Faculty Bibliography

BACKGROUND:Chronic axial spinal pain is a major contributor to disability and healthcare expenditures, with facet joints recognized as one of the established sources of pain. OBJECTIVE:To provide evidence-based guidance in performing diagnostic and therapeutic facet joint interventions. METHODS:A multidisciplinary panel of experts from various medical and pharmaceutical disciplines, convened by the American Society of Interventional Pain Physicians (ASIPP), reviewed the available evidence, considered patient perspectives, and formulated recommendations for facet joint interventions in the management of chronic pain.The methodology included the development of key questions with evidence-based statements and recommendations. Grading of the evidence and recommendations followed a modified approach described by ASIPP, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and the Agency for Healthcare Research and Quality (AHRQ) methods for grading strength of recommendations. The evidence review included existing guidelines, systematic reviews, comprehensive reviews, randomized controlled trials (RCTs), and observational studies evaluating the effectiveness and safety of facet joint interventions in chronic pain management.In the development of consensus statements and guidelines, a modified Delphi technique was utilized to minimize bias related to group interactions. Panelists without a primary conflict of interest voted on approval of specific guideline statements. Each panelist was permitted to suggest revisions to guideline wording and provide additional qualifying remarks or comments regarding implementation of the guidelines in clinical practice. To achieve consensus and inclusion in the final guidelines, each guideline statement required at least 80% agreement among eligible panel members without a primary conflict of interest. RESULTS:A total of 48 authors participated in the development of these guidelines, of whom 39 participated in the voting process. A total of 37 recommendations were developed, with 100% acceptance for all items. The Summary of Recommendations is presented separately. These recommendations addressed diagnostic, therapeutic, and special considerations related to facet joint interventions. For diagnostic and therapeutic interventions, the level of evidence ranged from II to III, with moderate to strong recommendations. For special considerations and safety assessments, the level of evidence ranged from II to V. The evidence provided recommendations regarding diagnosis, treatment, sedation, concurrent antithrombotic therapy, and precautions required in special clinical circumstances. LIMITATIONS/CONCLUSIONS:The limitations of these guidelines include a paucity of high-quality studies in some aspects of diagnosis and therapy. CONCLUSION/CONCLUSIONS:These guidelines for facet joint interventions were developed through a comprehensive review of the literature, including methodologic quality assessment and determination of the level of evidence and strength of recommendations. DISCLAIMER/CONCLUSIONS:These guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Brown adipose tissue is an evolutionary innovation in placental mammals that regulates body temperature through adaptive thermogenesis. Cold exposure activates brown adipose tissue thermogenesis through coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation; however, how these processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (SLIT3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Adipocyte progenitors secrete SLIT3, which is cleaved into functionally distinct SLIT3-N and SLIT3-C fragments that independently promote angiogenesis and sympathetic innervation. We identify PLXNA1 as a receptor for SLIT3-C and demonstrate its essential role in sympathetic innervation of brown adipose tissue. Moreover, we identify BMP1 as the first SLIT protease described in vertebrates. Coordinated neurovascular expansion mediated by distinct SLIT3 fragments provides a bifurcated yet integrated mechanism that ensures a synchronized brown adipose tissue response to environmental challenges. Finally, this study reveals a previously unrecognized role for adipocyte progenitors in regulating tissue innervation.

BACKGROUND:Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC. METHODS:Patients with locally advanced or metastatic PDAC after one prior regimen received 50 mg/m2 subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200 mg intravenously every 3 weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis. RESULTS:Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5 years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83 months, respectively. Exploratory analysis suggested higher baseline CD8+ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit. CONCLUSION/CONCLUSIONS:Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8+ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. (NCT03264404).

Brown adipose tissue (BAT) is an evolutionary innovation that enables placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure activates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (Slit3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We demonstrate that adipocyte progenitors secrete Slit3, which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which bind distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. We identify Plxna1 as a previously unrecognized receptor for Slit3-C and show that it is essential for sympathetic innervation and cold-induced neurite expansion in BAT. Moreover, we introduce bone morphogenetic protein 1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this work establishes a mechanistic framework for the coordinated regulation of sympathetic innervation and angiogenesis to enhance thermogenic function. The co-regulation of neurovascular expansion by distinct Slit3 fragments offers a bifurcated yet harmonized mechanism to ensure a synchronized BAT response to environmental challenges. Finally, this study provides the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

Animals need daily intakes of three macronutrients: sugar, protein, and fat. Under fasted conditions, however, animals prioritize sugar as a primary source of energy. They must detect ingested sugar-specifically D-glucose-and quickly report its presence to the brain. Hypothalamic neurons that can respond to the caloric content in the gut regardless of the identity of macronutrient have been identified, but until now, the existence of neurons that can encode the specific macronutrients remained unknown. We found that a subset of corticotropin-releasing factor (CRF)-expressing neurons in the hypothalamic paraventricular nucleus (CRF^PVN) respond specifically to D-glucose in the gut, separately from other macronutrients or sugars. CRF^PVN neuronal activity is essential for fasted mice to develop a preference for D-glucose. These responses of CRF^PVN neurons to intestinal D-glucose require a specific spinal gut-brain pathway including the dorsal lateral parabrachial nuclei. These findings reveal the neural circuit that encodes the identity of D-glucose.

BACKGROUND:Peripheral nerve stimulation (PNS) has been used for over 50 years to treat chronic pain by delivering electrical pulses through small electrodes placed near targeted peripheral nerves those outside the brain and spinal cord. Early PNS systems often required invasive neurosurgical procedures. However, since 2015, the Food and Drug Administration (FDA) approved percutaneously implanted PNS leads and neurostimulators  offering a much less invasive, non-opioid option for managing recalcitrant chronic pain. The following FDA-cleared PNS systems are commercially available in the United States for the management of chronic, intractable pain:•    Freedom® Peripheral Nerve Stimulator (PNS) System (Curonix LLC, 2017) •    StimRouter® Neuromodulation System (Bioness, now Bioventus, 2015)•    SPRINT® PNS System (SPR® Therapeutics, Inc., 2016) •    Nalu™ Neurostimulation System (Nalu Medical Inc., 2019)•    ReActiv8® Implantable Neurostimulation System (Mainstay Medical Limited, 2020) The American Society of Interventional Pain Physicians (ASIPP) has published evidence-based consensus guidelines for the application of PNS systems in managing chronic pain. OBJECTIVE:The guidelines aim to provide evidence-based recommendations for the utilization of peripheral nerve stimulation (PNS) in the management of moderate to severe chronic pain. These guidelines exclude field stimulation, or sacral nerve stimulation. METHODS:A multidisciplinary panel of experts in various medical and pharmaceutical fields, convened by ASIPP, reviewed the evidence, considered patient perspectives, and formulated recommendations for implantable peripheral nerve stimulation in chronic pain management. The methodology included developing key questions with evidence-based statements and recommendations. The grading of evidence and recommendations followed a modified approach described by ASIPP, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method, and the Agency for Healthcare Research and Quality (AHRQ) strength of recommendations methods. The evidence review includes existing guidelines, systematic reviews, comprehensive reviews, randomized controlled trials (RCTs), and observational studies on the effectiveness and safety of implantable peripheral nerve stimulation in managing chronic pain. The quality of published studies was assessed using appropriate instruments for systematic reviews, RCTs, and observational studies.In the development of consensus statements and guidelines, we used a modified Delphi technique, which has been described to minimize bias related to group interactions. Panelists without a primary conflict of interest voted to approve specific guideline statements. Each panelist could suggest edits to the guideline statement wording and could suggest additional qualifying remarks or comments as to the implementation of the guideline in clinical practice to achieve consensus and for inclusion in the final guidelines, each guideline statement required at least 80% agreement among eligible panel members without primary conflict of interest. RESULTS:A total of 31 authors participated in the development of these guidelines. Of these, 23 participated in the voting process. A total of 8 recommendations were developed. Overall, 100% acceptance was obtained for 8 of 8 items. Thus, with appropriate literature review, consensus-based statements were developed for implantable peripheral nerve stimulation in chronic pain management. In preparation of these guidelines, evidence synthesis included 7 systematic reviews, 8 RCTs, and 9 observational studies covering all PNS treatments. The evidence was developed using GRADE criteria or certainty of evidence, and qualitative synthesis based on the best available evidence. The evidence level and recommendations are as follows: For implantable peripheral nerve stimulation systems following a trial or selective lumbar medial branch stimulation without a trial, the evidence is Level III or fair with moderate certainty.  Evidence Level: Fair; Strength of Recommendation: ModerateFor temporary peripheral nerve stimulation for 60 days, the evidence is Level III or fair, with moderate certainty. EVIDENCE LEVEL/METHODS:Fair; Strength of Recommendation: ModerateBased on the available evidence, it is our recommendation to expand the existing PNS related local coverage determination (LCD) to include craniofacial pain, phantom limb pain, and nociceptive pain in the lower back as present evidence shows Level III or fair with moderate certainty. LIMITATIONS/CONCLUSIONS:The primary limitation of these guidelines is the paucity of the available literature. CONCLUSION/CONCLUSIONS:These evidence-based guidelines support the use of implantable peripheral nerve stimulation leads and neurostimulators in patients with moderate to severe chronic pain refractory to two or more conservative treatments. These guidelines aim to optimize patient outcomes and promote health equity through the integration of PNS technology in clinical practice.

Significant knowledge gaps exist in the perioperative pain management of patients with a history of chronic pain, substance use disorder, and/or opioid tolerance as highlighted in the US Health and Human Services Pain Management Best Practices Inter-Agency Task Force 2019 report. The report emphasized the challenges of caring for these populations and the need for multidisciplinary care and a comprehensive approach. Such care requires stakeholder alignment across multiple specialties and care settings. With the intention of codifying this alignment into a reliable and efficient processes, a consortium of 15 professional healthcare societies was convened in a year-long modified Delphi consensus process and summit. This process produced seven guiding principles for the perioperative care of patients with chronic pain, substance use disorder, and/or preoperative opioid tolerance. These principles provide a framework and direction for future improvement in the optimization and care of 'complex' patients as they undergo surgical procedures.

Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

BACKGROUND:The triglyceride (TG) transfer activity of microsomal triglyceride transfer protein (MTP) is essential for lipoprotein assembly in the liver and intestine; however, its function in adipose tissue, which does not assemble lipoproteins, is unknown. Here we have elucidated the function of MTP in adipocytes. APPROACH AND RESULTS/RESULTS:mice maintained higher body temperature by mobilizing more fatty acids. Biochemical studies indicated that MTP deficiency de-repressed adipose triglyceride lipase (ATGL) activity and increased TG lipolysis. Both wild type MTP and mutant MTP deficient in TG transfer activity interacted with and inhibited ATGL activity. Thus, the TG transfer activity of MTP is not required for ATGL inhibition. C-terminally truncated ATGL that retains its lipase activity interacted less efficiently than full-length ATGL. CONCLUSION/CONCLUSIONS:Our findings demonstrate that adipose-specific MTP deficiency increases ATGL-mediated TG lipolysis and enhances energy expenditure, thereby resisting diet-induced obesity. We speculate that the regulatory function of MTP involving protein-protein interactions might have evolved before the acquisition of TG transfer activity in vertebrates. Adipose-specific inhibition of MTP-ATGL interactions may ameliorate obesity while avoiding the adverse effects associated with inhibition of the lipid transfer activity of MTP.