The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.

Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Repeat percutaneous rhizotomy for trigeminal neuralgia is not associated with an increased risk of postoperative complications.

BACKGROUND AND OBJECTIVES: Patients undergoing percutaneous rhizotomy for trigeminal neuralgia (TN) may require several procedures to manage their pain. However, it is not fully understood whether repeat procedures influence postoperative complication rates. METHODS: We retrospectively reviewed patients undergoing rhizotomy at our institution from 2011 to 2022. Patients were included only if they had no history of prior interventions including microvascular decompression (MVD) or radiosurgery. We collected baseline patient information, pain characteristics, and postoperative complications for each patient. Patients were dichotomized into those undergoing primary rhizotomy versus those undergoing a repeat rhizotomy. Potential drivers of postoperative complications were included in a multivariate logistic regression model. RESULTS: Of the 1904 cases reviewed, 965 met our inclusion criteria. 392 patients underwent primary rhizotomy, and 573 patients underwent repeat rhizotomies. The repeat rhizotomy group was significantly older, p<0.001. Patients in the repeat rhizotomy group expressed higher frequencies of bilateral pain, p=0.01. Patients in the repeat rhizotomy group demonstrated a significantly higher rate of preoperative numbness and postoperative numbness, p<0.001. There were no significant differences in any of the considered complications between the single rhizotomy and repeat rhizotomy groups. On multivariate logistic regression, repeat rhizotomy did not predict an increased risk of any postoperative complications, p=0.14. CONCLUSIONS: Patients undergoing repeat rhizotomy may be at risk of postoperative numbness but are not at increased risk for postoperative complications. These results are of use to patients who are poor surgical candidates, and thus may require multiple rhizotomies to effectively manage their pain over time.

The Path to a Match for Interventional Cardiology Fellowship: A Major SCAI Initiative.

The field of interventional cardiology (IC) has evolved dramatically over the past 40 years. Training and certification in IC have kept pace, with the development of accredited IC fellowship training programs, training statements, and subspecialty board certification. The application process, however, remained fragmented with lack of a universal process or time frame. In recent years, growing competition among training programs for the strongest candidates resulted in time-limited offers and high-pressure situations that disadvantaged candidates. A grassroots effort was recently undertaken by a Society for Cardiovascular Angiography & Interventions task force, to create equity in the system by establishing a national Match for IC fellowship. This manuscript explores the rationale, process, and implications of this endeavor.

Diagnosis to Ablation in Persistent AF: Any Time Can Be a Good Time to Ablate.

BACKGROUND: Nonrandomized data suggest that longer diagnosis-to-ablation time (DAT) is associated with poorer outcomes; however, a recent randomized trial found no difference in recurrences when ablation was delayed by 12 months. OBJECTIVES: This study sought to assess the impact of DAT on atrial fibrillation (AF) recurrence in patients undergoing catheter ablation for persistent AF. METHODS: CAPLA (Effect of Catheter Ablation Using Pulmonary Vein Isolation With vs Without Posterior Left Atrial Wall Isolation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation: The CAPLA randomized clinical trial) was a multicenter trial that randomized patients with persistent AF to pulmonary vein isolation + posterior wall isolation or pulmonary vein isolation alone. Follow-up was 12 months. Outcomes were assessed after a 3-month blanking period. RESULTS: Median DAT in the 334 patients was 28 months (Q1-Q3: 12-66 months). Patients were divided into quartile groups: Q1 was DAT 0 to 12 months (n = 84, median DAT 7 months), Q2 was DAT 13 to 28 months (n = 85, median DAT 20 months), Q3 was DAT 29 to 66 months (n = 84, median DAT 41 months), and Q4 was DAT ≥67 months (n = 81, median DAT 119 months). AF recurrence rate was 36.9% for Q1, 44.7% for Q2, 47.6% for Q3, and 56.8% for Q4 (P = 0.082). On multivariable analysis, DAT Q4 was the only factor significantly associated with risk of recurrence (HR: 1.607; 95% CI: 1.005-2.570; P = 0.048). Median AF burden was 0% (Q1-Q3: 0%-0.47%) in Q1 and 0.33% (Q1-Q3: 0%-4.6%) in Q4 (P = 0.002). Quality of life (assessed by the Atrial Fibrillation Effect on Quality-of-Life questionnaire) improved markedly in all quartiles (Q1: Δ28.8 ± 24, Q2: Δ24.4 ± 23.4, Q3: Δ21.7 ± 26.6, Q4: Δ24.6 ± 21.4; P = 0.331). CONCLUSIONS: In a cohort of patients with persistent AF undergoing ablation in a prospective trial with standardized entry criteria and intensive electrocardiogram monitoring, those with shorter DAT had lower rates of AF recurrence. However, differences were modest, and all quartiles demonstrated very low AF burden and improvements in quality of life.

A history of stereotactic radiosurgery may predict failure of procedure following percutaneous glycerol rhizotomy for trigeminal neuralgia.

BACKGROUND: Both stereotactic radiosurgery (SRS) and percutaneous glycerol rhizotomy are excellent options to treat TN in patients unable to proceed with microvascular decompression. However, the influence of prior SRS on pain outcomes following rhizotomy is not well understood. METHODS: We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 2011 to 2022. Only patients undergoing percutaneous glycerol rhizotomy following SRS (SRS-rhizotomy) or those undergoing primary glycerol rhizotomy were considered. We collected basic demographic, clinical, and pain characteristics for each patient. Additionally, we characterized pain presentation and perioperative complications. Immediate failure of procedure was defined as presence of TN pain symptoms within 1-week of surgery, and short-term failure was defined as presence of TN pain symptoms within 3-months of surgery. A multivariate logistic regression model was used to evaluate the relationship of a history SRS and failure of procedure following percutaneous glycerol rhizotomy. RESULTS: Of all patients reviewed, 30 had a history of SRS prior to glycerol rhizotomy whereas 371 underwent primary percutaneous glycerol rhizotomy. Patients with a history of SRS were more likely to endorse V3 pain symptoms, p = 0.01. Additionally, patients with a history of SRS demonstrated higher preoperative BNI pain scores, p = 0.01. Patients with a history of SRS were more likely to endorse preoperative numbness, p < 0.0001. A history of SRS was independently associated with immediate failure [OR = 5.44 (2.06-13.8), p < 0.001] and short-term failure of glycerol rhizotomy [OR = 2.41 (1.07-5.53), p = 0.03]. Additionally, increasing age was found to be associated with lower odds of short-term failure of glycerol rhizotomy [OR = 0.98 (0.97-1.00), p = 0.01] CONCLUSIONS: A history of SRS may increase the risk of immediate and short-term failure following percutaneous glycerol rhizotomy. These results may be of use to patients who are poor surgical candidates and require multiple noninvasive/minimally invasive options to effectively manage their pain.

The impact of lifestyle factors on atrial fibrillation.

Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.

Strategies to prevent cardiovascular disease in Singapore: A call to action from Singapore Heart Foundation, Singapore Cardiac Society and Chapter of Cardiologists of the Academy of Medicine, Singapore.

Introduction: In 2022, the Minister for Health of Singapore launched Healthier SG, a national strategy in championing the shift towards a population health approach. Method: The Singapore Heart Foundation conducted a series of roundtable discussions, also attended by representatives of the Singapore Cardiac Society and the Chapter of Cardiologists of the Academy of Medicine Singapore. During the meetings, the authors formulated interventions supportive of Healthier SG that specifically aimed to uplift the state of cardiovascular (CV) preventive care in Singapore. Results: In line with Healthier SG, the authors propose a 3-pronged approach ("Healthier Heart SG") to augment the success of Healthier SG in achieving good CV outcomes. This proposal includes the following components: (1) a call to update the standards of care in addressing the 5 main modifiable risk factors of cardiovascular disease (CVD); (2) patient education through cooperation between healthcare professionals and community partners for a whole-of-system approach; and (3) support for integrated care, including access to cardiac rehabilitation in the community, improved referral processes and access to nutrition/dietetics counselling and tobacco cessation, optimal use of information technology, and continued CV research. Conclusion: Healthier Heart SG would bring the standards of care and CV care delivery in Singapore closer to achieving the vision of proactive prevention of CVD and CV morbidity and mortality. This can only be achieved through the concerted efforts of healthcare professionals, policymakers and community partners, coupled with the cooperation of community members.

Impact of Posterior Wall Isolation During AF Ablation on the Incidence of Left Atrial Flutter.

BACKGROUND: Linear and complex electrogram ablation (LCEA) beyond pulmonary vein isolation (PVI) is associated with an increase in left atrial macro-re-entrant tachycardias (LAMTs). Posterior wall isolation (PWI) is increasingly performed to improve AF ablation outcomes. However, the impact of PWI on the incidence of LAMT is unknown. OBJECTIVES: The purpose of this study was to establish the incidence of LAMT following PVI alone vs PVI + PWI vs PVI + PWI + LCEA. METHODS: Consecutive patients undergoing catheter ablation for AF or LAMT post-AF ablation between 2008 and 2022 from 4 electrophysiology centers were reviewed with a minimum follow-up of 12 months. RESULTS: In total, 5,619 (4,419 index, 1,100 redo) AF ablation procedures were performed in 4,783 patients (mean age 60.9 ± 10.6 years, 70.7% men). Over a mean follow-up of 6.4 ± 3.8 years, 246 procedures for LAMT were performed in 214 patients at a mean of 2.6 ± 0.6 years post-AF ablation. Perimitral (52.8% of patients), roof-dependent (27.1%), PV gap-related (17.3%), and anterior circuits (8.9%) were most common, with 16.4% demonstrating multiple circuits. The incidence of LAMT was significantly higher following PVI + PWI (6.2%) vs PVI alone (3.0%; P < 0.0001) and following PVI + PWI + LCEA vs PVI + PWI (12.5%; P = 0.019). Conduction gaps in previous ablation lines were responsible for LAMT in 28.4% post-PVI alone, 35.3% post-PVI + PWI (P = 0.386), and 81.8% post-PVI + PWI + LCEA (P < 0.005). CONCLUSIONS: The incidence of LAMT following PVI + PWI is higher than with PVI alone but significantly lower than with more extensive atrial substrate modification. Given a low frequency of LAMT following PWI, empiric mitral isthmus ablation is not justified and may be proarrhythmic.

Glioma.

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

Intra- and post-pandemic impact of the COVID-19 outbreak on Stanford Health Care.

Stanford Health Care, which provides about 7% of overall healthcare to approximately 9 million people in the San Francisco Bay Area, has undergone significant changes due to the opening of a second hospital in late 2019 and, more importantly, the COVID-19 pandemic. We examine the impact of these events on anatomic pathology (AP) cases, aiming to enhance operational efficiency in response to evolving healthcare demands. We extracted historical census, admission, lab tests, operation, and AP data since 2015. An approximately 45% increase in the volume of laboratory tests (P < 0.0001) and a 17% increase in AP cases (P < 0.0001) occurred post-pandemic. These increases were associated with progressively increasing (P < 0.0001) hospital census. Census increase stemmed from higher admission through the emergency department (ED), and longer lengths of stay mostly for transfer patients, likely due to the greater capability of the new ED and changes in regional and local practice patterns post-pandemic. Higher census led to overcapacity, which has an inverted U relationship that peaked at 103% capacity for AP cases and 114% capacity for laboratory tests. Overcapacity led to a lower capability to perform clinical activities, particularly those related to surgical procedures. We conclude by suggesting parameters for optimal operations in the post-pandemic era.

External assessment of preoperative scores for predicting outcome after microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Recently, two scoring systems have been developed for predicting pain-free outcomes after microvascular decompression (MVD). Evaluation of these scores on large external datasets has been limited. In this study, the authors aimed to evaluate the performance of published MVD scoring systems in predicting pain-free outcome. METHODS: A total of 458 patients who underwent MVD for trigeminal neuralgia (TN) between 2007 and 2020 and had at least 6 months of follow-up were included in this study. Hardaway and Panczykowski scores were retrospectively computed for each patient and compared with postoperative pain recurrence and pain-free duration. RESULTS: The mean ± SD area under the receiver operating characteristic curve for predicting any pain recurrence after MVD was 0.567 ± 0.081 using the Hardaway score and 0.546 ± 0.085 using the Panczykowski score. On log-rank tests and Kaplan-Meier analysis, the patients with Hardaway scores of 0-2 had significantly shorter pain-free survival times after MVD than did those with a score of 3. Patients with a Panczykowski score of 1 had a significantly shorter pain-free duration after surgery compared with both patients with scores of 2-3 and patients with scores of 4-5. Patients with Panczykowski scores of 2-3 also had significantly shorter pain-free duration compared with patients with scores of 4-5. CONCLUSIONS: Both the Hardaway and Panczykowski scores may be useful for predicting postoperative pain-free duration in TN patients, and their utility may be greatest when scores are clustered. Continued refinement of both scoring systems will help to improve our ability to predict patient outcomes after MVD.

Preoperative Opioid Use and Postoperative Outcomes in Patients Undergoing Microvascular Decompression for Trigeminal Neuralgia.

BACKGROUND AND OBJECTIVES: The prescription of opioid analgesics for trigeminal neuralgia (TN) is controversial, and their effect on postoperative outcomes for patients with TN undergoing microvascular decompression (MVD) has not been reported. We aimed to describe the relationship between preoperative opioid use and postoperative outcomes in patients with TN undergoing MVD. METHODS: We reviewed the records of 920 patients with TN at our institution who underwent an MVD between 2007 and 2020. Patients were sorted into 2 groups based on preoperative opioid usage. Demographic information, comorbidities, characteristics of TN, preoperative medications, pain and numbness outcomes, and recurrence data were recorded and compared between groups. Multivariate ordinal regression, Kaplan-Meier survival analysis, and Cox proportional hazards were used to assess differences in pain outcomes between groups. RESULTS: One hundred and forty-five (15.8%) patients in this study used opioids preoperatively. Patients who used opioids preoperatively were younger ( P = .04), were more likely to have a smoking history ( P < .001), experienced greater pain in modified Barrow Neurological Institute pain score at final follow-up ( P = .001), and were more likely to experience pain recurrence ( P = .01). In addition, patients who used opioids preoperatively were more likely to also have been prescribed TN medications including muscle relaxants and antidepressants preoperatively ( P < .001 and P < .001, respectively). On multivariate regression, opioid use was an independent risk factor for greater postoperative pain at final follow-up ( P = .006) after controlling for variables including female sex and age. Opioid use was associated with shorter time to pain recurrence on Kaplan-Meier analysis ( P = .005) and was associated with increased risk for recurrence on Cox proportional hazards regression ( P = .008). CONCLUSION: Preoperative opioid use in the setting of TN is associated with worse pain outcomes and increased risk for pain recurrence after MVD. These results indicate that opioids should be prescribed cautiously for TN and that worse post-MVD outcomes may occur in patients using opioids preoperatively.

Adult neuro-oncology trials in the United States over 5 decades: Analysis of trials completion rate to guide the path forward.

Background: Clinical trials are important to close the gap between therapeutic unmet needs and scientific advances in neuro-oncology. This study analyzes the landscape of neuro-oncology trials to identify completion rates and guide strategies for the path forward. Methods: US-registered adult neuro-oncology clinical trials were extracted from www.clinicaltrials.gov (1966-2019), including funding source, trial type, scope, phase, and subjects' demographics. Completed trials defined as those that had completed participants' examinations or intervention administration for the purpose of the final collection of data for the primary outcome were dichotomized against those that failed to reach completion. Univariate and multivariate analyses were used to detect differences across factors comparing the last 2 decades (2000-2009, 2010-2019). Results: Our search yielded 4522 trials, of which 1257 are eligible for this study. In 25 US states, neuro-oncology trial availability is <0.85/100,000 population. Comparing the past 2 decades, trial completion rate decreased from 88% to 64% (P < .001) and National Institutes of Health funding decreased from 47% to 24% (P < .001). Inclusion of subjects >65-year-old and women increased, while inclusion of Hispanic subjects decreased (P < .001). The top 2 reasons for lack of completion included accrual and operational difficulties. A larger proportion of women, non-Hispanic subjects, and older adults were enrolled in completed trials than in those that failed completion. Conclusions: Our study is the first report on the neuro-oncology clinical trial landscape in the United States and supports the development of strategies to further improve access to these trials. Additionally, attention is needed to identify and modify other factors contributing to lack of completion.

The influence of prior percutaneous rhizotomy on outcomes following microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Microvascular decompression (MVD) is an effective intervention in patients with trigeminal neuralgia (TN). How prior rhizotomy can impact long-term pain outcomes following MVD is not well understood. In this study, the authors sought to compare pain outcomes in patients who had undergone primary MVD versus those who had undergone secondary MVD after a single or multiple rhizotomies. METHODS: The authors retrospectively reviewed the data on all patients who had undergone MVD at their institution from 2007 to 2020. Patients were included in the study if they had undergone primary MVD or if their surgical history was notable for past rhizotomy. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and final follow-up appointments. Perioperative complications were noted for each patient, and evidence of pain recurrence was recorded as well. A history of rhizotomy as well as other variables that might influence TN pain recurrence were evaluated using a Cox proportional hazards model. The impact of prior rhizotomy on TN pain recurrence following MVD was further assessed using Kaplan-Meier survival analysis. RESULTS: Of 1044 patients reviewed, 947 met the study inclusion criteria. Of these, 796 patients had undergone primary MVD, 84 had a history of a single rhizotomy before MVD, and 67 had a history of ≥ 2 rhizotomies prior to MVD. Patients in the single rhizotomy and multiple rhizotomies cohorts exhibited a greater frequency of preoperative numbness (p < 0.001), higher preoperative BNI pain scores (p < 0.005), and higher rates of postoperative numbness (p = 0.04). However, final follow-up BNI pain scores were not significantly different between the primary MVD and prior rhizotomy groups (p = 0.34). Cox proportional hazards analysis revealed that younger age, multiple sclerosis, and female sex independently predicted an increased risk of pain recurrence following MVD. Neither a history of a single prior rhizotomy nor a history of multiple prior rhizotomies independently increased the risk of pain recurrence. Furthermore, Kaplan-Meier analysis of pain-free survival among the 3 groups revealed no relationship between a history of prior rhizotomy and pain recurrence following MVD (p = 0.57). CONCLUSIONS: Percutaneous rhizotomy does not complicate outcomes following subsequent MVD for TN pain. However, patients undergoing rhizotomy before MVD may have an increased risk of postoperative facial numbness compared to that in patients undergoing primary MVD.

Proteomic Analysis to Identify Prospective Biomarkers of Treatment Outcome After Microvascular Decompression for Trigeminal Neuralgia: A Preliminary Study.

Trigeminal neuralgia (TN) is a severe neuropathic facial pain disorder, often caused by vascular or neuronal compression of the trigeminal nerve. In such cases, microvascular decompression (MVD) surgery can be used to treat TN, but pain relief is not guaranteed. The molecular mechanisms that affect treatment response to MVD are not well understood. In this exploratory study, we performed label-free quantitative proteomic profiling of plasma and cerebrospinal fluid samples from patients undergoing MVD for TN, then compared the proteomic profiles of patients graded as responders (n = 7) versus non-responders (n = 9). We quantified 1,090 proteins in plasma and 1,087 proteins in the cerebrospinal fluid, of which 12 were differentially regulated in the same direction in both sample types. Functional analyses of differentially regulated proteins in protein-protein interaction networks suggested pathways of the immune system, axon guidance, and cellular stress response to be associated with response to MVD. These findings suggest potential biomarkers of response to MVD, as well as possible mechanisms of variable treatment success in TN patients. PERSPECTIVE: This exploratory study evaluates proteomic profiles in plasma and cerebrospinal fluid of patients undergoing microvascular decompression surgery for trigeminal neuralgia. Differential expression of proteins between surgery responders versus non-responders may serve as biomarkers to predict surgical success and provide insight into surgical mechanisms of pain relief in trigeminal neuralgia.

Application of a Clinical Approach to Diagnosing Primary Pain: Prevalence and Correlates of Primary Back and Neck Pain in a Community Physiatry Clinic.

Chronic back or neck pain (CBNP) can be primary (nociplastic or neuroplastic; without clear peripheral etiology) or secondary (to nociceptive or neuropathic causes). Expanding on available models of nociplastic pain, we developed a clinic-ready approach to diagnose primary/nociplastic pain: first, a standard physical exam and review of imaging to rule out secondary pain; and second, a detailed history of symptom presentation to rule in primary pain. We trained a physician who evaluated 222 patients (73.9% female, age M = 59.6) with CBNP; patients separately completed pain and psychosocial questionnaires. We estimated the prevalence of primary CBNP and explored biomedical, imaging, and psychological correlates of primary CBNP. Although almost all patients (97.7%) had at least 1 spinal anomaly on imaging, the diagnostic approach estimated that 88.3% of patients had primary pain, 5.0% had secondary pain, and 6.8% had mixed pain. Patients with primary pain were more likely than the other 2 groups of patients (combined as "non-primary pain") to report certain functional conditions, central sensitization, and features such as sensitivity to light touch, spreading pain, and pain worsening with stress; however, no difference was detected in depression, anxiety, and pain catastrophizing between those with primary and nonprimary pain. These findings are consistent with prior estimates that 85 to 90% of CBNP is "nonspecific." Further research is needed to validate and perhaps refine this diagnostic approach, which holds the potential for better outcomes if patients are offered treatments targeted to primary pain, such as pain neuroscience education and several emerging psychological therapies. PERSPECTIVE: We developed an approach to diagnose chronic primary pain, which was applied in a physiatry clinic to 222 patients with CBNP. Most patients (88.3%) had primary pain, despite almost universal anomalies on spinal imaging. This diagnostic approach can guide educational and psychological treatments tailored for primary pain.