Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Glomerular Filtration Rate Estimation Using ß2-Microglobulin and ß-Trace Protein in Adults With Solid Tumors: A Prospective Cross-Sectional Study.

RATIONALE & OBJECTIVE: ß2-microglobulin (B2M), and ß-trace-protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFRcr-cys), but they have not been assessed in patients with cancer. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017. EXPOSURE: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3- or 4-marker panel eGFR). OUTCOMES: Performance of equations compared to eGFRcr-cys. Non-GFR determinants of serum B2M and BTP (SB2M, and SBTP, respectively). mGFR was determined using the plasma clearance of 51Cr-EDTA. ANALYTICAL APPROACH: Bias was defined as the median of the differences between mGFR and eGFR. 1-P30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P30). Linear regression was used to assess association of clinical and laboratory variables with SB2M, and SBTP after adjustment for mGFR. RESULTS: Mean (SD) age and mGFR were 58.8 (13.2) years and 78.4 (21.7) ml/min/1.73 m2, respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys (lesser bias and 1-P30). Performance of 2-marker panel equations was as good as eGFRcr-cys (lesser bias and similar 1-P30). SB2M and SBTP were not strongly influenced by cancer site. LIMITATIONS: Participants may have had better clinical performance status than the general population of patients with solid tumors. CONCLUSIONS: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in multi-marker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine.

Refractory occipital neuralgia treatment with nerve decompression surgery: a case series.

Background: The management of refractory occipital neuralgia (ON) can be challenging. Selection criteria for occipital nerve decompression surgery are not well defined in terms of clinical features and best preoperative medical management. Methods: In total, 15 patients diagnosed with ON by a board-certified, fellowship-trained headache specialist and referred to a plastic surgeon for nerve decompression surgery were prospectively enrolled. All subjects received trials of occipital nerve blocks (NB), at least three preventive medications, and onabotulinum toxin (BTX) prior to surgery before referral to a plastic surgeon. Treatment outcomes included headache frequency (headache days/month), intensity (0-10), duration (h), and response to medication/injectable therapies at 12 months postoperatively. Results: Preoperatively, median headache days/month was 30 (20-30), intensity 8 (8-10), and duration 24 h (12-24). Patients trialed 10 (±5.8) NB and 11.7 (±9) BTX cycles. Postoperatively, headache frequency was 5 (0-16) days/month (p < 0.01), intensity was 4 (0-6) (p < 0.01), and duration was 10 (0-24) h (p < 0.01). Median patient-reported percent resolution of ON headaches was 80% (70-85%). All patients reported improvement of comorbid headache disorders, most commonly migraine, and a reduction, discontinuation, or increased effectiveness of medications, NB and BTX. Conclusion: All patients who underwent treatment for refractory ON by a headache specialist and plastic surgeon benefited from nerve decompression surgery in various degrees. The collaborative selection criteria employed in this study may be replicable in clinical practice.

Treatment Delay From Onset of Occipital Neuralgia Symptoms to Treatment with Nerve Decompression Surgery: A Prospective Cohort Study.

BACKGROUND: The aim of this study was to a) evaluate the time between onset of occipital neuralgia symptoms and nerve decompression surgery, b) perform a cost comparison analysis between surgical and non-surgical treatment of occipital neuralgia and c) report postoperative results of nerve decompression for occipital neuralgia. METHODS: 1,112 subjects who underwent screening for nerve decompression surgery were evaluated for occipital neuralgia. 367 (33%) patients met the inclusion criteria. Timing of occipital neuralgia symptom onset and pain characteristics were prospectively collected. Cost associated with the non-surgical treatment of occipital neuralgia was calculated for the period between onset of symptoms and surgery. RESULTS: 226 (73%) patients underwent occipital nerve decompression. The average time between onset of occipital neuralgia and surgery was 19 years (7.1-32). Postoperatively, the median number of pain days per month decreased by 17 (0-26, 57%) (p < 0.001), the median pain intensity decreased by 4 (2-8, 44%) (p < 0.001), and median pain duration in hours was reduced by 12 (2-23, 50%) (p < 0.001). The annual mean cost of non-surgical occipital neuralgia treatment was $28,728.82 ($16,419.42-$41,198.41) per patient. The mean cost during the 19-year timeframe prior to surgery was $545,847.75($311,968.90-$782,769.82). CONCLUSION: This study demonstrates that patients suffer from occipital neuralgia for an average of 19 years prior to undergoing surgery. Nerve decompression reduces symptom severity significantly and should be considered earlier in the treatment course of occipital neuralgia that is refractory to conservative treatment to prevent patient morbidity and decrease direct and indirect healthcare costs. IRB REGISTRATION NUMBER & NAME: Weill Cornell Medicine: 23-04025985, Prospective Cohort Study Investigating Long- Term Outcomes After Headache Surgery.The Massachusetts General Hospital: 2012P001527, Correlation of pre-operative pain self-efficacy and post-operative migraine-specific symptoms and disability.

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study.

BACKGROUND: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. METHODS: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2. RESULTS: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC. CONCLUSIONS: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02599324.

CT guided injection of 99mTc-MAA for lung nodule localization prior to VATS.

AIM: CT guided technetium99m-macroaggregated albumin (99mTc-MAA) injection for lung nodule localization prior to video-assisted thoracoscopic surgery (VATS) is employed at our institution for more than a decade. We retrospectively studied the success rate, factors that affect outcomes, and complications of this procedure. MATERIALS AND METHODS: 147 patients with 164 nodules underwent this procedure before VATS. Imaging and procedure characteristics, complications of the procedure, successful intra-operative localization and wedge resection, if there was conversion of primary VATS to open thoracotomy and if so the reason, and histopathological diagnosis for each nodule were reviewed by two radiologists in consensus. In case of unsuccessful wedge resection, reasons for failure were derived from electronic medical record. The impact of nodule and procedure characteristics on successful intra-operative localization was assessed. RESULTS: Excluding 9 nodules with unsuccessful localization due to non-procedure related reasons, the CT guided procedure was successful in 96.1% for intraoperative localization (149/155). Pleural leak of the radiotracer, split injection within the lobe, injection into a wrong nodule and gamma probe malfunction were primary reasons for failure. Nodule size, depth from pleura, and time between radiotracer injection and surgical incision did not impact success of the procedure. Among the 6 cases with procedure related failure, only 1 required conversion to open thoracotomy. CONCLUSION: CT guided 99mTc-MAA injection for intra-operative lung nodule localization is a feasible procedure with a high success rate and low complication rate. Attention to technique can potentially avoid procedure failure.

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine-Clinical Considerations: A Narrative Review.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

A prospective cross-sectional study estimated glomerular filtration rate from creatinine and cystatin C in adults with solid tumors.

Current guidelines recommend estimating glomerular filtration rate (eGFR) using creatinine (eGFRcr) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as the first test for GFR evaluation, but the Cockcroft-Gault (CG) equation is still commonly used in oncology practice and clinical trials despite increasing evidence of its inaccuracy compared to measured GFR (mGFR). Guidelines recommend eGFR using cystatin C (eGFRcys) or both markers (eGFRcr-cys) as a confirmatory test, but neither was carefully evaluated in cancer patients. Therefore, we compared performance of the CKD-EPI equations and others to the CG equation in adults with a variety of solid tumors. The mGFR was determined by plasma clearance of 51Cr-EDTA. Bias was defined as the median of the differences between mGFR and eGFR while accuracy was defined as the percentage of estimates that differed by more than 30% from the measured GFR (1-P30). We prospectively recruited 1,200 patients between April 2015 and September 2017 with a mean age and mGFR of 58.8 years and 78.4 ml/min/1.73m2, respectively. Bias among eGFRcr equations varied from -8.1 to +6.1 ml/min/1.73 m2. CG was the least accurate, 1-P30 (95% confidence interval) was 24.9 (22.4- 27.3)%; CKD-EPI had 1-P30 of 19.1 (16.8-21.2)% while eGFRcr-cys had the best performance: bias -2.0 (-2.6 to -1.1) ml/min/1.73m2 and 1-P30 7.8 (6.3-9.4)%. Thus, the CG equation should not be preferred over CKD-EPI equation, and eGFRcr-cys can be used as a confirmatory test in adults with solid tumors. Hence, a major policy implication would be to adopt general practice guideline-recommended methods for GFR evaluation in oncology practice and clinical trials.

Advance Care Planning, Shared Decision Making, and Serious Illness Conversations in Onconephrology.

Advance care planning, shared decision making, and serious illness conversations are communication processes designed to promote patient-centered care. In onconephrology, patients face a series of complex medical decisions regarding their care at the intersection of oncology and nephrology. Clinicians who aim to ensure that patient preferences and values are integrated into treatment planning must work within a similarly complex care team comprising multiple disciplines. In this review, we describe key decision points in a patient's care trajectory, as well as guidance on how and when to engage in advance care planning, shared decision making, and serious illness discussions. Further research on these processes in the complex context of onconephrology is needed.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5 mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥50 compared to baseline and sustained for 48 h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, secondary infections, duration of supplemental oxygen support, and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953 ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. IP-10 and CXCL-9 declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, P-value 0.0006). INTERPRETATION: Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Intravenous Ketorolac Infusion for Intractable Pleuritic Pain Secondary to Metastatic Epithelioid Hemangioendothelioma.

Background: Epithelioid hemangioendothelioma (EHE) patients can experience severe pain. Nonsteroidal anti-inflammatory drugs, including ketorolac tromethamine, can effectively treat cancer-related pain, provide an opioid-sparing effect, and may be particularly effective for EHE pain. There are limited data describing prolonged (>5 days) continuous intravenous (IV) ketorolac infusion for cancer-related pain and no data on its use in EHE. Case Description: A 67-year-old woman with metastatic hepatic EHE suffered from chronic intractable pleuritic pain unresponsive to trials of nonopioid, opioid, adjuvant medications, and nonpharmacological interventions. In the hospital, continuous IV ketorolac infusion at 3.8 mg/hour (91.2 mg/day) effectively managed pain. With thorough monitoring, the patient was discharged on continuous IV ketorolac infusion at 3 mg/hour (72 mg/day). Infusion continued for 79 days without clinical or laboratory evidence of ketorolac toxicity. Conclusion: Ketorolac tromethamine as a long-term infusion is a potentially viable analgesic for patients with intractable EHE-related pain unresponsive to standard therapies.

The Diagnosis and Management of Posttraumatic Headache with Associated Painful Cranial Neuralgias: a Review and Case Series.

BACKGROUND: Cranial neuralgias are common in the setting of posttraumatic headache. They may exacerbate underlying primary headache disorders and therefore may be overlooked in clinical practice. Frequently, cranial neuralgias generate neuropathic symptoms such as lancinating pain and sensory dysesthesias. Cranial neuralgias are identified based on a clinical history of focal neuropathic pain and physical exam findings including tenderness with palpation and percussion, at times eliciting radiating pain or paresthesias in the corresponding sensory nerve distribution. PURPOSE OF REVIEW: This article is a brief review of the literature and a retrospective report of 2 cases of posttraumatic headache with associated painful cranial neuralgias. RECENT FINDINGS: Two patients presented with headaches that met criteria for posttraumatic headache, but their history and physical examination suggested the presence of a focal painful cranial neuralgia. One patient was diagnosed with auriculotemporal neuralgia, which was exquisitely responsive to an auriculotemporal nerve block. The second patient was diagnosed with supratrochlear neuralgia, which was effectively treated with a supratrochlear nerve block. In both cases, adequate treatment of the painful cranial neuralgia resulted in significant improvement of the baseline PTH. Painful cranial neuralgias frequently occur within the clinical spectrum of posttraumatic headache, but are often undiagnosed. Treatment options for painful cranial neuralgias are often different than those traditionally employed for posttraumatic headache without cranial neuralgias, which can include peripheral nerve blockade, neuropathic medications, and in refractory cases, peripheral nerve decompression surgery.

Transient Horner syndrome associated with COVID-19: A case report.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has spread as a global pandemic with significant morbidity and mortality. As the prevalence of COVID-19 has risen, so has the diversity of its clinical presentation. SARS-CoV-2 is considered to have neuroinvasive and neurotropic qualities that can lead to central and peripheral nervous system manifestations. We describe a 65-year-old woman who developed new-onset unilateral ptosis and mitosis following a diagnosis of COVID-19. To our knowledge, this is the first reported case describing transient Horner syndrome in association with COVID-19.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-α antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN- γ , TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). INTERPRETATION: Consistent with a pathophysiological role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences.

Prevalence of Occipital Neuralgia at a Community Hospital-based Headache Clinic.

BACKGROUND: Occipital neuralgia (ON) is a paroxysmal disorder involving lancinating pain that originates in the neck or skull base with superior radiation toward the apex. ON more commonly occurs in patients with other coexisting headache disorders. There are limited data regarding the prevalence of ON. This study aims to demonstrate the prevalence of ON in a community hospital-based headache clinic. METHODS: This IRB-approved retrospective study was conducted at the Cambridge Health Alliance Headache Clinic. Medical records of patients presenting with headache as a chief complaint were reviewed from January 2010 to September 2015. RESULTS: Of 800 study patients, 81% were females (n = 648). A total of 195 patients were diagnosed with ON, and 146 patients had a positive occipital Tinel sign on examination. Isolated ON was present in 15.38% (n = 30) of patients. Multiple regression analysis demonstrated that the odds of ON were higher in patients with chronic migraine vs episodic migraine (adjusted odds ratio = 2.190 [95% confidence interval: 1.364-3.515]), even when adjusted for significant covariates. CONCLUSION: ON occurred in nearly 25% of patients presenting with a chief complaint of headache to a community hospital-based headache clinic. Among patients with ON, 15% presented with ON as the chief complaint without another coexisting headache disorder. As such, up to 85% of ON cases occurred in patients having an additional headache type. Approximately 75% of patients with ON had a positive occipital Tinel sign on examination. Elevated body mass index, higher age at presentation, and chronic migraine increased the odds of having ON. Undiagnosed or inadequate treatment of ON can increase the frequency and intensity of other comorbid headache disorders.

An Ethically Justified Approach That Integrates Advance Directives Discussions With Care of the Patient With Cancer.

Although the frequency of advance directives discussions may be increasing, there is a need to improve the quality of these discussions. In a range of advanced medical illnesses, including cancer, poor outcomes with advanced cardiopulmonary life support (ACLS) have been well documented. However, when speaking to patients at the end-of-life, physicians frequently withhold evidence-based information and guidance about prognosis or outcomes of ACLS. Tools and models developed to facilitate communication at the end-of-life do not explicitly include recommendations on advance directives and specifically do not discuss the available evidence on ACLS outcomes in the seriously ill. Here, we review the current literature on outcomes of ACLS and current tools and communications for end-of-life discussions. A majority of patients have a preference for truth-telling and guidance. We advocate an approach that integrates individual goals and preferences with a shared understanding of prognosis and appropriate management options, as judged and recommended by the disease experts, in order to reach an evidence-based decision on advance directives. This pragmatic and ethically justified approach emphasizes active empathic communication to prioritize the care of the patient over the mechanical details of ACLS, thereby aligning end-of-life discussions with current practices in other domains of medicine.

Erenumab-Induced Severe Nausea Leading to Smoking Cessation: A Retrospective Case Series.

OBJECTIVE: Erenumab is a novel treatment modality with a relatively benign and safe side effect profile, currently approved for the prevention of migraine headache. We present 3 cases with chronic migraine who are cigarette smokers were prescribed erenumab, and developed an intense smoking-induced nausea which eventually led to smoking cessation. METHODS: A multicenter retrospective review of 3 cases with cigarette smoking, one of whom was also smoking marijuana, suffering from chronic migraine resistant to multiple preventive therapies was studied. All were prescribed monthly injections of erenumab 70 mg. Response in terms of headache frequency and intensity and smoking habits was obtained through medical record review. RESULTS: Out of 3 patients, 2 reported reduced headache frequency and intensity. All patients developed severe nausea while smoking cigarettes after their first dose of erenumab, leading to smoking cessation. One patient co-smoked marijuana, which did not result in nausea after being treated. CONCLUSION: To the best of our knowledge, this is the first report of severe nausea secondary to erenumab administration and smoking cigarettes, which finally resulted in complete cigarette smoking cessation. As such, further study is indicated on the benefit of erenumab and other calcitonin gene-related peptide antagonists in migraineurs who smoke to promote smoking cessation.

Aberrant integrin αv and α5 expression in prostate adenocarcinomas and bone-metastases is consistent with a bone-colonizing phenotype.

BACKGROUND: Collaborative signaling between fibronectin-binding αv and α5 integrins has been implicated in the lethal dissemination of prostate cancer in the bone-metastatic niche, the major source of morbidity and mortality in the disease. METHODS: We assessed the frequency and pattern of expression of these integrins in primary high-grade adenocarcinomas and bone metastases compared to the physiological gland. Formalin-fixed paraffin-embedded (FFPE) radical prostatectomy (RP) samples (n=25) containing ≥ Gleason grade 4 cancer and decalcified surgical or diagnostic bone metastatic samples from 10 patients were stained for integrin αv (ITGAV) and integrin α5 (ITGA5) expression. Antibody optimization and antigen-retrieval was performed beforehand. RESULTS: ITGAV was exclusively expressed in the basal layer of physiological prostate glands whereas αv expression was invariably recapitulated in the malignant gland and bone metastases (100%) in multiple distinct patterns: epithelial membranous, basilar/luminal membranous, punctate cytoplasmic, intense foci as single cells or clusters, and rim stromal layers. The luminal/basilar layer of ITGAV expression was striking in cribriform carcinomas, suggestive of a role in molecular pathogenesis. ITGA5 infrequently highlighted the basal layer of the physiological gland, was absent in primary adenocarcinoma, but was expressed with ITGAV exclusively in bone metastases (71%). CONCLUSIONS: We conclude that ITGAV expression is aberrantly expressed in high frequency in high-grade prostatic adenocarcinomas in patterns suggestive of recapitulated basal cell functions, consistent with a stem-regulatory role that has been proposed. Co-expression and enrichment of αv and α5 in osseous metastases supports their proposed collaborative role in colonization of the bone microenvironment and as candidate targets for therapy.