SUNCT, SUNA and short-lasting unilateral neuralgiform headache attacks: Debates and an update.

BACKGROUND: Short-lasting unilateral neuralgiform headache attacks (SUNHA) have the features of both short-lasting unilateral neuralgiform pain, such as trigeminal neuralgia or stabbing headache, and associated trigeminal autonomic symptoms, such as paroxysmal hemicrania or cluster headache. Recognizing and adequately treating SUNHA is essential but current treatment methods are ineffective in treating SUNHA. METHODS: We reviewed the changes in the concept of short-lasting unilateral neuralgiform headache attacks and provide a narrative review of the current medical and surgical treatment options, from the first choice of treatment for patients to treatments for selective intractable cases. RESULTS: Unlike the initial impression of an intractable primary headache disorder affecting older men, SUNHA affects both sexes throughout their lifespan. One striking feature of SUNHA is that the attacks are triggered by cutaneous or intraoral stimulation. The efficacy of conventional treatments is disappointing and challenging, and preventive therapy is the mainstay of treatment because of highly frequent attacks of a very brief duration. Amongst them, lamotrigine is effective in approximately two-third of the patients with SUNHA, and intravenous lidocaine is essential for the management of acute exacerbation of intractable pain. Topiramate, oxcarbazepine and gabapentin are considered good secondary options for SUNHA, and botulinum toxin can be used in selective cases. Neurovascular compression is commonly observed in SUNHA, and surgical approaches, such as neurovascular compression, have been reported to be effective for intractable cases. CONCLUSIONS: Recent advances in the understanding of SUNHA have improved the recognition and treatment approaches for this unique condition.

Effect of prednisolone for the treatment of medication-overuse headache: A 3-month result from a multicenter REgistry for Load and management of mEdicAtion overuSE headache (RELEASE) study.

OBJECTIVE: To evaluate the efficacy of prednisolone in the treatment of medication-overuse headache (MOH) using data from a multicenter prospective registry (Registry for Load and Management of Medication Overuse Headache [RELEASE]). BACKGROUND: The treatment of MOH is challenging, especially when withdrawal headache manifests during the cessation of overused medication. Although systemic corticosteroids have been empirically used to reduce withdrawal headaches, their efficacy on the long-term outcomes of MOH has not been documented. METHODS: This was a post hoc analysis of the RELEASE study. The RELEASE is an ongoing multicenter observational cohort study in which patients with MOH have been recruited from seven hospitals in Korea since April 2020. Clinical characteristics, disease profiles, treatments, and outcomes were assessed at baseline and specific time points. We analyzed the effect of prednisolone on MOH reversal at 3 months. RESULTS: Among the 309 patients enrolled during the study period, prednisolone was prescribed to 59/309 (19.1%) patients at a dose ranging from 10 to 40 mg/day for 5-14 days; 228/309 patients (73.8%) completed the 3-month follow-up period. The MOH reversal rates at 3 months after baseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the non-prednisolone group (p = 0.034). The effect of steroids remained significant (adjusted odds ratio 2.78, 95% confidence interval 1.27-6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of preventive medications combined. CONCLUSIONS: Although our observational study could not draw a definitive conclusion, prednisolone may be effective in the treatment of MOH.

Clinical profile and treatment outcomes of idiopathic intracranial hypertension: a multicenter study from Korea.

BACKGROUND: Currently, there is a relative lack of detailed reports regarding clinical presentation and outcome of idiopathic intracranial hypertension in Asians. This study aims to describe the clinical features and treatment outcomes of Korean patients with idiopathic intracranial hypertension. METHODS: We prospectively recruited patients with idiopathic intracranial hypertension from one hospital and retrospectively analyzed the medical records of 11 hospitals in Korea. We collected data regarding preceding medical conditions or suspected medication exposure, headache phenotypes, other associated symptoms, detailed neuroimaging findings, treatments, and outcomes after 1-2 and 3-6 months of treatment. RESULTS: Fifty-nine (83.1% women) patients were included. The mean body mass index was 29.11 (standard deviation, 5.87) kg/m2; only 27 patients (45.8%) had a body mass index of ≥ 30 kg/m2. Fifty-one (86.4%) patients experienced headaches, patterns of which included chronic migraine (15/51 [29.4%]), episodic migraine (8/51 [15.7%]), probable migraine (4/51 [7.8%]), chronic tension-type headache (3/51 [5.9%]), episodic tension-type headache (2/51 [3.9%]), probable tension-type headache (2/51 [3.9%]), and unclassified (17/51 [33.3%]). Medication overuse headache was diagnosed in 4/51 (7.8%) patients. After 3-6 months of treatment, the intracranial pressure normalized in 8/32 (25.0%), improved in 17/32 (53.1%), no changed in 7/32 (21.9%), and worsened in none. Over the same period, headaches remitted or significantly improved by more than 50% in 24/39 patients (61.5%), improved less than 50% in 9/39 (23.1%), and persisted or worsened in 6/39 (15.4%) patients. CONCLUSION: Our findings suggest that the features of Asian patients with idiopathic intracranial hypertension may be atypical (i.e., less likely obese, less female predominance). A wide spectrum of headache phenotypes was observed. Medical treatment resulted in overall favorable short-term outcomes; however, the headaches did not improve in a small proportion of patients.

Integrated Genomic and Clinicopathologic Approach Distinguishes Pancreatic Grade 3 Neuroendocrine Tumor From Neuroendocrine Carcinoma and Identifies a Subset With Molecular Overlap.

Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Although current recommendations suggest that immunohistochemistry for p53, Rb, ATRX, and DAXX can distinguish most cases, some cases remain difficult to classify using this approach. In this study, we reviewed 47 high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains, we performed capture-based sequencing of approximately 500 cancer genes and immunohistochemistry for p16 and trypsin or chymotrypsin. Using an integrated molecular and clinicopathologic approach, 42 (89%) of 47 cases had a clear final diagnosis of either G3 PanNET (n = 17), PanNEC (n = 17), or mixed acinar-NEC (n = 8). The 17 G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. The 17 PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was coaltered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. The 8 acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Five cases remained difficult to classify, 3 of which exhibited overlapping molecular features with alterations in MEN1 with or without ATRX, and RB1 with or without TP53, making it unclear whether to classify as PanNET or PanNEC. Our data demonstrate that molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.

Treatment pattern and response for cluster headache in Korea: A prospective multicenter observation study.

BACKGROUND: Only limited data are available regarding the treatment status and response to cluster headache in an Asian population. Therefore, this study aimed to provide a real-world treatment pattern of cluster headache and the response rate of each treatment in an Asian population. METHODS: Patients with cluster headache were recruited between September 2016 and January 2019 from 16 hospitals in Korea. At the baseline visit, we surveyed the patients about their previous experience of cluster headache treatment, and acute and/or preventive treatments were prescribed at the physician's discretion. Treatment response was prospectively evaluated using a structured case-report form at 2 ± 2 weeks after baseline visit and reassessed after three months. RESULTS: Among 295 recruited patients, 262 experiencing active bouts were included. Only one-third of patients reported a previous experience of evidence-based treatment. At the baseline visit, oral triptans (73.4%), verapamil (68.3%), and systemic steroids (55.6%) were the three most common treatments prescribed by the investigators. Most treatments were given as combination. For acute treatment, oral triptans and oxygen were effective in 90.1% and 86.8% of the patients, respectively; for preventive treatment, evidence-based treatments, i.e. monotherapy or different combinations of verapamil, lithium, systemic steroids, and suboccipital steroid injection, helped 75.0% to 91.8% of patients. CONCLUSION: Our data provide the first prospective analysis of treatment responses in an Asian population with cluster headache. The patients responded well to treatment despite the limited availability of treatment options, and this might be attributed at least in part by combination of medications. Most patients were previously undertreated, suggesting a need to raise awareness of cluster headache among primary physicians.

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.

Li-Ion Intercalation, Rectification, and Solid Electrolyte Interphase in Molecular Tunnel Junctions.

This paper describes Li-ion intercalation into a pyrenyl-terminated self-assembled monolayer (SAM) on gold, inspired by the graphite anode in a Li-ion battery, and its effect on tunneling performance in a molecular junction incorporating the SAM. As the concentration of the Li-ion precursor ([LiPF6]) increased from 0 to 10-2 M, the rectification ratio increased to ∼102. Further experiments revealed that the intercalation-induced changes in the orientation of PYR group and in the HOMO energy level account for the enhanced rectification. Treatment with high concentrations of LiPF6 (from 10-2 to 100 M) yielded a considerable solid electrolyte interphase (SEI), mainly composed of LiF, on the surface of the SAM, resulting in the disappearance of rectification. This was attributed to renormalization of the HOMO level back to that of the intact SAM, caused by the SEI layer. Our work demonstrates the interplay among Li-ion intercalation, SEI, and tunneling in the molecular junction, benefiting the research of molecular electronics as well as SAM-based batteries.

Preventive therapy with galcanezumab for two consecutive cluster bouts in patients with episodic cluster headache: an observational multicenter study.

BACKGROUND: Cluster headache is a severe and disabling primary headache disorder. Galcanezumab is a monoclonal antibody against calcitonin gene-related peptide and a preventive therapy for episodic cluster headache. However, the approval and insurance coverage for episodic cluster headache differ in each country. Additionally, the consistency of efficacy of galcanezumab therapy has not yet been evaluated. This study aimed to assess the efficacy and safety of 240 mg of galcanezumab therapy for consecutive cluster bouts in patients with episodic cluster headache. METHODS: The study enrolled patients with episodic cluster headache who received two courses of galcanezumab therapy at three university hospitals in Republic of Korea between February 2020 and April 2022. The efficacy and safety of galcanezumab were analyzed by comparing daily headache frequency, the number of headache days, and headache intensity and adverse effects during the one-week period before and the third week after galcanezumab injection for each episode of cluster bouts. Paired t-test was used for comparing repeated data from different episodes of cluster bout. RESULTS: Sixteen patients were enrolled in this study. Fourteen patients received galcanezumab therapy for two consecutive cluster bouts. Galcanezumab was administered 24 days and 11 days after the first and second cluster bouts, respectively. The proportion of patients with 50% or more reduction in frequency of daily headache at week 3 from baseline was 86% and 64% during the first and second episodes, respectively. The proportion of patients who received transitional therapy before galcanezumab therapy was higher in the first episode of cluster bout than that in the second episode of cluster bout. No serious adverse reactions or significant differences in adverse effects between cluster bouts were noticed. Two patients received a second galcanezumab therapy during the pre-cluster period, and their cluster periods ended without typical cluster headache attacks 10-60 days after galcanezumab therapy. CONCLUSIONS: This exploratory analysis suggests that galcanezumab may be effective as a preventive therapy in subsequent cluster bouts. Patients with episodic cluster headaches who underwent galcanezumab therapy tended to receive a second round of treatment in the early stages of their next cluster bout without transitional therapy.

Health equity, care access and quality in headache - part 2.

BACKGROUND: Headache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide. MAIN BODY: Organized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages. Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited. Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies. CONCLUSIONS: Healthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.

Rethinking headache as a global public health case model for reaching the SDG 3 HEALTH by 2030.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Cilostazol Versus Aspirin on White Matter Changes in Cerebral Small Vessel Disease: A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. METHODS: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. RESULTS: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02-0.89]). CONCLUSIONS: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01932203.

Interim analysis of the Registry for Load and Management of Medication Overuse Headache (RELEASE): A multicenter, comprehensive medication overuse headache registry.

BACKGROUND: Characteristics, disabilities, and optimal management of medication overuse headache remain uncertain. This study aimed to elucidate the clinical characteristics of patients with medication overuse headache enrolled in a medication overuse headache registry in Korea. METHODS: The Registry for Load and Management of MEdicAtion OveruSE Headache (RELEASE), a cross-sectional prospective observational study including seven referral headache centers in Korea, started enrolling adult patients with medication overuse headache in April 2020. Data included information on headache characteristics, burden on daily function, depression, anxiety, history of acute and preventive medications, and treatment strategies. RESULTS: A total of 229 patients (85.6% females; mean age, 45.5 ± 13.5 years) were enrolled by June 2021. The average durations of chronic headaches and medication overuse were 6.5 and 4.3 years, respectively. In the past month before enrollment, patients had headaches for 25 days and severe headaches for 12 days, and used acute medications for 20 days. Patients were disabled in 66.8 days in the past 3 months and had moderate/severe depression and anxiety in 56% and 35%, respectively. The proportion of patients on preventive treatments increased from 38% to 93% during the study period. CONCLUSIONS: RELEASE study reflects the current management status and opportunities to improve the quality of care in patients with medication overuse headache.

Characteristics of pre-cluster symptoms in cluster headache: A cross-sectional multicentre study.

BACKGROUND: Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache. METHODS: In this multicentre study, 184 patients with episodic cluster headache were recruited between October 2018 and December 2020. They were interviewed by investigators and completed a structured questionnaire. To investigate pre-cluster and pre-attack symptoms, we assessed 20 symptoms and signs using the questionnaire. RESULTS: The upcoming cluster bout was predictable in 35.3% (n = 65/184) of the patients. When present, pre-cluster symptoms occurred at a median duration of 7 days (interquartile range, 2.3-14 days) before the onset of the cluster bout. Patients with pre-cluster symptoms showed a higher proportion of women, prevalence of pre-attack symptoms and seasonal rhythmicity, frequency of cluster headache attacks per day, and total number of cluster bouts compared to patients without pre-cluster symptoms. In univariable and multivariable logistic regression analyses, female sex was associated with the predictability of pre-cluster symptoms (odds ratio = 2.297, p = 0.016). CONCLUSIONS: The upcoming cluster bout was predicted in approximately 35% of patients with episodic cluster headache, which may allow for an earlier preventive treatment and help understand the pathophysiology.

Crystal-clear days and unclear days in migraine: A population-based study.

OBJECTIVE: To investigate crystal-clear days and unclear days in participants with migraine. BACKGROUND: Migraine affects individuals during the headache-free period. Therefore, headache-free days do not indicate migraine symptom-free days. Crystal-clear days can be characterized by days without headache and having minimal or no migraine symptoms. In contrast, days without headache, but with more than minimal migraine symptoms, can be defined as unclear days. METHODS: We used the baseline respondent data set of the Circannual Change in Headache and Sleep study, a nationwide population survey on headache and sleep. This study was a cross-sectional and case-control analysis of longitudinally collected data. The number of crystal-clear days per 30 days was assessed by asking "How many days have you had crystal-clear days without headache during the previous 30 days?". We defined headache-free, but not crystal-clear days, as unclear days. The number of unclear days per 30 days was calculated as follows: 30 - the number of headache days per 30 days - the number of crystal-clear days per 30 days. RESULTS: Of 170 participants with migraine, 165 (97.1%) had unclear days. The numbers of crystal-clear days (median [interquartile range] 20.0 [15.0-25.0] vs. 25.0 [20.0-29.0], p < 0.001) and unclears days (4.0 [0.0-8.0] vs. 1.0 [0.0-7.0], p < 0.001) per 30 days in participants with migraine were significantly lower and higher, respectively, than in those with non-migraine headache. Headache days (incident rate ratio and 95% confidence interval, 0.94 [0.90-0.97], p < 0.001) and weekly average sleep duration (0.95 [0.91-1.00], p = 0.035) were significant factors for crystal-clear days. CONCLUSIONS: The number of crystal-clear days were different from that of headache-free days. Almost all participants with migraine had unclear days. Our findings will facilitate understanding the symptoms and burden of migraine.

Clinical characteristics of medication-overuse headache according to the class of acute medication: A cross-sectional multicenter study.

OBJECTIVE: To characterize the clinical features of patients with medication-overuse headache (MOH) according to the class of acute medications being overused. BACKGROUND: MOH is a common global health problem, severely disabling the majority of the patients affected. Although various medications can cause MOH, whether clinical features differ according to the overused medication type remains unclear. METHODS: We analyzed data from a multicenter cross-sectional study in neurology clinics in Korea from April 2020 to June 2021. RESULTS: Among 229 eligible patients, MOH was documented in patients who overused multiple drug classes (69/229, 30.1%; most frequent occurrence), triptans (50/229, 21.8%), non-opioid analgesics (48/229, 21.0%), and combination-analgesics (40/229, 17.4%). Patients who overused multiple drug classes reported more frequent use of acute medications (median [25th-75th percentiles]: 25.0 [15.0-30.0] vs. 17.5 [10.0-25.5] days/month, p = 0.029) and fewer crystal-clear days (0.0 [0.0-9.5] vs. 9.0 [0.0-10.0] days/month, p = 0.048) than those who overused triptans. Patients who overused multiple drug classes also reported shorter intervals from chronic daily headache to the onset of MOH than patients who overused combination-analgesics (0.6 [0.2-1.9] vs. 2.4 [0.7-5.4] years, p = 0.001) or non-opioid analgesics (1.5 [0.6-4.3] years, p = 0.004). Patients who overused multiple drug classes reported more emergency room visits (1.0 [0.0-1.0] visits/year) than those who overused combination-analgesics (0.0 [0.0-1.0], p = 0.024) or non-opioid analgesics (0.0 [0.0-1.0], p = 0.030). Patients who overused triptans reported fewer headache days (21.0 [20.0-30.0] vs. 30.0 [20.5-30.0] days/month, p = 0.008) and fewer severe headache days (7.0 [4.0-10.0] vs. 10.0 [5.0-15.0] days/month, p = 0.017) than those who overused non-opioid analgesics. CONCLUSIONS: Some clinical characteristics of MOH significantly differed according to the class of overused medications. The findings from this study may contribute to the understanding of the clinical characteristics and pathophysiology of MOH.

Visceral Adipose Tissue Inflammation and Radiographic Visceral-to-Subcutaneous Adipose Tissue Ratio in Patients with Cirrhosis.

BACKGROUND AND AIMS: Accumulation of visceral adipose tissue is associated with hepatic inflammation and fibrosis, suggestive of its metabolic and inflammatory properties. We aimed to examine the histologic findings of visceral and subcutaneous adipose tissue and to associate these findings with clinical and radiologic characteristics in patients with cirrhosis. METHODS: Included were 55 adults with cirrhosis who underwent liver transplantation from 3/2017-12/2018 and had an abdominal computed tomography (CT) scan within 6 months prior to transplant. Visceral-to-subcutaneous adipose tissue ratio (VSR) was calculated using visceral (VATI) and subcutaneous adipose tissue index (SATI) quantified by CT at the L3-vertebral level and normalized for height (cm2/m2). VAT (greater omentum), SAT (abdominal wall), and skeletal muscle (rectus abdominis) biopsies were collected at transplant. RESULTS: Majority of patients had VAT inflammation (71%); only one patient (2%) had SAT inflammation. Patients with VAT inflammation had similar median VATI (42 vs 41 cm2/m2), lower median SATI (64 vs 97 cm2/m2), and higher median VSR (0.63 vs 0.37, p = 0.002) than patients without inflammation. In univariable logistic regression, VSR was associated with VAT inflammation (OR 1.47, 95%CI 1.11-1.96); this association remained significant even after adjusting for age, sex, BMI, HCC, or MELD-Na on bivariable analyses. CONCLUSION: In patients with cirrhosis undergoing liver transplantation, histologic VAT inflammation was common, but SAT inflammation was not. Increased VSR was independently associated with VAT inflammation. Given the emerging data demonstrating the prognostic value of VSR, our findings support the value of CT-quantified VSR as a prognostic marker for adverse outcomes in the liver transplant setting.

Comment regarding: what is the efficacy of aerobic exercise versus strength training in the treatment of migraine? A systematic review and network meta­analysis of clinical trials.

In Woldeamanuel and Oliveira (2022)'s article about the efficacy of exercise in the treatment of migraine, the ranking of the efficacy of strength training (mean difference, - 3.55), aerobic exercise (mean difference, - 2.18 to - 3.13), topiramate (mean difference, - 0.98), and amitriptyline (mean difference, 3.82) using network meta-analysis can mislead readers. First, the inclusion criteria were reported at a monthly frequency of migraine and the end of the intervention, but some article did not meet the inclusion criteria or had data inconsistency. Second, there was an inconsistency in the placebos used in the included studies, which can be problematic in network meta-analysis. Third, all three articles on strength training were rated as high-risk or exhibited some risk of bias. Finally, the effectiveness of this statistical method is questionable for assessing physical activities because strength training, aerobic exercise, and preventive medications can be simultaneously recommended for possible synergistic effects in the prevention of migraine.

Real-world experience with 240 mg of galcanezumab for the preventive treatment of cluster headache.

BACKGROUND: Galcanezumab of 300 mg monthly is the FDA approved preventive medication for cluster headache (CH) during the cluster period. Compared to the 120 mg galcanezumab syringe for the treatment of migraines, the 100 mg syringe for CH has globally not been as widely available. The aim of our study was to investigate the preventive efficacy and tolerability of two 120 mg galcanezumab doses for episodic CH in clinical practices. METHODS: We evaluated patients with CH who received at least 1 dose of 240 mg (2 prefilled syringe of 120 mg) of galcanezumab in the 3 university hospitals from February 2020 to September 2021. In the patients with episodic CH, the efficacy and safety data of galcanezumab were analyzed regarding to the presence of the conventional preventive therapy at the timing of therapy of galcanezumab. The data of other subtypes of CH were separately described. RESULTS: In 47 patients with episodic CH, galcanezumab was started median 18 days after the onset of current bout (range 1-62 days) and 4 patients (10.8%) received second dose of galcanezumab. The median time to the first occurrence of 100% reduction from baseline in CH attacks per week after galcanezumab therapy was 17 days (25% to 75% quartile range: 5.0 ~ 29.5) in all patients with episodic CH, 15.5 days (3.8 ~ 22.1) in 36 patients with galcanezumab therapy add-on conventional preventive therapy, 21.0 days (12.0 ~ 31.5) in 11 patients started galcanezumab as initial preventive therapy. Among 33 patients with headache diary, the proportion of patients with 50% or more reduction in weekly CH attacks at week 3 from baseline were 78.8%. There was no significant difference in the proportion of patients with a reduction of at least 50% in weekly frequency of CH attacks at week 3 between 24 patients received galcanezumab therapy add-on conventional preventive therapy and 9 patient who received initial galcanezumab therapy. (83.3%, vs 66.7%, p = 0.36). There were no significant differences in proportion of "very much better or "much better" between 36 patients received galcanezumab therapy add-on conventional preventive therapy and 11 patient who received initial GT (86.1%, vs 63.6%, p = 0.18). CONCLUSION: One 240 mg dose of galcanezumab with/without conventional therapy for the prevention of CH is considered effective and safe in clinical practices, as seen in the clinical trial of galcanezumab.

Long COVID headache.

Headache is among the most frequent symptoms persisting or newly developing after coronavirus disease 2019 (COVID-19) as part of the so-called long COVID syndrome. The knowledge on long COVID headache is still limited, however growing evidence is defining the features of this novel condition, in particular regarding clinical characteristics, some pathophysiological mechanisms and first treatment recommendations. Long COVID headache can present in the form of worsening of a preexisting primary headache, or, more specifically, in the form of a new (intermittent or daily) headache starting during the acute infection or after a delay. It often presents together with other long COVID symptoms, most frequently with hyposmia. It can manifest with a migrainous or, more frequently, with a tension-type-like phenotype. Persistent activation of the immune system and trigeminovascular activation are thought to play a role. As there are virtually no treatment studies, treatment currently is largely guided by the existing guidelines for primary headaches with the corresponding phenotype. The present report, a collaborative work of the international group of the Junior Editorial Board of The Journal of Headache and Pain aims to summarize the most recent evidence about long COVID headache and suggests approaches to the diagnosis and treatment of this disorder.

Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma.

BACKGROUND: Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. METHODS: Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. RESULTS: We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. CONCLUSIONS: Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.