Drug Holiday Research Articles

Improvement of osteoblast adhesion, viability, and mineralization by restoring the cell cytoskeleton after bisphosphonate discontinuation in vitro.

Bisphosphonates are prescribed to treat excessive bone resorption in patients with osteoporosis. However, its use is associated with potential adverse effects such as medication-related osteonecrosis of the jaw, prompting the introduction of the drug holiday concept in patients prior to dentoalveolar surgery. Furthermore, bisphosphonate discontinuation has been studied in vivo, in humans, and in animal models. However, it is not known whether this approach could affect bone cells in vitro. Therefore, the objective of this study was to investigate the potential effects of bisphosphonate discontinuation on pre-osteoblast and osteoblast activities in vitro. Pre-osteoblasts (MC3T3) and osteoblasts were treated with bisphosphonate (alendronate) at concentrations of 1, 5, and 10 µM. Alendronate was then withdrawn at different time points. The negative control consisted of untreated cells (0 µM), while the positive control consisted of cells incubated with alendronate throughout the experiment. Cell viability, cell adhesion, cell cytoskeleton, mineralization, and gene expressions were investigated. Pre-osteoblasts and osteoblasts showed a decrease in cell viability after treatment with 5-10 μM alendronate for 4 days or longer. Two days of alendronate discontinuation significantly increased cell viability compared with the positive control. However, these levels did not reach those of the negative control. Bone nodule formation was reduced by alendronate. Discontinuation of alendronate regained bone nodule formation. Longer periods of discontinuation were more effective in restoring nodule formation than shorter periods. Addition of alendronate resulted in an increase in the percentage of dead cells, which, in turn, decreased when alendronate was discontinued. Alendronate affected the cell cytoskeleton by disassembling actin stress fibers. Cell adhesion and cell morphological parameters were also affected by alendronate. Discontinuation of alendronate restored cell adhesion and these parameters. Overall, the highest improvement after alendronate discontinuation was seen at 10 µM. However, alendronate treatment and discontinuation did not affect osteoblast gene expression. Discontinuation of alendronate helps to reverse the negative effects of the drug on cell viability, cell adhesion, and mineralization by restoring the cell cytoskeleton. Our data suggest the benefits of drug holiday and/or intermittent strategies for alendronate administration at the cellular level.

Interplay of mutations, alternate mechanisms, and treatment breaks in leukaemia: Understanding and implications studied with stochastic models

Bcr-Abl1 kinase domain mutations are the most prevalent cause of treatment resistance in chronic myeloid leukaemia (CML). Alternate resistance pathways nevertheless exist, and cell line experiments show certain patterns in the gain, and loss, of some of these alternate adaptations. These adaptations have clinical consequences when the tumour develops mechanisms that are beneficial to its growth under treatment, but slow down its growth when not treated. The results of temporarily halting treatment in CML have not been widely discussed in the clinic and there is no robust theoretical model that could suggest when such a pause in therapy can be tolerated. We constructed a dynamic model of how mechanisms such as Bcr-Abl1 overexpression and drug transporter upregulation evolve to produce resistance in cell lines, and investigate its behaviour subject to different treatment schedules, in particular when the treatment is paused (‘drug holiday’). Our study results suggest that the presence of additional resistance mechanisms creates an environment which favours mutations that are either preexisting or occur late during treatment. Importantly, the results suggest the existence of tumour drug addiction, where cancer cells become dependent on the drug for (optimal) survival, which could be exploited through a treatment holiday. All simulation code is available at https://github.com/Sandalmoth/dual-adaptation.

Non-biological Antiresorptive: Bisphosphonates.

Bisphosphonates, synthetic analogs of endogenous pyrophosphates, are pivotal in managing various bone disorders, primarily osteoporosis, which affects millions globally. While osteoporosis, especially postmenopausal osteoporosis, significantly benefits from bisphosphonate therapy, considerations arise regarding their administration and potential side effects. Bisphosphonates, divided into nitrogen-containing and non-nitrogenous groups, exert their influence through distinct mechanisms, with the former being notably more potent. The role of bisphosphonates in other diseases, such as Paget's bone and skeletal metastasis disease is also discussed. Detailed information on the administration routes, dosage regimens, and considerations for drug holidays is provided. The article navigates through the chemical structure, generations, and mechanism of action of bisphosphonates. The article covers administration routes, dosage regimens, and drug holidays, in addition to discussing potential adverse effects and contraindications. Bisphosphonates hold an unrivaled legacy in the management of osteoporosis. The ubiquitous availability and the cost-effectiveness of these time-tested medications make them an invaluable asset in the osteoporosis treatment landscape, especially in developing nations like India.

Outcomes with MEK Inhibitor Therapy Among Adults with Langerhans Cell Histiocytosis (LCH): A Multi-Institutional Study from the Adult LCH Working Group for the Histiocyte Society

Purpose: The discovery of MAPK/ERK pathway mutations has led to the approval of MEK-inhibitor (MEKi) cobimetinib in histiocytic neoplasms. However, the pivotal clinical trial that led to the approval of cobimetinib included only 4 patients with Langerhans cell histiocytosis (LCH). Therefore, there is a need to define outcomes with MEKi therapy in patients with LCH. We undertook a multi-center collaboration through the Adult LCH Working Group for the Histiocyte Society to address this gap in knowledge. Methods: Adults with LCH who received MEKi therapy were included from five institutions. Objective response rate (ORR) was evaluated using PET/CT criteria, and CT/MRI if PET scan was not available; response categories were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free (PFS) and overall survival (OS) were calculated from the time of targeted therapy initiation. Risk organ disease was defined as liver, spleen, or bone marrow involvement. Results: 25 adults with LCH were included in this study; median age at MEKi initiation 43y (range, 18-85). Most common systems involved at diagnosis were bone (52%), pituitary (44%), and lung (36%). Risk organ involvement was observed in 7 (28%, 6 liver, 1 liver and spleen) and 2 (8%) patients had intra-axial CNS involvement. Median lines of prior therapy received were 2 (range: 1-5), and 4 (16%) patients received MEKi in first-line. MAPK/ERK pathway status was assessed via target capture next generation sequencing (NGS) in 22 (96%) cases. Amongst those who underwent NGS, alterations identified included: BRAF V600E (2/22, 9%), BRAF deletions (11/22 50%), MAP2K1 or MEK mutations (4/22, 18%), and MAPK1 or ERK2 (n=1, 5%). Overall, 5 patients also received BRAF inhibitors (4 patients as first therapy prior to MEKi and 1 concomitantly due to BRAF V600E positive melanoma). Specific MEKi agents utilized included cobimetinib (n=13) and trametinib (n=12). Among the response evaluable patients (n=23), ORR to MEKi treatment was 78% (9 CR, 9 PR, 4 SD, 1 PD). Among the 7 patients with liver involvement, responses were seen in 2 (29%) cases. ORR did not significantly differ according to mutation status among those with NGS data (78% MAPK mutated vs. 100% unmutated; p=1.0). In this subcohort, all of the 4 cases that did not respond to MEKi had liver involvement; 3 had BRAF deletions (2 SD and 1 PD), and one had MAPK1 mutation (SD). Median follow-up duration after MEKi initiation in the entire cohort was 18 months (95% CI 6 - 30). The median PFS and OS were not reached; 2-year PFS and OS were 78.1% and 79.9%, respectively (Figure 1A). The median PFS was much shorter in those with liver involvement (7 months [95% CI 0 - 14]) compared with those without liver disease (not reached [95% CI 19-not reached] P=0.047; Figure 1B). PFS did not differ significantly between MAPK pathway mutated and unmutated patients (p=0.34) Adverse events (AEs) were reported in 36% (n=9) and most commonly included rash (n=5) and fatigue (n=3). Four patients experienced grade 3-4 AEs including rash, fatigue, and thrombocytopenia. Common causes of MEKi discontinuation included AEs (n=3), progression (n=2), and drug holiday (n=2). At last follow-up, 5 patients died and 18 remained on MEKi. Death was attributable to LCH (n=3), concomitant malignancy (n=1), or unknown causes (n=1). Conclusions: In our multi-institutional study of adults with LCH, we found MEKi therapy to be highly efficacious. However, liver involvement correlated with a lack of response and worse PFS, while mutational status did not. Future studies are needed to evaluate optimum treatment for high-risk subgroups of LCH like liver disease.

Drug dependence in cancer is exploitable by optimally constructed treatment holidays.

Cancers with acquired resistance to targeted therapy can become simultaneously dependent on the presence of the targeted therapy drug for survival, suggesting that intermittent therapy may slow resistance. However, relatively little is known about which tumours are likely to become dependent and how to schedule intermittent therapy optimally. Here we characterized drug dependence across a panel of over 75 MAPK-inhibitor-resistant BRAFV600E mutant melanoma models at the population and single-clone levels. Melanocytic differentiated models exhibited a much greater tendency to give rise to drug-dependent progeny than their dedifferentiated counterparts. Mechanistically, acquired loss of microphthalmia-associated transcription factor in differentiated melanoma models drives ERK-JunB-p21 signalling to enforce drug dependence. We identified the optimal scheduling of 'drug holidays' using simple mathematical models that we validated across short and long timescales. Without detailed knowledge of tumour characteristics, we found that a simple adaptive therapy protocol can produce near-optimal outcomes using only measurements of total population size. Finally, a spatial agent-based model showed that optimal schedules derived from exponentially growing cells in culture remain nearly optimal in the context of tumour cell turnover and limited environmental carrying capacity. These findings may guide the implementation of improved evolution-inspired treatment strategies for drug-dependent cancers.

A Review of Various Clinical Practice Guidelines on Osteoporosis in the Last 5 Years.

Osteoporosis, also called the silent disease, affects the elderly with a significant contribution to their morbidity and mortality through fragility fractures. Most nations have developed their own guidelines on managing this condition. Clinical Practice Guidelines (CPGs) are the highest quality evidence documents on a particular topic prepared by expert panels. CPGs offer standardised recommendations on a particular topic. We looked at the CPGs of nations in the last five years and present the results of this review here. This review is divided into Risk assessment, prevention, diagnosis, Non pharmacological and pharmacological management with information from major CPGs only. Most CPGs agree on the broad principles of assessment , core risk factors, prevention and management with some finer differences in subtle aspects of assessment and management. There are differences in the use of screening tools based on the population numbers and affordability between nations. FRAX has been advocated for the screening with or without DEXA. Most CPGs use DEXA for confirmation of diagnosis. Intervention is based on FRAX scoring. Intervention thresholds vary. We discuss non-pharmacological management included diet and nutrition, calcium and Vitamin D, Exercise and physiotherapy, lifestyle changes and falls prevention. Pharmacological management included aspects of using different medications and their indications. The key agents recommended include Bisphosphonates, Teriparatide, Denosumab, SERMs, Hormone Replacement Therapy, and other agents including any drug holidays and duration of therapy. This review identified some key recommendations from CPGs from multiple nations in each of the above given aspects of osteoporosis.

A youth-centred approach to improving engagement in HIV services: human-centred design methods and outcomes in a research trial in Kisumu County, Kenya

IntroductionInnovative interventions are needed to improve HIV outcomes among adolescents and young adults (AYAs) living with HIV. Engaging AYAs in intervention development could increase effectiveness and youth acceptance, yet research...

Three-dimensional clinical assessment for MRONJ risk in oncologic patients following tooth extractions.

To identify clinical and local radiographic predictors for medication-related osteonecrosis of the jaws (MRONJ) by the assessment of pre-operative CBCT images of oncologic patients treated with anti-resorptive drugs (ARDs) undergoing tooth extractions. This retrospective, longitudinal, case-control study included clinical and imaging data of 97 patients, divided into study and control group. Patients in the study group (n = 47; 87 tooth extractions) had received at least one dose of ARD, undergone tooth extraction(s), and had a pre-operative CBCT. An age-, gender-, and tooth extraction-matched control group (n = 50; 106 tooth extractions) was selected. Three calibrated, blinded, and independent examiners evaluated each tooth extraction site. Statistical analysis used χ2/Fisher's exact/Mann-Whitney U test to contrast control and study group, ARD type used, and sites with or without MRONJ development. p-value ≤ 0.05 was considered significant. From the study group, 15 patients (32%) and 33 sites (38%) developed MRONJ after tooth extraction. When controls were compared to study sites, the latter showed significantly more thickening of the lamina dura, widened periodontal ligament space, osteosclerosis, osteolysis, and sequestrum formation. In the study group, MRONJ risk significantly increased in patients who had multiple tooth extractions, were smokers, and had shorter drug holidays. Periosteal reaction and sequestrum formation may indicate latent MRONJ lesions. Additionally, patients given bisphosphonates showed considerably more osteosclerosis than those given denosumab. Periosteal reaction and sequestrum formation are suspected to be pre-clinical MRONJ lesions. Furthermore, ARD induced bony changes and radiographic variations between ARD types were seen.

Planned drug holidays during treatment with lenvatinib for radioiodine-refractory differentiated thyroid cancer: a retrospective study.

In the phase 3 SELECT study, lenvatinib significantly improved prognostic outcomes vs. placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, toxicity of lenvatinib is sometimes considerable and requires frequent dose interruptions and modifications. Recently, planned drug holidays have been proposed as a means of avoiding severe adverse events (AEs). We retrospectively reviewed medical records to compare the efficacy and safety of lenvatinib in RR-DTC patients who underwent planned drug holidays (planned holiday group) vs. those who received conventional daily oral administration (daily group). The subjects were 25 patients in the planned holiday group and 21 in the daily group. Median age was 73 years (range 43-84) and 62 years (range 42-75), and histologic subtype of papillary/follicular was 21/4 cases and 15/6 cases, respectively. Time to treatment failure (TTF) and overall survival (OS) were significantly longer in the planned holiday group than the daily group (not reached [NR] vs. 14.9 months, hazard ratio [HR] 0.25, 95% confidence interval [Cl] 0.11-0.58, p<0.001; NR vs. 26.6 months, HR 0.20, 95% CI 0.073-0.58, p=0.001, respectively). Median progression-free survival (PFS) was NR in the planned holiday group vs. 15.1 months in the daily group (HR 0.31, 95% CI 0.14-0.68, p=0.002). Duration of the period with lenvatinib dose ≥10 mg was significantly longer in the planned holiday group (NR vs. 6.5 months, HR 0.22, 95% CI 0.10-0.49, p<0.001), and the frequency of drug interruption due to intolerable AEs was lower (68.0% vs. 95.2%, p=0.027). Planned drug holidays for lenvatinib demonstrated significantly longer PFS, TTF, and OS than daily oral administration, and less intolerable toxicity leading to further unplanned treatment interruption. These benefits were apparently associated with a more extended period of lenvatinib administration at ≥10 mg. These findings might contribute to a favorable patient prognosis and safer toxicity profile.

Pitolisant-supported bridging during drug holidays to deal with tolerance to modafinil in patients with narcolepsy

Study objectivesModafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil. MethodsNarcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to “bridge” the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients’ diaries. Results41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly. ConclusionPatients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil. Clinical trial registration numberClinical Trials.gov Identifier NCT05321355.

THU170 Clinical And Immunological Response To Somatrogon In Two Siblings With A Homozygous Whole Gene Deletion Of The Growth Hormone 1 Gene

Abstract Disclosure: R. Gupta: None. R. Khadgawat: None. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. M.T. Dattani: Advisory Board Member; Self; Ferring Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sandoz. Consulting Fee; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Speaker; Self; Pfizer, Inc., Novo Nordisk, Sandoz, Ipsen. L. Dyer: Employee; Self; GeneDx. B. Friedman: Employee; Self; GeneDx. J. Korth-Bradley: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J. Hsiao: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone (LAGH), is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (GHD). A global Phase 3 study in pediatric subjects with GHD compared the efficacy and safety of once-weekly somatrogon (0.66 mg/kg/wk) vs once-daily Genotropin® (0.24 mg/kg/wk) in a 12-mo main study, followed by an open-label extension (OLE) where all subjects received somatrogon (0.66 mg/kg/wk). Results: Subjects #1 (male; 6 y) and #2 (female; 9 y) are siblings from India randomized in the main study to somatrogon and Genotropin, respectively. Both had severe growth and weight attenuation at baseline, with peak GH levels (GH stimulation test) of 0.1 ng/ml; their IGF-1 standard deviation scores (SDS) were -3.96 and -3.94, respectively. At main study Mo 12, subject #1 had an annual height velocity (HV) of 11.77 cm/year (height SDS improved from -7.48 to -6.4) and IGF-I SDS increased to -1.84. After a 116-day drug holiday (started at the end of main study Mo 12), he continued into the OLE; at OLE Mo 9, his HV decreased to 3.08 cm/y, there was no additional improvement in height SDS (-6.76) and his IGF-1 SDS was -2.31. A test for anti-drug antibodies (ADAs) to somatrogon was positive at main study Mo 6; tests for ADAs, and neutralizing antibodies (NAbs) were positive at Mo 12. At OLE ∼Mo 1 and 3, tests were ADA+ and NAb-; at OLE Mo 6 and 9, tests were ADA-. At main study Mo 12, subject #2 had an annual HV of 11.87 cm/year (height SDS improved from -9.93 to -7.36); IGF-I SDS increased to -2.97. After a 123-day drug holiday, she switched to somatrogon during the OLE (per protocol) and had an HV of 10.01 cm/y and IGF-1 SDS of -1.83 at OLE Mo 9. Low titer ADAs to human GH were detected during the drug holidays. In the OLE, anti-GH ADAs were still detected, but at very low titers and tests were NAb−. Whole exome sequencing revealed a homozygous whole gene deletion of the GH1 gene in both siblings. Both completed the main study and OLE without any serious adverse events or dose reductions. Conclusions: Both siblings have classic congenital isolated GHD due to a homozygous GH1 deletion. Development of anti-GH ADAs and growth attenuation during GH therapy are likely due to lack of exposure to GH during fetal life followed by exposure to exogenous GH. The variability in antibody production and heterogeneity in clinical responsiveness to GH replacement has been well described, even in siblings,1 and if encountered in clinical practice, should prompt clinicians to consider the possibility of a GH1 deletion. To our knowledge, this is the first description of GH1 deletions in LAGH-treated subjects and the study findings are wholly consistent with those for daily GH products. Clinicaltrials.gov: NCT02968004 Reference: Ghosh et al. J Clin Res Pediatr Endocrinol 2021;13:456-60. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Thursday, June 15, 2023

FRI684 So Strong Yet So Fragile: Bilateral Periprosthetic Fractures On Denosumab

Abstract Disclosure: A. Syeda: None. F.S. Mirza: None. Background: Denosumab (DN) is a potent antiresorptive and has been associated rarely with atypical femoral fractures. We hereby report the first case of simultaneous bilateral femoral periprosthetic fractures (PPF) while on DN therapy (DNT). Clinical Case: A 78-year-old female with severe osteoporosis on DNT presented in January 2023 with bilateral femoral PPF after a mechanical fall whereby she tripped and landed on her knees. The patient had initially presented to us in late 2012. Treatment history included alendronate (ALN) for 5 years, on drug holiday since 2010. She underwent bilateral knee replacement surgeries in 2012 and DNT was started in 2013 after initial evaluation. She also had primary biliary cirrhosis, and although bone density (BD) improved on DNT, she exhibited escape from DN mediated suppression of bone resorption possibly related to the liver disease that was previously reported (1). DNT was stopped 5 years later when spine BD improved to osteopenic range and ALN 70 mg weekly was started. 1 year later, bone resorption markers were still elevated and zoledronic acid was substituted for ALN. She fell and had a pubic ramus fracture 11 months later. BD showed a 6% decrease for mean total hip and baseline forearm BD showed T-score of -3.7 on the right. DNT was restarted in December 2020 and continued every 6 months. Her health continued to deteriorate over next two years, with increase in LFTS, new anemia and thrombocytopenia due to a combination of myelodysplastic syndrome and splenomegaly. She also needed transcatheter aortic valve replacement for worsening CHF. She tripped and fell in January 2023. X-ray showed acute supracondylar bilateral PPF with comminution. She was high risk for anesthesia and anticoagulation was withheld due to a history of thrombocytopenia and gastrointestinal bleeding. Prior to the anticipated orthopaedic procedure, the patient developed severe hypotension and a rapid drop in hematocrit due to hemorrhagic shock. The family had requested DNR due to the multitude of medical issues. Conclusion: Occasional PPF have been reported in the setting of DNT, which may reflect the severity of osteoporosis. Altered stress distribution and decreased tensile strength of the bone secondary to screw/pin placement are thought to contribute to PPF, although the occurrence of PPF as an unusual presentation of an AFF cannot be excluded. Contribution of other comorbidities to poor bone quality may also have contributed to the bilateral PPF with poor outcome in our patient. 1. Vedere, T.R. and Mirza, F.S., 2017, April. Escape from Denosumab Mediated Suppression of Bone Resorption in Primary Biliary Cirrhosis. In 99th Annual Meeting of the Endocrine Society. Endocrine Society. Presentation: Friday, June 16, 2023

The Relationship Between Prognosis and Duration of Drug Holidays after Docetaxel Therapy for Castration-Resistant Prostate Cancer

The next treatment strategy after drug holidays following docetaxel (DTX) therapy for patients with castration-resistant prostate cancer (CRPC) is unclear. This study investigated the relationship between the duration of drug holidays and prognosis after DTX therapy. This study retrospectively assessed 26 patients treated with DTX in our hospital. Overall survival duration was significantly longer in the long-term withdrawal group (duration of drug holidays ≥6 months) than in the short-term withdrawal group (duration of drug holidays ＜6 months) (P＝0.015). Similarly, progression-free survival duration was significantly longer in the long-term withdrawal group than in the short-term withdrawal group (P＝0.008). The short-term withdrawal group had a significantly lower body mass index (P＝0.009) and higher prostate-specific antigen (PSA) (P＝0.017) at the initiation of DTX therapy, higher PSA nadir during DTX therapy (P＝0.009), and higher PSA at the end of DTX therapy (P＝0.022), compared to the long-term withdrawal group. This study suggests that the optimal opportunity to introduce DXT therapy is when the patients with CRPC are physically able to tolerate chemotherapy and their tumor volume remains a lower burden. This may provide a clinical benefit, longer drug holidays, and a better prognosis.

1176P Planned drug holidays during immunotherapy in advanced and metastatic melanoma patients: A nation-wide study

1176P Planned drug holidays during immunotherapy in advanced and metastatic melanoma patients: A nation-wide study

Safety and Efficacy of Drug Holidays for Women with Sexual Dysfunction Induced by Selective Serotonin Reuptake Inhibitors (SSRIs) Other than Fluoxetine: An Open-Label Randomized Clinical Trial.

Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of psychopharmacology. However, they cause side effects such as sexual dysfunction, leading to the discontinuation of treatment. We aimed to investigate the efficacy and safety of drug holidays for women experiencing sexual dysfunction Induced by SSRIs other than fluoxetine. This study was an 8-week randomized, open-label, controlled trial including married women aged between 18 and 50 years who had experienced sexual dysfunction while undergoing treatment with SSRIs. The intervention group implemented drug holidays by not taking medications on Thursdays and Fridays, while the control group continued regular medication use. The female sexual function index (FSFI) and the 28-question general health questionnaire (GHQ-28) were administered to assess sexual function and mental health, respectively. A total of 50 participants completed the trial. The drug holidays' group showed significant improvements in arousal (p < 0.001), desire (p = 0.001), orgasm (p < 0.001), satisfaction (p < 0.001), lubrication (p = 0.021), and overall sexual health (p < 0.001). The between-group difference of pain was significant (p < 0.001), despite no significant within-group change. Mental health improved in both groups, despite no significant between-group difference. No major adverse effects were reported. Drug holidays did not introduce immediate safety concerns or significant adverse effects during the timeframe of eight weeks, suggesting that it may be a safe and effective strategy for managing SSRI-induced sexual dysfunction in women, alongside improving mental health. Further research is needed to reach a definitive conclusion.

B-063 Towards Improving mRNA Vaccine Effectiveness in Immunosuppressed Adults: Elucidating the Mechanisms and Evaluating Potential Improvement Strategies

Abstract Background The success of COVID-19 mRNA vaccines (Co-mV) has provided a renewed impetus in developing “onetime universal flu, COVID”, and other mRNA-based vaccines to offer broader and long-lasting protection. However, to bring this endeavor to fruition, it is of prime importance to address the mechanism(s) underlying poor vaccine response in some patients and close this gap of inequitable effectiveness through improvement strategies, which is the focus of our current study. To date, there is no ‘empirical’ evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency, to its dampened response. Methods This IRB approved study involved 1) an assessment of a total of 1009 immunocompromised (IC) patients and immunocompetent subjects who had received 2 or more doses of Co-mV, 2) in vitro cell-culture experiments, and 3) in vivo animal studies. Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. In vivo impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgGSp) in serum were longitudinally assessed (26 days) in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgGSp levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV. In addition, 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV were assessed. Expression of Sp and p70S6K phosphorylation (translation surrogate) were evaluated following higher vaccine doses and transient drug holidays. Statistical analysis was performed using GraphPad software 9.3.1. p &amp;lt; 0.05 was considered as statistically significant. Results The 2D and 3D Co-mV received IC patients showed a significantly lower IgGSP response (p &amp;lt; 0.0001) relative to their matched controls. M or S profoundly dampened (p &amp;lt; 0.001) the IgGSP response following Co-mV in the IC patients relative to those that were not on these drugs. M and S, when used individually or in combination in HEK293 cells, significantly (p &amp;lt; 0.05) attenuated the Co-mV-induced Sp expression concurrently with translation surrogates. In contrast, T did not change these indices. Notably, the cellular uptake of Co-Mv was not altered by these drugs. In vivo sirolimus combo pretreatment significantly (p &amp;lt; 0.05) attenuated the Co-mV induced IgMSp and IgGSp production. This correlated with a decreasing trend in the early levels (after day 1) of Co-mV-induced Sp immunogen levels. Neither higher Co-mV concentrations (6μg) nor a 1-day break of S could overcome the repressed Sp protein levels. Interestingly, 3-days of S holiday or using T alone rescued Sp levels in vitro. Conclusion This is the first study to reveal that ISs, sirolimus and mycophenolate restrain Co-mV-induced Sp protein synthesis via translation suppression. Transient holiday of sirolimus or selective use of tacrolimus at the time of vaccination can be a potential option to rescue translation-dependent Sp protein production. These compelling findings lay a solid foundation for guiding future studies aimed at improving mRNA-based vaccine effectiveness in high-risk IC patients.

What makes a multidisciplinary medication review and deprescribing intervention for older people work well in primary care? A realist review and synthesis

BackgroundA third of older people take five or more regular medications (polypharmacy). Conducting medication reviews in primary care is key to identify and reduce/ stop inappropriate medications (deprescribing). Recent recommendations for effective deprescribing include shared-decision making and a multidisciplinary approach. Our aim was to understand when, why, and how interventions for medication review and deprescribing in primary care involving multidisciplinary teams (MDTs) work (or do not work) for older people.MethodsA realist synthesis following the Realist And Meta-narrative Evidence Syntheses: Evolving Standards guidelines was completed. A scoping literature review informed the generation of an initial programme theory. Systematic searches of different databases were conducted, and documents screened for eligibility, with data extracted based on a Context, Mechanisms, Outcome (CMO) configuration to develop further our programme theory. Documents were appraised based on assessments of relevance and rigour. A Stakeholder consultation with 26 primary care health care professionals (HCPs), 10 patients and three informal carers was conducted to test and refine the programme theory. Data synthesis was underpinned by Normalisation Process Theory to identify key mechanisms to enhance the implementation of MDT medication review and deprescribing in primary care.FindingsA total of 2821 abstracts and 175 full-text documents were assessed for eligibility, with 28 included. Analysis of documents alongside stakeholder consultation outlined 33 CMO configurations categorised under four themes: 1) HCPs roles, responsibilities and relationships; 2) HCPs training and education; 3) the format and process of the medication review 4) involvement and education of patients and informal carers. A number of key mechanisms were identified including clearly defined roles and good communication between MDT members, integration of pharmacists in the team, simulation-based training or team building training, targeting high-risk patients, using deprescribing tools and drawing on expertise of other HCPs (e.g., nurses and frailty practitioners), involving patents and carers in the process, starting with ‘quick wins’, offering deprescribing as ‘drug holidays’, and ensuring appropriate and tailored follow-up plans that allow continuity of care and management.ConclusionWe identified key mechanisms that could inform the design of future interventions and services that successfully embed deprescribing in primary care.

Effective targeting of breast cancer by the inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells

Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by chemotherapy, epithelial breast cancer cells adopt a transient drug tolerant phenotype characterized by cell cycle arrest, epithelial-to-mesenchymal transition (EMT) and the reversible upregulation of the multidrug resistance (MDR) efflux transporter P-glycoprotein (P-gp). The drug tolerant persister (DTP) state is reversible, as cells eventually resume proliferation, giving rise to a cell population resembling the initial, drug-naïve cell lines. However, recovery after doxorubicin treatment is almost completely eliminated when DTP cells are cultured in the presence of the P-gp inhibitor Tariquidar. Mechanistically, P-gp contributes to the survival of DTP cells by removing reactive oxygen species-induced lipid peroxidation products resulting from doxorubicin exposure. In vivo, prolonged administration of Tariquidar during doxorubicin treatment holidays resulted in a significant increase of the overall survival of Brca1−/−;p53−/− mammary tumor bearing mice. These results indicate that prolonged administration of a P-gp inhibitor during drug holidays would likely benefit patients without the risk of aggravated side effects related to the concomitantly administered toxic chemotherapy. Effective targeting of DTPs through the inhibition of P-glycoprotein may result in a paradigm shift, changing the focus from countering drug resistance mechanisms to preventing or delaying therapy resistance.

Group 3 ITI Consensus Report: Materials and antiresorptive drug-associated outcomes in implant dentistry.

The aim of Working Group 3 was to address the influence of both material- and anti-resorptive drug- related factors on clinical and biological outcomes and complications in implant dentistry. Focused questions were addressed on (a) implant materials other than titanium (alloy)s, (b) transmucosal abutment materials and (c) medications affecting bone metabolism were addressed. Three systematic reviews formed the basis for discussion in Group 3. Consensus statements and clinical recommendations were formulated by group consensus based on the findings of the systematic reviews. Patient perspectives and recommendations for future research were also conveyed. These were then presented and accepted following further discussion and modifications as required by the plenary. Zirconia is a valid alternative to titanium as material for implant and transmucosal components, allowing soft and hard tissue integration with clinical outcomes-identified by implant survival, marginal bone loss and peri-implant probing depths-up to 5-years comparable to titatnium. However, most of the evidence for zirconia implants is based on 1-piece implants limiting the indication range. Furthermore, based on expert opinion, zirconia transmucosal components might be preferred in the esthetic zone. In patients receiving low-dose bisphosphonate therapy, the rate of early implant failure is not increased, while the long-term effects remain poorly studied. Although it has not been sufficiently addressed, similar outcomes can be expected with low-dose denosumab. A drug holiday is not recommended when considering implant placement in patients treated with low-dose ARD. However, the specific therapeutic window, the cumulative dose and the administration time should be considered. Access to peri-implant supportive care is mandatory to prevent peri-implantitis-related medication-related osteonecrosis of the jaw (MRONJ) or implant-related sequestra (IRS). In patients receiving low-dose anti-resorptive drugs (ARD) therapy, the risk of complications related to implant placement is high, and implant procedures in this specific population should be strictly treated in a comprehensive multidisciplinary center. Finally, healthy dental implants should not be removed before low or high-dose ARD. Zirconia implants can be an alternative to titanium implants in selected indications. However, the current state of evidence remains limited, especially for 2-piece implant designs. Administration of low-dose ARD did not show any negative impact on early implant outcomes, but careful follow-up and supportive care is recommended in order to prevent peri-implant MRONJ and IRS. Implant placement in high-dose patients must be strictly considered in a comprehensive multidisciplinary center.

Osteoporosis: treatment of high-risk patients

Nowadays, different drugs are available for specific treatment of osteoporosis. On the one hand, antiresorptives (raloxifene, bisphosphonates, denosumab) and, on the other hand, bone anabolic drugs (teriparatide and romosozumab) can be used. For both bone anabolic agents, superiority over oral bisphosphonates in high-risk patients was shown in randomized comparative studies. High-risk patients represent asubgroup of osteoporosis patients requiring treatment with aparticularly high fracture risk. The very high risk can be recognized by the clinical manifestation (hip or vertebral fracture), the very low T‑score and/or the clinical risk factors (exceeding the bone anabolic threshold of the DVO risk calculator). High-risk patients should be treated with bone anabolic drugs in the first line of treatment. Patients treated with antiresorptives, who develop avery high risk in the course of the disease should be escalated to bone anabolic compounds. Every bone anabolic treatment requires an antiresorptive follow-up treatment. Drug holidays are only possible in exceptional cases for high-risk patients.