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Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.

Limb trauma remains the most prevalent survivable major combat injury. In the First World War, more than 700,000 British soldiers received limb wounds and more than 41,000 underwent an amputation, creating one of the largest amputee cohorts in history. Postamputation pain affects up to 85% of military amputees, suggesting that up to 33,000 British First World War veterans potentially reported postamputation pain. This qualitative systematic review explores the professional medical conversation around clinical management of chronic postamputation pain in this patient cohort, its development over the 20th century, and how this information was disseminated among medical professionals. We searched The Lancet and British Medical Journal archives (1914-1985) for reports referring to postamputation pain, its prevalence, mechanisms, descriptors, or clinical management. Participants were First World War veterans with a limb amputation, excluding civilians and veterans of all other conflicts. The search identified 9809 potentially relevant texts, of which 101 met the inclusion criteria. Reports emerged as early as 1914 and the discussion continued over the next 4 decades. Unexpected findings included early advocacy of multidisciplinary pain management, concerns over addiction, and the effect of chronic pain on mental health emerging decades earlier than previously thought. Chronic postamputation pain is still a significant issue for military rehabilitation. Similarities between injury patterns in the First World War and recent Iraq and Afghanistan conflicts mean that these historical aspects remain relevant to today\'s military personnel, clinicians, researchers, and policymakers.

OBJECTIVE: To describe the ultrasound (US) appearance of regenerative peripheral nerve interfaces (RPNIs) in humans, and correlate clinically and with histologic findings from rat RPNI.
METHODS: Patients (≥ 18 years) who had undergone RPNI surgery within our institution between the dates of 3/2018 and 9/2019 were reviewed. A total of 21 patients (15 male, 6 female, age 21-82 years) with technically adequate US studies of RPNIs were reviewed. Clinical notes were reviewed for the presence of persistent pain after RPNI surgery. Histologic specimens of RPNIs in a rat model from prior studies were compared with the US findings noted in this study.
RESULTS: There was a variable appearance to the RPNIs including focal changes involving the distal nerve, nerve-muscle graft junction, and area of the distal sutures. The muscle grafts varied in thickness with accompanying variable echogenic changes. No interval change was noted on follow-up US studies. Diffuse hypoechoic swelling with loss of the fascicular structure of the nerve within the RPNI and focal hypoechoic changes at the nerve-muscle graft junction were associated with clinical outcomes. US findings corresponded to histologic findings in the rat RPNI.
CONCLUSIONS: Ultrasound imaging can demonstrate various morphologic changes involving the nerve, muscle, and interface between these two biological components of RPNIs. These changes correspond to expected degenerative and regenerative processes following nerve resection and muscle reinnervation and should not be misconstrued as pathologic in all cases. N5 and N1 morphologic type changes of the RPNI were found to be associated with symptoms.

Neuromas are a difficult-to-treat peripheral nerve pathology that can cause crippling pain. Optimal treatment is widely debated as pharmacological intervention frequently is not sufficient and surgical interventions are plagued with recurrence. The majority of amputees report severe and chronic stump pain. Avoiding complex surgery at the stump site would prevent infection or wound dehiscence. Recent advances in neuromodulation with external pulse emitters allow for pain relief with localized nerve stimulation. The authors describe the novel placement of a sciatic nerve stimulator in a 77-year-old man for painful stump neuromas of the common peroneal and tibial nerves. The video can be found here: https://youtu.be/96kKs3qjtqc.

Peripheral nerve stimulation (PNS) is a powerful interventional option for the management of otherwise intractable pain. This technique involves the implantation of electrodes to apply electrical stimulation to named peripheral nerves, thereby alleviating pain in the territory of the target nerves. Recent advancements, largely driven by physician-industry relationships, have transformed the therapy into one that is minimally invasive, safe, evidence-based, and effective. Ongoing research has expanded the indications beyond chronic neuropathic pain in a peripheral nerve distribution. This article provides an overview of recent advances in this field.

BACKGROUND: Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas among adults. It is characterized by large size, high grade, and biological aggressiveness. There are many reports of MFH after local stimulation, such as bone fracture, implants, and chronic osteomyelitis. In this paper, we report a patient who developed MFH 6 years after amputation, suggesting that wound healing and mechanical force play a role in the local stimulation of this disease.
METHODS: A 66-year-old man complained of persistent pain in his residual mid-thigh. He had undergone amputation surgery due to a traffic accident 6 years prior. Physical examination showed tenderness but no abnormalities in appearance. X-ray radiographs and magnetic resonance imaging supported the diagnosis of a tumor, and a biopsy confirmed that the lesion was MFH. The patient received neoadjuvant chemotherapy and left hip disarticulation. During the 6-mo follow-up, there were no symptoms of recurrence.
CONCLUSIONS: Postsurgery MFH has been reported before, and many studies have attributed it to the biological effects of implants. Our case report shows that this disease can develop without an implant and thus highlights the importance of local stimulation. The wound-healing process and mechanical force can both promote this tumor, but whether they directly cause MFH needs further investigation.

OBJECTIVE: To develop a scale to diagnose and assess the severity of postamputation pain (PAP) in dogs.
METHODS: Single-center retrospective study.
METHODS: A total of 66 dogs that underwent thoracic or pelvic limb amputation and 139 dogs that underwent tibial plateau leveling osteotomy (TPLO) at a veterinary teaching hospital.
METHODS: An online survey regarding postoperative behavioral changes was sent to owners. Categorical, multiple-choice responses were entered into a univariable logistic regression model and tested for association with amputation using the Wald test. If p < 0.2, variables were forwarded to a multivariable logistic regression model for manual build. Model simplicity and predictive ability were optimized using the area under the receiver operating curve (AUROC) characteristic, and model calibration was assessed using the Hosmer-Lemeshow test. The selected model was converted to an integer scale (0-10), the Canine Postamputation Pain (CAMPPAIN) scale. Univariable logistic regression related each dog\'s calculated score to the probability of PAP.
RESULTS: Multivariable logistic regression identified four independent predictors of PAP (p < 0.05): 1) restlessness or difficulty sleeping, 2) episodes of panic or anxiety, 3) sudden vocalization, and 4) compulsive grooming of the residual limb. Score AUROC was 0.70 (95% confidence interval = 0.63-0.78) with good calibration (Hosmer-Lemeshow statistic p = 0.82). A score of 2 corresponded to a risk probability of 0.5. Taking a score ≥ 2 to indicate PAP, score specificity and sensitivity were 92.1% and 36.4%, respectively. When this score was used to diagnose PAP, prevalence was 36.4% (24/66) and 7.9% (11/139) in the amputation and TPLO groups, respectively.
CONCLUSIONS: Postamputation pain is characterized by specific postoperative behaviors and appears to affect approximately one-third of canine amputees. The CAMPPAIN scale generated from these data could facilitate diagnosis, treatment and further study of PAP but requires external validation.

UNASSIGNED: The inconsistent use of standardized approaches for classifying postamputation pain (PAP) has been a barrier to establishing its prevalence.
UNASSIGNED: The primary objective of this systematic review and meta-analysis is to determine the prevalence of nontraumatic lower-extremity PAP using an established taxonomy. The secondary objective is to determine the prevalence of PAP subtypes, including phantom limb pain and residual limb pain (RLP).
UNASSIGNED: An a priori protocol was registered, and a database search was conducted by a reference librarian. Randomized trials and uncontrolled studies were eligible for inclusion. The risk of bias was assessed using a tool developed for uncontrolled studies. A total of 2679 studies were screened, and 13 studies met inclusion criteria (n = 1063).
UNASSIGNED: The sources of risk of bias included selection bias and, to a lesser extent, whether the outcome was adequately ascertained. Two studies reported the prevalence of PAP and the pooled prevalence was 61% (95% confidence interval [CI], 33%-86%) with high heterogeneity (I2 = 93%). Thirteen studies reported the prevalence of phantom limb pain and the pooled prevalence was 53% (95% CI, 40%-66%) with high heterogeneity (I2 = 93%). Eight studies reported the prevalence of RLP and the pooled prevalence was 32% (95% CI 24%-41%) with high heterogeneity (I2 = 76%). Clinical subtypes of RLP were not reported.
UNASSIGNED: The prevalence of PAP is high in patients with nontraumatic lower-extremity amputations. Ongoing research that uses a taxonomy for PAP is needed to fully delineate the prevalence of PAP subtypes.

UNASSIGNED: Postamputation pain (PAP) is a serious problem, and thus far, there is no perfect treatment strategy. Clinically, minimally invasive treatments for peripheral neuromas are simple and feasible. This study aimed to investigate the immediate and long-term effects of ultrasonography-guided radiofrequency ablation (RFA) on PAP.
UNASSIGNED: Eighteen PAP subjects with painful peripheral neuromas were treated with ultrasonography-guided RFA.
UNASSIGNED: A total of 18 PAP subjects were included in the final analyses. Fourteen of the 17 subjects with residual limb pain (RLP) (82.4%) had successful outcomes. A successful outcome was noted in 9 of the 13 subjects with phantom limb pain (PLP) (69.2%). There were no significant associations between symptom relief and sex, age, or the duration of symptoms. There were no severe complications.
UNASSIGNED: Ultrasonography-guided RFA for painful stump neuromas can effectively relieve stump pain and PLP in amputees with PAP (follow-up time was 12 months). Ultrasonography-guided RFA is easy and safe and does not involve radiation exposure, making it very suitable for clinical applications.