Squibb (consulting, funding, teaching), Eisai (consulting), ESMO IOTECH (Editor-in-chief), Gadeta (Scientific Advisory Board), Immunocore (Scientific Advisory Board), Instil Bio (consulting, teaching), Iovance Biotherapeutics (consulting, teaching), Ipsen Bioscience Inc (consulting), Merck Serono (consulting, teaching), Merck Sharp & Dohme Corporation (funding, consulting, teaching), Molecular Partners (consulting), Neogene Therapeutics (Scientific Advisory Board, shareholder), Novartis (funding, consulting, teaching), Pfizer (consulting, teaching), PokeAcel (Scientific Advisory Board), Roche/Genentech (consulting, teaching), Sanofi (consulting, teaching), Scenic (Scientific Advisory Board), Seattle Genetics (consulting), T-Knife (Scientific Advisory Board), Vaximm (Scientific Advisory Board). IMS: Adaptimmune (funding), Bristol-Myers Squibb (speaking engagement), Enara Bio (funding), Evaxion (funding), IO biotech (funding, stock, consulting), Lytix Biopharma (funding), Merck (speaking engagement and funding), Novartis (consulting), Pierre Fabre Pharmaceuticals, Inc (speaking engagement and consulting), Sanofi Pasteur Inc (speaking engagement), TILT Biotherapeutics (funding). Other authors declare to have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

While body decompensation is mainly facilitated by bacteria, investigating the antimicrobial properties of body preservation methods is still a neglected research area. We performed microbiological sampling for potentially pathogenic bacteria species of brain, lung, liver, colon, and subcutis samples obtained from bodies perfused with embalming solutions of variable composition with emphasis on variable formaldehyde concentrations. We, thereby, identified spore-forming aerobic and anaerobic bacteria mainly in the samples obtained from the colon of ethanol- and lower-concentrated formaldehyde formulation embalmed bodies. Moreover, we could identify Enterococcus species in bodies preserved with the latter method. Tissue samples of the subcutis remained sterile. Long-term incubation of special mycobacteria growth indicator tubes revealed no growth of mycobacteria in all 60 samples analyzed. Overall, we show survival of bacterial genera known to be especially environmentally resistant but also include potentially pathogenic members. Knowledge of bactericidal capacities of embalming solutions are therefore critical to assess risk and apply appropriate disinfection routines while working with human bodies. Moreover, new formulations to reduce potentially toxic substances for embalming needs to be evaluated regarding their bactericidal capacities., (© The Author(s) 2022. Published by Oxford University Press on behalf of Applied Microbiology International.)

Basic processes of the fatty acid metabolism have an important impact on the function of intestinal epithelial cells (IEC). However, while the role of cellular fatty acid oxidation is well appreciated, it is not clear how de novo fatty acid synthesis (FAS) influences the biology of IECs. We report here that interfering with de novo FAS by deletion of the enzyme Acetyl-CoA-Carboxylase (ACC)1 in IECs results in the loss of epithelial crypt structures and a specific decline in Lgr5 + intestinal epithelial stem cells (ISC). Mechanistically, ACC1-mediated de novo FAS supports the formation of intestinal organoids and the differentiation of complex crypt structures by sustaining the nuclear accumulation of PPARδ/β-catenin in ISCs. The dependency of ISCs on cellular de novo FAS is tuned by the availability of environmental lipids, as an excess delivery of external fatty acids is sufficient to rescue the defect in crypt formation. Finally, inhibition of ACC1 reduces the formation of tumors in colitis-associated colon cancer, together highlighting the importance of cellular lipogenesis for sustaining ISC function and providing a potential perspective to colon cancer therapy., (© 2022. The Author(s).)

Objective: To assess the cost-effectiveness of preterm preeclampsia (PE) screening versus routine screening based on maternal characteristics in Germany and Switzerland., Methods: A health economic model was used to analyse the cost-effectiveness of PE screening versus routine screening based on maternal characteristics. The analysis was conducted from the healthcare perspective with a time horizon of one year from the start of pregnancy. The main outcome measures were incremental health care costs and incremental costs per PE case averted., Results: The incremental health care costs for PE screening versus routine screening per woman were €14 in Germany, and -CHF42 in Switzerland, the latter representing cost savings. In Germany, the incremental costs per PE case averted were €3,795. In Switzerland, PE screening was dominant. The most influential parameter in the one-way sensitivity analysis was the cost of PE screening (Germany) and the probability of preterm PE in routine screening (Switzerland). In Germany, at a willingness-to-pay for one PE case avoided of €4,200, PE screening had a probability of more than 50% of being cost-effective compared to routine screening. In Switzerland, at a willingness-to-pay of CHF0, PE screening had a 78% probability of being the most cost-effective screening strategy., Conclusion: For Switzerland, PE screening is expected to be cost saving in comparison to routine screening. For Germany, the additional health care costs per woman were expected to be €14. Future cost-effectiveness studies should be conducted with a longer time horizon., Competing Interests: The authors have declared that no competing interests exist. The expressed views in this publication are solely the opinions of the authors.

Background: A first pilot study showed that an image-guided navigation system could improve resection margin rates in locally advanced (LARC) and locally recurrent rectal cancer (LRRC) patients. Incremental surgical innovation is often implemented without reimbursement consequences, health economic aspects should however also be taken into account. This study evaluates the early cost-effectiveness of navigated surgery compared to standard surgery in LARC and LRRC., Methods: A Markov decision model was constructed to estimate the expected costs and outcomes for navigated and standard surgery. The input parameters were based on pilot data from a prospective (navigation cohort n = 33) and retrospective (control group n = 142) data. Utility values were measured in a comparable group (n = 63) through the EQ5D-5L. Additionally, sensitivity and value of information analyses were performed., Results: Based on this early evaluation, navigated surgery showed incremental costs of €3141 and €2896 in LARC and LRRC. In LARC, navigated surgery resulted in 2.05 Quality-Adjusted Life Years (QALYs) vs 2.02 QALYs for standard surgery. For LRRC, we found 1.73 vs 1.67 QALYs respectively. This showed an Incremental Cost-Effectiveness Ratio (ICER) of €136.604 for LARC and €52.510 for LRRC per QALY gained. In scenario analyses, optimal utilization rates of the navigation technology lowered the ICER to €61.817 and €21.334 for LARC and LRRC. The ICERs of both indications were most sensitive to uncertainty surrounding the risk of progression in the first year after surgery, the risk of having a positive surgical margin, and the costs of the navigation system., Conclusion: Adding navigation system use is expected to be cost-effective in LRRC and has the potential to become cost-effective in LARC. To increase the probability of being cost-effective, it is crucial to optimize efficient use of both the hybrid OR and the navigation system and identify subgroups where navigation is expected to show higher effectiveness., (© 2022. The Author(s).)

Background: Over the past decade, many hospitals have adopted hybrid operating rooms (ORs). As resources are limited, these ORs have to prove themselves in adding value. Current estimations on standard OR costs show great variety, while cost analyses of hybrid ORs are lacking. Therefore, this study aims to identify the cost drivers of a conventional and hybrid OR and take a first step in evaluating the added value of the hybrid OR., Methods: A comprehensive bottom-up cost analysis was conducted in five Dutch hospitals taking into account: construction, inventory, personnel and overhead costs by means of interviews and hospital specific data. The costs per minute for both ORs were calculated using the utilization rates of the ORs. Cost drivers were identified by sensitivity analyses., Results: The costs per minute for the conventional OR and the hybrid OR were €9.45 (€8.60-€10.23) and €19.88 (€16.10- €23.07), respectively. Total personnel and total inventory costs had most impact on the conventional OR costs. For the hybrid OR the costs were mostly driven by utilization rate, total inventory and construction costs. The results were incorporated in an open access calculation model to enable adjustment of the input parameters to a specific hospital or country setting., Conclusion: This study estimated a cost of €9.45 (€8.60-€10.23) and €19.88 (€16.10-€23.07) for the conventional and hybrid OR, respectively. The main factors influencing the OR costs are: total inventory costs, total construction costs, utilization rate, and total personnel costs. Our analysis can be used as a basis for future research focusing on evaluating value for money of this promising innovative OR. Furthermore, our results can inform surgeons, and decision and policy-makers in hospitals on the adoption and optimal utilization of new (hybrid) ORs., (© 2022 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

The increasing prevalence of antimicrobial resistance in pathogens is a growing public health concern, with the potential to compromise the success of infectious disease treatments in the future. Particularly, the number of infections by macrolide antibiotics-resistant Streptococcus pneumoniae is increasing. We show here that Clarithromycin impairs both the frequencies and number of interleukin (IL)-17 producing T helper (Th) 17 cells within the lungs of mice infected with a macrolide-resistant S. pneumoniae serotype 15A strain. Subsequently, the tissue-resident memory CD4 + T cell (Trm) response to a consecutive S. pneumoniae infection was impaired. The number of lung resident IL-17 + CD69 + Trm was diminished upon Clarithromycin treatment during reinfection. Mechanistically, Clarithromycin attenuated phosphorylation of the p90-S6-kinase as part of the ERK pathway in Th17 cells. Moreover, a strong increase in the mitochondrial-mediated maximal respiratory capacity was observed, while mitochondrial protein translation and mTOR sisgnaling were unimpaired. Therefore, treatment with macrolide antibiotics may favor the spread of antimicrobial-resistant pathogens not only by applying a selection pressure but also by decreasing the natural T cell immune response. Clinical administration of macrolide antibiotics as standard therapy procedure during initial hospitalization should be reconsidered accordingly and possibly be withheld until microbial resistance is determined. KEY MESSAGES: • Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin • Clarithromycin treatment hinders Th17 and tissue-resident memory responses • Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition.

Background: To improve surgical performance, image-guided (IG) technologies are increasingly introduced. Yet, it is unknown which oncological procedures yield most value from these technologies. This study aimed to select the most promising IG technology per oncologic indication., Methods: An Analytic Hierarchical Process was used to evaluate three IG technologies: navigation, optical imaging, and augmented reality, in five oncologic indications compared with usual care. Sixteen decision criteria were selected. The relative importance of the criteria and the expected performance of the technologies were evaluated among surgeons. The combination of these scores gives the expected value per technology., Results: On criteria level, sparing critical tissue (9%-18%) and reducing the risk of local recurrence (11%-27%) were most important. Navigation was preferred in three indications-removal of lymph nodes (42%), liver (47%), and rectal tumors (33%). In removing rectal tumors, optical imaging was equally preferred (34%). In removing breast and tongue tumors, no technology was clearly preferred., Conclusions: In selecting IG technologies, especially optical and navigation technologies are expected to add value in addition to usual care. Further development of those technologies for the preferred indications seems valuable. Multi-attribute analysis showed to be useful in prioritization of conducting clinical studies and steer research and development initiatives., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites such as polyamines by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine, and spermidine are abundant within the gastrointestinal tract and might substantially contribute to gut immunity., Objective: We aimed to characterize the polyamine spermidine as a modulator of T-cell differentiation and function., Methods: Naive T cells were isolated from wild-type mice or cord blood from healthy donors and submitted to polarizing cytokines, with and without spermidine treatment, to evaluate CD4 + T-cell differentiation in vitro. Moreover, mice were subjected to oral supplementation of spermidine, or its precursor l-arginine, to assess the frequency and total numbers of regulatory T (Treg) cells in vivo., Results: Spermidine modulates CD4 + T-cell differentiation in vitro, preferentially committing naive T cells to a regulatory phenotype. After spermidine treatment, activated T cells lacking the autophagy gene Atg5 fail to upregulate Foxp3 to the same extent as wild-type cells. These results indicate that spermidine's polarizing effect requires an intact autophagic machinery. Furthermore, dietary supplementation with spermidine promotes homeostatic differentiation of Treg cells within the gut and reduces pathology in a model of T-cell transfer-induced colitis., Conclusion: Altogether, our results highlight the beneficial effects of spermidine, or l-arginine, on gut immunity by promoting Treg cell development., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment with tumor-Infiltrating Lymphocytes (TIL) is an innovative therapy for advanced melanoma with promising clinical phase I/II study results and likely beneficial cost-effectiveness. As a randomized controlled trial on the effectiveness of TIL therapy in advanced melanoma compared to ipilimumab is still ongoing, adoption of TIL therapy by the field is confronted with uncertainty. To deal with this, scenario drafting can be used to identify potential barriers and enables the subsequent anticipation on these barriers. This study aims to inform adoption decisions of TIL by evaluating various scenarios and evaluate their effect on the cost-effectiveness., Methods: First, 14 adoption scenarios for TIL-therapy were drafted using a Delphi approach with a group of involved experts. Second, the likelihood of the scenarios taking place within 5 years was surveyed among international experts using a web-based questionnaire. Third, based on the questionnaire results and recent literature, scenarios were labeled as being either "likely" or "-unlikely". Finally, the cost-effectiveness of TIL treatment involving the "likely" scored scenarios was calculated., Results: Twenty-nine experts from 12 countries completed the questionnaire. The scenarios showed an average likelihood ranging from 29 to 58%, indicating that future developments of TIL-therapy were surrounded with quite some uncertainty. Eight of the 14 scenarios were labeled as "likely". The net monetary benefit per patient is presented as a measure of cost-effectiveness, where a positive value means that a scenario is cost-effective. For six of these scenarios the cost-effectiveness was calculated: "Commercialization of TIL production" (the price was assumed to be 3 times the manufacturing costs in the academic setting) (-€51,550), "Pharmaceutical companies lowering the prices of ipilimumab" (€11,420), "Using TIL-therapy combined with ipilimumab" (-€10,840), "Automatic TIL production" (€22,670), "TIL more effective" (€23,270), "Less Interleukin-2" (€20,370)., Conclusions: Incorporating possible future developments, TIL-therapy was calculated to be cost-effective compared to ipilimumab in the majority of "likely" scenarios. These scenarios could function as facilitators for adoption. Contrary, TIL therapy was expected to not be cost-effective when sold at commercial prices, or when combined with ipilimumab. These scenarios should be considered in the adoption decision as these may act as crucial barriers.

The aim of this study was to investigate the functionality of two disintegrants (crospovidone and croscarmellose sodium) in tablet formulations processed via roll compaction and subsequent tableting. The influence of different fillers and the effect of sodium lauryl sulfate on the disintegration process were studied using full factorial design. For a direct comparison of disintegrant functionality, the center point formulations were manufactured via direct compression. Tablet characteristics, such as tensile strength, solid fraction, disintegration time and mechanism, and dissolution profile were determined. The results allow the conclusion that the functionality of the disintegrants is impaired by dry granulation. Both the disintegration mechanism and the disintegration time were different when comparing tablets made after dry granulation and by direct compression. The effect was more pronounced on the functionality of crospovidone than on that of croscarmellose sodium. In addition, sodium lauryl sulfate showed a notable influence on all tablet properties due to its lubricating effect. The variation of the filler also had a remarkable effect on the tablet characteristics. The results link excipient functionality to drug product properties depending on the applied manufacturing process and could contribute to extend the Manufacturing Classification System to excipient characteristics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Models were verified by comparison of simulated pharmacokinetics for acidulant and non-acidulant containing formulations to clinical data from a food effect study and relative bioavailability studies with and without the gastric acid-reducing agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug interaction for the market formulation were predicted based on biorelevant in vitro measurements, dissolution studies, and in silico modelling and were confirmed in clinical studies. These outcomes were explained as due to the acidulant counteracting entrectinib self-buffering and greatly reducing the effect of gastric pH changes. Finally, sensitivity analyses with the verified model were applied to support drug product quality. PBBM has great potential to streamline late-stage drug development and may have impact on regulatory questions.

Introduction: Current localization techniques used in breast conserving surgery for non-palpable tumors show several disadvantages. Magnetic Seed Localization (MSL) is an innovative localization technique aiming to overcome these disadvantages. This study evaluated the expected budget impact of adopting MSL compared to standard of care., Methods: Standard of care with Wire-Guided Localization (WGL) and Radioactive Seed Localization (RSL) use was compared with a future situation gradually adopting MSL next to RSL or WGL from a Dutch national perspective over 5 years (2017-2022). The intervention costs for WGL, RSL and MSL and the implementation costs for RSL and MSL were evaluated using activity-based costing in eight Dutch hospitals. Based on available list prices the price of the magnetic seed was ranged €100-€500., Results: The intervention costs for WGL, RSL and MSL were respectively: €2,617, €2,834 and €2,662 per patient and implementation costs were €2,974 and €26,826 for MSL and RSL respectively. For standard of care the budget impact increased from €14.7m to €16.9m. Inclusion of MSL with a seed price of €100 showed a budget impact of €16.7m. Above a price of €178 the budget impact increased for adoption of MSL, rising to €17.6m when priced at €500., Conclusion: MSL could be a cost-efficient localization technique in resecting non-palpable tumors in the Netherlands. The online calculation model can inform adoption decisions internationally. When determining retail price of the magnetic seed, cost-effectiveness should be considered., Competing Interests: The authors have declared that no competing interests exist.

In preclinical studies, 5-fluoro-2'-deoxycytidine (FdCyd), an inhibitor of DNA methyltransferase and DNA hypermethylation, has shown treatment efficacy against multiple malignancies by suppressing epigenetic hypermethylation in tumor cells. Several ongoing clinical trials are using FdCyd, and although some patients may respond to this drug, in most patients it is ineffective. Thus, establishing a noninvasive imaging modality to evaluate the distribution of the drug may provide insight into the variable responses. A novel experimental radiopharmaceutical, 18 F-labeled FdCyd, was developed as a companion imaging agent to the nonradioactive form of the drug, FdCyd. We present the first-in-humans radiation dosimetry results and biodistribution of 18 F-FdCyd, administered along with tetrahydrouridine, an inhibitor of cytidine/deoxycytidine deaminase, in patients with a variety of solid tumors undergoing FdCyd therapy. Methods: This phase 0 imaging trial examined the 18 F-FdCyd biodistribution and radiation dosimetry in 5 human subjects enrolled in companion therapy trials. In each subject, 4 sequential PET scans were acquired to estimate whole-body and individual organ effective dose, using OLINDA/EXM, version 1.0. Tumor-to-background ratios were also calculated for the tumor sites visualized on PET/CT imaging. Results: The average whole-body effective dose for the experimental radiopharmaceutical 18 F-FdCyd administered in conjunction with tetrahydrouridine was 2.12E-02 ± 4.15E-03 mSv/MBq. This is similar to the radiation dose estimates for 18 F-FDG PET. The critical organ, with the highest absorbed radiation dose, was the urinary bladder wall at 7.96E-02 mSv/MBq. Other organ doses of note were the liver (6.02E-02mSv/MBq), kidneys (5.26E-02 mSv/MBq), and gallbladder (4.05E-02 mSv/MBq). Tumor target-to-background ratios ranged from 2.4 to 1.4, which potentially enable tumor visualization in static PET images. Conclusion: This phase 0 imaging clinical trial provides evidence that 18 F-FdCyd administered in conjunction with tetrahydrouridine yields acceptable individual organ and whole-body effective doses, as well as modest tumor-to-background ratios that potentially enable tumor visualization. Dose estimates for 18 F-FdCyd are comparable to those for other PET radiopharmaceuticals, such as 18 F-FDG. Further studies with larger study populations are warranted to assess 18 F-FdCyd imaging as a predictor of FdCyd treatment effectiveness., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Vesicular stomatitis virus (VSV) is an insect-transmitted rhabdovirus that is neurovirulent in mice. Upon peripheral VSV infection, CD169 + subcapsular sinus (SCS) macrophages capture VSV in the lymph, support viral replication, and prevent CNS neuroinvasion. To date, the precise mechanisms controlling VSV infection in SCS macrophages remain incompletely understood. Here, we show that Toll-like receptor-7 (TLR7), the main sensing receptor for VSV, is central in controlling lymph-borne VSV infection. Following VSV skin infection, TLR7 -/- mice display significantly less VSV titers in the draining lymph nodes (dLN) and viral replication is attenuated in SCS macrophages. In contrast to effects of TLR7 in impeding VSV replication in the dLN, TLR7 -/- mice present elevated viral load in the brain and spinal cord highlighting their susceptibility to VSV neuroinvasion. By generating novel TLR7 floxed mice, we interrogate the impact of cell-specific TLR7 function in anti-viral immunity after VSV skin infection. Our data suggests that TLR7 signaling in SCS macrophages supports VSV replication in these cells, increasing LN infection and may account for the delayed onset of VSV-induced neurovirulence observed in TLR7 -/- mice. Overall, we identify TLR7 as a novel and essential host factor that critically controls anti-viral immunity to VSV. Furthermore, the novel mouse model generated in our study will be of valuable importance to shed light on cell-intrinsic TLR7 biology in future studies.

The purpose of this study was to compare the diagnostic performance of 18 F-DCFBC PET/CT, a first-generation 18 F-labeled prostate-specific membrane antigen (PSMA)-targeted agent, and 18 F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18 F-DCFBC PET/CT and 18 F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2-12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18 F-NaF or 18 F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue-only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18 F-DCFBC only and 185 bone lesions detected on 18 F-NaF or 18 F-DCFBC. 18 F-NaF detected significantly more bone lesions than 18 F-DCFBC ( P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18 F-DCFBC (ρ > 0.5, P < 0.01) and poor in 18 F-NaF (ρ < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy ( n = 11) demonstrated more lesions on 18 F-NaF than 18 F-DCFBC ( P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy ( n = 8) showed equal to or more lesions on 18 F-DCFBC than on 18 F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18 F-NaF PET/CT, 18 F-DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18 F-DCFBC PET/CT shows good concordance with NaF PET/CT., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)