Anti-CGRP antibody galcanezumab modifies the function of the trigeminovascular nocisensor complex in the rat.

BACKGROUND: Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) are effective in the prevention of chronic and frequent episodic migraine. Since the antibodies do not cross the blood brain barrier, their antinociceptive effect is attributed to effects in meningeal tissues. We aimed to probe if such an antibody can be visualized within the dura mater and the trigeminal ganglia following its administration to rats and to examine if the activity of the trigeminovascular nocisensor complex is influenced by this treatment. METHODS: Effects of the anti-CGRP antibody galcanezumab on the trigeminovascular nocisensor complex was examined by measuring release of sensory neuropeptides and histamine from the rat dura mater. Deposits of galcanezumab were visualized by fluorescence microscopy in the trigeminal ganglion and the dura mater. RESULTS: Fluorophore-labelled galcanezumab was detected in the dura mater and the trigeminal ganglion up to 30 days after treatment affirming the long-lasting modulatory effect of this antibody. In female rats, seven days after systemic treatment with galcanezumab the capsaicin-induced release of CGRP was decreased, while that of substance P (SP) was increased in the dura mater. In control rats, release of the inhibitory neuropeptide somatostatin (SOM) was higher in females than in males. Stimulation with high concentration of KCl did not significantly change the release of SOM in control animals, while in rats treated with galcanezumab SOM release was slightly reduced. Galcanezumab treatment also reduced the amount of histamine released from dural mast cells upon stimulation with CGRP, while the effect of compound 48/80 on histamine release was not changed. CONCLUSIONS: Galcanezumab treatment is followed by multiple changes in the release of neuropeptides and histamine in the trigeminal nocisensor complex, which may contribute to the migraine preventing effect of anti-CGRP antibodies. These changes affecting the communication between the components of the trigeminal nocisensor complex may reduce pain susceptibility in migraine patients treated with CGRP targeting monoclonal antibodies.

Insulin sensitizes neural and vascular TRPV1 receptors in the trigeminovascular system.

BACKGROUND: Clinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache. In the present study we examined the effect of insulin on transient receptor potential vanilloid 1 (TRPV1) receptor-dependent meningeal nociceptor functions in rats. METHODS: The effects of insulin on the TRPV1 receptor stimulation-induced release of calcitonin gene related peptide (CGRP) from trigeminal afferents and changes in meningeal blood flow were studied. Colocalization of the insulin receptor, the TRPV1 receptor and CGRP was also analyzed in trigeminal ganglion neurons. RESULTS: Insulin induced release of CGRP from meningeal afferents and consequent increases in dural blood flow through the activation of TRPV1 receptors of trigeminal afferents. Insulin sensitized both neural and vascular TRPV1 receptors making them more susceptible to the receptor agonist capsaicin. Immunohistochemistry revealed colocalization of the insulin receptor with the TRPV1 receptor and CGRP in a significant proportion of trigeminal ganglion neurons. CONCLUSIONS: Insulin may activate or sensitize meningeal nociceptors that may lead to enhanced headache susceptibility in persons with increased plasma insulin concentration.

Variation in communication of side effects in prostate cancer treatment consultations.

BACKGROUND: Effective communication of treatment side effects (SE) is critical for shared decision-making (SDM) in localized prostate cancer. We sought to qualitatively characterize how physicians communicate SE in consultations. METHODS: We transcribed 50 initial prostate cancer treatment consultations across nine multidisciplinary providers (Urologists, Radiation Oncologists, Medical Oncologists) at our tertiary referral, academic center. Coders identified quotes describing SE and used an inductive approach to establish a hierarchy for granularity of communication: (1) not mentioned, (2) name only, (3) generalization("high"), (4) average incidence without timepoint, (5) average incidence with timepoint, and (6) precision estimate. We reported the most granular mode of communication for each SE throughout the consultation overall and across specialty and tumor risk. RESULTS: Among consultations discussing surgery (n = 40), erectile dysfunction (ED) and urinary incontinence (UI) were omitted in 15% and 12%, not quantified (name only or generalization) in 47% and 30%, and noted as average incidence without timeline in 8% and 8%, respectively. In only 30% and 49% were ED and UI quantified with timeline (average incidence with timeline or precision estimate), respectively. Among consultations discussing radiation (n = 36), irritative urinary symptoms, ED, and other post-radiotherapy SE were omitted in 22%, 42%, and 64-67%, not quantified in 61%, 33%, and 23-28%, and noted as average incidence without timeline in 8%, 22%, and 6-8%, respectively. In only 3-8% were post-radiotherapy SE quantified with timeline. Specialty concordance (but not tumor risk) was associated with higher granularity of communication, though physicians frequently failed to quantify specialty-concordant SE. CONCLUSIONS: SE was often omitted, not quantified, and/or lacked a timeline in treatment consultations in our sample. Physicians should articulate, quantify, and assign a timeline for SE to optimize SDM.

Investigating trends in interest for benign prostatic hyperplasia surgery options using Google Trends.

Understanding patient interest among surgical options is challenging. We used Google Trends to analyze interest in benign prostatic hyperplasia (BPH) surgeries recommended for prostate volumes <80 cc. Google Trends was queried with five BPH surgeries. Final rank of search terms was TURP, UroLift, Rezum, Aquablation, and Greenlight. Google Trends can be an effective tool for evaluating public interest trends in BPH surgery.

Variation in content discussed by specialty in consultations for clinically localized prostate cancer.

INTRODUCTION: Multidisciplinary consultations improve decisional conflict and guideline-concordant treatment for men with prostate cancer (PC), but differences in the content discussed by specialty during consultations are unknown. METHODS: We audiorecorded and transcribed 50 treatment consultations for localized PC across a multidisciplinary sample of urologists, radiation oncologists, and medical oncologists. Conversation was coded for narrative content using an open coding approach, grouping similar topics into major content areas. The number of words devoted to each content area per consult was used as a proxy for time spent. Multivariable Poisson regression calculated incidence rate ratios (IRR) for content-specific word count across specialties after adjustment for tumor risk and patient demographics. RESULTS: Coders identified 8 narrative content areas: overview of PC; medical history; baseline risk; cancer prognosis; competing risks; treatment options; physician recommendations; and shared decision making (SDM). In multivariable models, specialties significantly differed in proportion of time spent on treatment options, SDM, competing risks, and cancer prognosis. Urologists spent 1.8-fold more time discussing cancer prognosis than medical oncologists (IRR1.80, 95%CI:1.14-2.83) and radiation oncologists (IRR1.84, 95%CI:1.10-3.07). Urologists (IRR11.38, 95%CI:6.62-19.56) and medical oncologists (IRR10.60, 95%CI:6.01-18.72) spent over 10-fold more time discussing competing risks than radiation oncologists. Medical oncologists (IRR2.60, 95%CI:1.65-4.10) and radiation oncologists (IRR1.77, 95%CI:1.06-2.95) spent 2.6- and 1.8-fold more time on SDM than urologists, respectively. CONCLUSIONS: Specialists focus on different content in PC consultations. Our results suggest that urologists should spend more time on SDM and radiation oncologists on competing risks. Our results also highlight the importance of medical oncologists in facilitating SDM.

Semi-Automated Recording of Facial Sensitivity in Rat Demonstrates Antinociceptive Effects of the Anti-CGRP Antibody Fremanezumab.

Migraine pain is frequently accompanied by cranial hyperalgesia and allodynia. Calcitonin gene-related peptide (CGRP) is implicated in migraine pathophysiology but its role in facial hypersensitivity is not entirely clear. In this study, we investigated if the anti-CGRP monoclonal antibody fremanezumab, which is therapeutically used in chronic and episodic migraines, can modify facial sensitivity recorded by a semi-automatic system. Rats of both sexes primed to drink from a sweet source had to pass a noxious mechanical or heat barrier to reach the source. Under these experimental conditions, animals of all groups tended to drink longer and more when they had received a subcutaneous injection of 30 mg/kg fremanezumab compared to control animals injected with an isotype control antibody 12-13 days prior to testing, but this was significant only for females. In conclusion, anti-CGRP antibody, fremanezumab, reduces facial sensitivity to noxious mechanical and thermal stimulation for more than one week, especially in female rats. Anti-CGRP antibodies may reduce not only headache but also cranial sensitivity in migraineurs.

Relative search popularity of five advanced prostate cancer medications using Google Trends.

BACKGROUND: There are many FDA-approved drugs for advanced prostate cancer (PC), yet public interest in these drugs is not well understood. We compared public interest and state-level predictors of interest in five common oral adjunctive hormonal therapies. METHODS: Google Trends™ was queried for: "Enzalutamide", "Abiraterone Acetate", "Bicalutamide", "Apalutamide", and "Darolutamide" in the United States from January 2004 to November 2022. Data are presented as relative search index (RSI) by month. RSI ranges from 0 to 100 with 100 being peak popularity, 50 being half of the peak popularity, and 0 representing insufficient data to be determined. RESULTS: Several drugs abruptly increased in popularity following FDA approval including abiraterone, enzalutamide, and apalutamide. All drugs decreased in popularity from January 2020 to July 2020, corresponding with the COVID-19 pandemic. In the most recent 5 years, enzalutamide and abiraterone were the most common searched drugs, with bicalutamide a close 3rd place. States that did not expand Medicaid were significantly more likely to have bicalutamide as the top search drug vs. states that expanded Medicaid (p = 0.012). Across all states with data (n = 39), higher bicalutamide RSIs were significantly associated with lower household income (r = 0.385, p = 0.02) and greater percent of uninsured adults (r = 0.426, p = 0.007). This is the first study using Google Trends to compare advanced PC drugs by search popularity. CONCLUSIONS: Despite the emergence of more effective medications, bicalutamide remains relatively popular, particularly in states with lower household income, more uninsured adults, or those that did not expand Medicaid, possibly due to its lower cost.

Are higher follicle-stimulating hormone levels before androgen deprivation therapy for prostate cancer associated with oncological and cardiac outcomes and overall survival?-a population-level analysis.

Background: Androgen deprivation therapy (ADT), commonly delivered via a luteinizing hormone-releasing hormone (LHRH) agonist, is the standard treatment for advanced prostate cancer (PC). While quite effective, it has been associated with an increased risk of major adverse cardiovascular events (MACE). The exact mechanisms are not clear. However, it has been theorized that follicle-stimulating hormone (FSH), a pituitary hormone that is involved in controlling normal testosterone levels, which is decreased with LHRH-agonist therapy, may be the culprit. We performed a retrospective population-level study to test the link of FSH levels on the development of MACE, castrate-resistant PC (CRPC), and death among men starting ADT. Methods: All men (n=1,539) who had an FSH level between 1999 and 2018 within 2 years prior to starting ADT and complete data were identified within the Veterans Affairs (VA) Health System. FSH was dichotomized as low/normal (≤8 IU/mL) and high (>8 IU/mL), using established cut-points. The associations between FSH and time to MACE, death, and CRPC were tested using log-rank tests and multivariable Cox proportional hazards models. Results: Patients with high FSH were older (median 76 vs. 73 years, P<0.001), started ADT earlier (median 2007 vs. 2009, P=0.027), and had lower body mass index (BMI) (median 29.1 vs. 30.1 kg/m2, P=0.004) compared to those with low/normal FSH. On multivariable analysis, there was no association between FSH and time from ADT to MACE, CRPC, or death. Conclusions: In this population-level study of men receiving an FSH test prior to starting ADT, there was no association between FSH levels and time from ADT to MACE, CRPC, or death. Although further studies are needed, these results do not support a link between pre-ADT FSH and long-term oncological or cardiovascular outcomes.

27-hydroxycholesterol and DNA damage repair: implication in prostate cancer.

Introduction: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects. Methods: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays. Results: Transcriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced "BRCAness" by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects. Discussion: These results suggest 27HC induces "BRCAness", a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.