Therapeutic Gain Research Articles

Suppression of MYC by PI3K/AKT/mTOR pathway inhibition in combination with all-trans retinoic acid treatment for therapeutic gain in acute myeloid leukaemia.

Aberrant activity of the phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR [PAM]) pathway, as well as suppressed retinoic acid signalling, contribute to enhanced proliferation and the differentiation blockade of immature myeloid cells in acute myeloid leukaemia (AML). Inhibition of the PAM pathway was shown to affect especially mixed-lineage leukaemia-rearranged AML. Here, we sought to test a combined strategy using small molecule inhibitors against members of the PAM signalling pathway in conjunction with all-trans retinoic acid (ATRA) to target a larger group of different AML subtypes. We find that ATRA treatment in combination with inhibition of PI3K (ZSTK474), mTOR (WYE132) or PI3K/mTOR (BEZ235, dactolisib) drastically reduces protein levels of the proto-oncogene MYC. In combination with BEZ235, ATRA treatment led to almost complete eradication of cellular MYC, G1 arrest, loss of clonal capacity and terminal granulocytic differentiation. We demonstrate that PAM inhibitor/ATRA treatment targets MYC via independent mechanisms. While inhibition of the PAM pathway causes MYC phosphorylation at threonine 58 via glycogen synthase kinase 3 betaand subsequent degradation, ATRA reduces its expression. Here, we present an approach using a combination of known drugs to synergistically reduce aberrant MYC levels, thereby effectively blocking proliferation and enabling differentiation in various AML subtypes.

Herbal oils in healthcare: a review

The herbal medicine market has grown considerably as an alternative currently used for the application of plants in the treatment of various diseases. In this environment, studies on the bioactivity of essential oils and the search for those that have antimicrobial, analgesic, anti-inflammatory, anti-tumor, antioxidant properties and also oils that can inhibit key enzymes are highlighted. However, research on the use of plants in the pharmaceutical industry, chemical composition of native species and possible biological activities are still scarce. Therefore, studies for the knowledge of native species with therapeutic potential gain great relevance. This study carried out a review of the research already done on essential oils from species with potentially promising biological activities for the contribution of the sustainable use of biodiversity and the relevance of their medicinal potential.

Nano to rescue: repository of nanocarriers for targeted drug delivery to curb breast cancer.

Breast cancer is a heterogeneous disease with different intrinsic subtypes. The conventional treatment of surgical resection, chemotherapy, immunotherapy and radiotherapy has not shown significant improvement in the survival rate of breast cancer patients. The therapeutics used cause bystander toxicities deteriorating healthy tissues. The breakthroughs of nanotechnology have been a promising feat in selective targeting of tumor site thus increasing the therapeutic gain. By the application of nanoenabled carriers, nanomedicines ensure targeted delivery, stability, enhanced cellular uptake, biocompatibility and higher apoptotic efficacy. The present review focuses on breakthrough of nanoscale intervention in targeted drug delivery as novel class of therapeutics. Nanoenabled carriers like polymeric and metallic nanoparticles, dendrimers, quantum dots, liposomes, solid lipid nanoparticles, carbon nanotubes, drug-antibody conjugates and exosomes revolutionized the targeted therapeutic delivery approach. These nanoassemblies have shown additional effect of improving the solubility of drugs such as paclitaxel, reducing the dose and toxicity. The present review provides an insight on the different drug conjugates employed/investigated to curb breast cancer using nanocarrier mediated targeted drug delivery. However, identification of appropriate biomarkers to target, clearer insight of the biological processes, batch uniformity, reproducibility, nanomaterial toxicity and stabilities are the hurdles faced by nanodrugs. The potential of nano-therapeutics delivery necessitates the agglomerated efforts of research community to bridge the route of nanodrugs for scale-up, commercialization and clinical applications.

Erenumab dosage for migraine prevention: An evidence-based narrative review with recommendations.

Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70mg monthly, with guidance that some patients may benefit from the 140mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options. To evaluate therapeutic and tolerability differences between erenumab 70 and 140mg based on evidence from published literature. This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021. From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140mg erenumab once monthly-especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140mg has a numerically better efficacy than 70mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine. Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140mg and a rationale for initiating 140mg in selected patients.

ADAM8 signaling drives neutrophil migration and ARDS severity.

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.

Cardiac macrophages regulate isoproterenol-induced Takotsubo-like cardiomyopathy.

Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.

Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.

Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a “bystander effect”. In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling. The approach employs a number of experimental model systems to define parameters for the cellular uptake, metabolism and diffusion of both the prodrug and its metabolites. The model predicts rapid uptake of CP-506 to high intracellular concentrations with its long plasma half-life driving tissue diffusion to a penetration depth of 190 µm, deep within hypoxic activating regions. While bioreductive metabolism is restricted to regions of severe pathological hypoxia (<1 µM O2), its active metabolites show substantial bystander potential with release from the cell of origin into the extracellular space. Model predictions of bystander efficiency were validated using spheroid co-cultures, where the clonogenic killing of metabolically defective “target” cells increased with the proportion of metabolically competent “activator” cells. Our simulations predict a striking bystander efficiency at tissue-like densities with the bis-chloro-mustard amine metabolite (CP-506M-Cl2) identified as a major diffusible metabolite. Overall, this study shows that CP-506 has favourable pharmacological properties in tumour tissue and supports its ongoing development for use in the treatment of patients with advanced solid malignancies.

Opportunities for Precision Treatment of GRIN2A and GRIN2B Gain-of-Function Variants in Triheteromeric N-Methyl-D-Aspartate Receptors.

N-methyl-D-aspartate receptors (NMDARs) are tetrameric assemblies of two glutamate N-methyl-D-aspartate receptor subunits, GluN1 and two GluN2, that mediate excitatory synaptic transmission in the central nervous system. Four genes (GRIN2A-D) encode four distinct GluN2 subunits (GluN2A-D). Thus, NMDARs can be diheteromeric assemblies of two GluN1 plus two identical GluN2 subunits, or triheteromeric assemblies of two GluN1 subunits plus two different GluN2 subunits. An increasing number of de novo GRIN variants have been identified in patients with neurologic conditions and with GRIN2A and GRIN2B harboring the vast majority (> 80%) of variants in these cases. These variants produce a wide range of effects on NMDAR function depending upon its subunit subdomain location and additionally on the subunit composition of diheteromeric versus triheteromeric NMDARs. Increasing evidence implicates triheteromeric GluN1/GluN2A/GluN2B receptors as a major component of the NMDAR pool in the adult cortex and hippocampus. Here, we explore the ability of GluN2A- and GluN2B-selective inhibitors to reduce excess current flow through triheteromeric GluN1/GluN2A/GluN2B receptors that contain one copy of GRIN2A or GRIN2B gain-of-function variants. Our data reveal a broad range of sensitivities for variant-containing triheteromeric receptors to subunit-selective inhibitors, with some variants still showing strong sensitivity to inhibitors, whereas others are relatively insensitive. Most variants, however, retain sensitivity to non-selective channel blockers and the competitive antagonist D-(-)-2-amino-5-phosphonopentanoic acid. These results suggest that with comprehensive analysis, certain disease-related GRIN2A and GRIN2B variants can be identified as potential targets for subunit-selective modulation and potential therapeutic gain. SIGNIFICANCE STATEMENT: Triheteromeric NMDA receptors that contain one copy each of the GluN2A and GluN2B subunits show intermediate sensitivity to GluN2A- and GluN2B-selective inhibitors, making these compounds candidates for attenuating overactive, GRIN variant-containing NMDA receptors associated with neurological conditions. We show that functional evaluation of variant properties with inhibitor pharmacology can support selection of a subset of variants for which GluN2 subunit-selective agents remain effective inhibitors of variant-containing triheteromeric NMDA receptors.

Three discipline collaborative radiation therapy (3DCRT) special debate: FLASH radiotherapy needs ongoing basic and animal research before implementing it to a large clinical scale.

Three discipline collaborative radiation therapy (3DCRT) special debate: FLASH radiotherapy needs ongoing basic and animal research before implementing it to a large clinical scale.

KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II–induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

Loco-regional radiosensitizing nanoparticles-in-gel augments head and neck cancer chemoradiotherapy

The therapeutic gain in loco-regionally advanced unresectable head and neck squamous cell carcinoma (HNSCC) is limited with the traditional use of concurrent chemoradiotherapy (CRT) owing to dose-limiting toxicities of systemic clinical radiosensitizers. Delivery through regional platforms is challenging due to limited drug permeation but allows spatio-temporal control of combinatorial regimens locally to overcome drug resistance. We address these challenges by developing biodegradable gellan- and lipid-based dual nanocarriers-in-ion-triggered porous mucoadhesive hydrogels for enhanced site-specific delivery of clinically relevant radiosensitizers i.e. cisplatin and paclitaxel. Interestingly, the nanoparticle-in-gel prolonged the tumor bioaccumulation of both the chemotherapeutic drugs with reduced systemic absorption, thereby improving in vivo efficacy which was confirmed by PET-CT imaging and safety as compared to systemic commercial formulations approved for HNSCC chemoradiotherapy. The nanoparticles facilitated intracellular radiosensitizer uptake and cell arrest to synergistically enhance radiation-induced DNA nicks and apoptosis. Our findings suggest the clinical potential of the present platform in the loco-regional management of HNSCC requiring curative CRT.

Systematic Review of Research and Interventions With Frequent Callers to Suicide Prevention Helplines and Crisis Centers.

Background: Helplines worldwide have frequent callers who may occupy a large proportion of call volume. Therapeutic gain from frequent calling has been questioned. We conducted this review to identify the characteristics of frequent callers and to compile recommendations about how best to help them. Method: Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) standards, we searched for all empirical research in English and French from inception to May, 2020 in PubMed, PsycInfo, and the CRISE library. Results: We identified 738 manuscripts and retained 27 for analyses. Nine provided no definition of frequent callers; nine mixed frequent callers with repeat callers (>1 calls); nine concerned frequent callers (≥8 calls/month). The limited data suggest frequent callers are similar to other callers and often experience mental health problems, loneliness, and suicide risk. From recommendations in all 27 studies, we identified 10 suggestions to better manage and help frequent callers that merit validation. Limitations: The small number of empirical investigations and the diversity of their goals and methodologies limit generalizations. Although recommendations for helping callers may have face validity, empirical data on their effectiveness are scarce. Conclusion: Rather than focusing on reducing call frequency, we should empirically evaluate the benefits of interventions for frequent callers with different calling patterns, characteristics, and reasons for calling.

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3\xa0T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study

PurposeResective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). MethodsWe present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up.ResultsAll patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded.ConclusionThis protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences.Trial registration numberwww.trialregister.nl: NTR7536.

Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.

RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.

Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma.

Cancer cells frequently undergo metabolic reprogramming to support tumorigenicity and malignancy, which is recognized as a hallmark of cancer. In addition to glycolysis and glutaminolysis, alterations in fatty acid (FA) metabolism have received increasing concerns in the past few years. Recently, accumulating evidence has shown that fatty acid β-oxidation (FAO) is abnormally activated in various tumors, which is associated with the machinery of proliferation, stemness, metastasis, and radiochemotherapeutic resistance of cancer cells. Acyl-CoA synthetases 3 (ACSL3) belongs to a family of enzymes responsible for converting free long-chain FAs into fatty acyl-CoA esters, which act as substrates both for lipid synthesis and FAO.Here, we demonstrate that transforming growth factor beta 1 (TGFβ1) induces the up-regulation of ACSL3 through sterol regulatory element-binding protein 1 (SREBP1) signaling to promote energy metabolic reprogramming in colorectal carcinoma (CRC) cells. ACSL3 mediates the epithelial mesenchymal transition (EMT) and metastasis of CRC cells by activation of FAO pathway to produce ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH), which sustain redox homeostasis and fuel cancer cells for invasion and distal metastasis. Thus, targeting ACSL3 and FAO metabolic pathways might be exploited for therapeutic gain for CRC and other FAs- addicted cancers.

Pulmonary macrophages and SARS-Cov2 infection.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the largest global pandemic in living memory, with between 4.5 and 15M deaths globally from coronavirus disease 2019 (COVID-19). This has led to an unparalleled global, collaborative effort to understand the pathogenesis of this devastating disease using state-of-the-art technologies. A consistent feature of severe COVID-19 is dysregulation of pulmonary macrophages, cells that under normal physiological conditions play vital roles in maintaining lung homeostasis and immunity. In this article, we will discuss a selection of the pivotal findings examining the role of monocytes and macrophages in SARS-CoV-2 infection and place this in context of recent advances made in understanding the fundamental immunobiology of these cells to try to understand how key homeostatic cells come to be a central pathogenic component of severe COVID-19 and key cells to target for therapeutic gain.

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology: Part II: Pathology.

It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change—size, number, and physicochemical composition—in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.

Use of priority and provisional approval pathways by the Australian Therapeutic Goods Administration in approving new medicines: a cross-sectional study.

Objective Examine the use of priority and provisional approval pathways by the Australian Therapeutic Goods Administration (TGA) for evaluating new medicines. Methods This observational study assessed all new medicines approved by the TGA between 1 January 2018 and 18 October 2021. It examined how frequently priority and provisional approval pathways are being used, the conditions which the medicines are being approved to treat, how long medicines are spending in the approval pathways, the additional therapeutic value of the medicines being approved through these pathways and how the use of the pathways compares with similar regulatory pathways used by Health Canada. Results The TGA approved 138 new medicines in the time period under study, of which 33 were approved through either the priority or provisional approval pathways. Sixteen were approved to treat cancer. It took the TGA a mean of 130 (95% CI 118, 143) and 144 (95% 101, 188) working days for priority and provisional pathways, respectively. Therapeutic evaluations were available for 16 of these medicines and 11 offered little to no therapeutic gain over existing medicines. There was moderate agreement between the TGA and Health Canada in their use of these pathways (Kappa = 0.5458, 95% CI 0.3900, 0.7016). Conclusions The priority and provisional approval pathways are now being used by the TGA for about one-third of all new medicine approvals. Although the medicines approved in these ways are moving through the review process more quickly than those approved through the standard approval pathway, the majority of these medicines, for which an evaluation of therapeutic value is available, do not offer any substantial additional therapeutic value over existing medicines.

Evaluation of Efficacy and Tolerance of Radical Radiotherapy and Radiochemotherapy in Treatment of Locally Advanced, Unresectable Rectal Cancer.

Background: A retrospective evaluation of tolerance and efficacy of two schemes of neoadjuvant treatment in patients (pts) with unresectable rectal cancer: radiochemotherapy (CRT) and radiotherapy (RT), including conventional and accelerated hyperfractionation. Material and Method: A total of 145 consecutive pts with unresectable, locally advanced rectal cancer. The schemes used are RT in 73 (50%) or CRT in 72 (50%). In CRT, 54 Gy in 1.8 Gy fractions was given with chemotherapy, In the RT group, conventional fractionation (CFRT) and hyperfractionated accelerated radiotherapy (HART). HART was introduced at first as an alternative to CFRT, after radiobiological studies suggesting a therapeutic gain of hyperfractionation in other cancers, and second to administer relatively high dose needed in unresectable cancer, which is not feasible in hypofractionation because of critical organs sensitivity to high fraction doses (fd). HART was an alternative option in pts with medical contraindications to chemotherapy and to shorten overall treatment time with greater radiobiological effectiveness than CFRT. Results: Objective response (OR) in the RT and CRT group was 60% versus 75%. Resection rate (RR) in RT and CRT: 37% versus 65%. Tumor mobility and laparotomy-based unresectability were significant factors for OR. Performance status (PS), tumor mobility, and neoadjuvant treatment method were significant for RR.

Placebo response with subcutaneous injections in calcitonin gene-related peptide receptor monoclonal antibody migraine preventative trials – A systematic review and meta-analysis

Background: The majority of CGRP monoclonal antibodies for migraine prevention are administered subcutaneously. Therefore, we attempted to calculate the pooled placebo response with subcutaneous placebo injections in this systematic review and meta-analysis. Methods: We identified 16 randomized controlled trials that met our inclusion and exclusion criteria through a comprehensive search in five electronic databases (PubMed Central, EMBASE, MEDLINE, Cochrane library and clinicaltrials.gov ). The risk of bias was assessed for all included studies. Random effects model was used to calculate pooled mean monthly migraine days and 50% response rates. Results: A total of 4240 subjects were included from 16 studies in this meta-analysis. The pooled mean monthly migraine day reduction with subcutaneous placebo injections was 2.15 (95% CI: 1.60–2.69). The pooled proportion of patients achieving a 50% reduction in mean monthly headache days was 26% (95% CI: 20%–31%). Placebo response accounted for more than 50% of therapeutic gain in our study. Conclusion: A substantial placebo response was noted with subcutaneous injections in migraine CGRP monoclonal antibody clinical trials. This meta-analysis may serve as a reference point to calculate sample size in clinical trials using subcutaneous interventions for migraine prevention. We registered our study at PROSPERO (CRD42020185300).