Defining the Minimal and Optimal Thresholds for Lymph Node Resection and Examination for Intraductal Papillary Mucinous Neoplasm Derived Pancreatic Cancer: A Multicenter Retrospective Analysis.

OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.

Pain in the Context of Sensory Deafferentation.

Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results.

Multicenter, Randomized, Placebo-controlled Crossover Trial Evaluating Topical Lidocaine for Mechanical Cervical Pain.

BACKGROUND: There are few efficacious treatments for mechanical neck pain, with controlled trials suggesting efficacy for muscle relaxants and topical nonsteroidal anti-inflammatory drugs. Although studies evaluating topical lidocaine for back pain have been disappointing, the more superficial location of the cervical musculature suggests a possible role for topical local anesthetics. METHODS: This study was a randomized, double-blind, placebo-controlled crossover trial performed at four U.S. military, Veterans Administration, academic, and private practice sites, in which 76 patients were randomized to receive either placebo followed by lidocaine patch for 4-week intervals (group 1) or a lidocaine-then-placebo patch sequence. The primary outcome measure was mean reduction in average neck pain, with a positive categorical outcome designated as a reduction of at least 2 points in average neck pain coupled with at least a 5-point score of 7 points on the Patient Global Impression of Change scale at the 4-week endpoint. RESULTS: For the primary outcome, the median reduction in average neck pain score was -1.0 (interquartile range, -2.0, 0.0) for the lidocaine phase versus -0.5 (interquartile range, -2.0, 0.0) for placebo treatment (P = 0.17). During lidocaine treatment, 27.7% of patients experienced a positive outcome versus 14.9% during the placebo phase (P = 0.073). There were no significant differences between treatments for secondary outcomes, although a carryover effect on pain pressure threshold was observed for the lidocaine phase (P = 0.015). A total of 27.5% of patients in the lidocaine group and 20.5% in the placebo group experienced minor reactions, the most common of which was pruritis (P = 0.36). CONCLUSIONS: The differences favoring lidocaine were small and nonsignificant, but the trend toward superiority of lidocaine suggests more aggressive phenotyping and applying formulations with greater penetrance may provide clinically meaningful benefit.

Comparative-Effectiveness study evaluating outcomes for transforaminal epidural steroid injections performed with 3% hypertonic saline or normal saline in lumbosacral radicular pain.

BACKGROUND: Transforaminal epidural steroid injection (TFESI) are commonly employed to treat lumbosacral radiculopathy. Despite anti-inflammatory properties, the addition of 3% hypertonic saline has not been studied. OBJECTIVE: Compare the effectiveness of adding 0.9% NaCl (N-group) vs. 3% NaCl (H-group) in TFESI performed for lumbosacral radiculopathy. METHODS: This retrospective study compared TFESI performed with lidocaine, triamcinolone and 0.9% NaCl. The primary outcome was the proportion of patients who experienced a ≥ 30% reduction in pain on a verbal rating scale (VRS; 0-100) at 3 months. Secondary outcome measures included the proportion of patients who improved by at least 30% for pain at 1- and 6-months, and who experienced ≥15% from baseline on the Oswestry disability index (ODI) at follow-up. RESULTS: The H-group experienced more successful pain outcomes than the N-group at 3 months (59.09% vs. 41.51%; P = 0.002) but not at 1 month (67.53% vs. 64.78%; P = 0.61) or 6 months (27.13% vs 21.55%: P = 0.31). For functional outcome, there was a higher proportion of responders in the H-group than N-group at 3 months (70.31% vs. 53.46%; P = 0.002). Female, age ≤ 60 years and duration of pain ≤ 6 months were associated with superior outcomes at the 3-month endpoint. Although those with a herniated disc experienced better outcomes in general with TFESI, the only difference favoring the H-group was for spondylolisthesis patients. CONCLUSIONS: 3% hypertonic saline is a viable alternative to normal saline as an adjunct for TFESI, with randomized studies needed to compare its effectiveness to steroids as a possible alternative. REGISTRATION: Thai Clinical Trials Registry ID TCTR 20231110006.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

BACKGROUND: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. METHODS: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. RESULTS: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. CONCLUSIONS: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Prevalence of bilateral ulnar nerve subluxation among professional baseball pitchers.

BACKGROUND: Radiographic and physical examination findings of ulnar nerve instability have been recognized in overhead throwing athletes, despite the fact that some of these abnormalities may be asymptomatic and represent adaptive changes. While recommendations for screening and early detection have been made that can adversely impact an athletes' career, the presence of bilateral ulnar nerve subluxation and its relationship with medial elbow symptoms has not been characterized in professional overhead throwing athletes. PURPOSE: To characterize the prevalence of bilateral ulnar nerve subluxation among professional baseball pitchers. METHODS: A cross-sectional observational analysis was conducted utilizing standardized ultrasonographic examinations of bilateral elbows in 91 consecutive professional baseball pitchers (median age, 22 years; range, 17-30 years). The relationship between ulnar nerve subluxation and ulnar nerve signs, symptoms, and provocative physical examination maneuvers was also investigated. RESULTS: The prevalence of bilateral ulnar nerve subluxation was 26.4% (95% CI, 17.7%-36.7%; 24 of the 91 athletes). Thirty-five athletes (38.5%; 95% CI, 28.4%-49.2%) had subluxation in at least 1 elbow. No athletes with subluxation had positive ulnar nerve signs, symptoms, or provocative tests. CONCLUSION: Ulnar nerve subluxation is common among professional pitchers, and is more often than not bilateral. In this population of athletes, ulnar nerve subluxation does not appear to be associated with pathological findings.

Fat Grafting to the Breast for Aesthetic Indications: Techniques and Outcomes in 165 Consecutive Patients.

PURPOSE: Fat grafting to the breast for aesthetic indications has become increasingly popular. Herein, methods, aesthetic outcomes, and complications are reviewed in a retrospective case series. METHODS: Female patients (n=165) with an average age of 45 years (range: 17-78 years) who underwent fat grafting to breast were evaluated. Demographic parameters, the type of procedure, the amount of fat transferred, the site(s) of fat harvest, operative times, and the patient's postoperative recovery and outcomes were recorded. RESULTS: Of the 165 patients, 105 had breast augmentation with fat only. Of these 105 patients, 14(8%) had implant removal with and without capsulectomy, and 61(37%) had mastopexies. Composite augmentation was performed in the remaining 60 patients. The average amount of fat used was 208 cc (range: 10 to 945 cc) per breast. Forty-five patients (27%) underwent a second procedure. Of the 165 patients, 37(22%) had adverse events unrelated to the fat graft, including suture abscesses, scarring, and minor incision cite skin breakdown. Four patients (2.4%) had a complication related to fat grafting including 'lump' formation between the breast, abnormal mammograms, and the need for simple aspiration of a lipid cyst. CONCLUSIONS: Autologous fat grafting should be considered for both primary and secondary aesthetic breast surgery to enhance outcomes. Complications related to fat grafting are uncommon. Revisional and secondary surgeries may be needed to achieve the desired outcome. Power-assisted liposuction, with vibratory infiltration of the tumescent solution, auto-infusion of fat, and Expansion Vibration Lipofilling using a closed system has become our preferred technique. Fat grafting to breast can be considered for both primary and secondary aesthetic breast surgery Complications related to fat grafting are uncommon There does not appear to be an overall increase in complications of associated mastopexy and composite augmentation LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

5. Sacroiliac joint pain.

INTRODUCTION: Sacroiliac (SI) joint pain is defined as pain localized in the anatomical region of the SI joint. The reported prevalence of SI joint pain among patients with mechanical low back pain varies between 15% and 30%. METHODS: In this narrative review, the literature on the diagnosis and treatment of SI joint pain was updated and summarized. RESULTS: Patient's history provides clues on the source of pain. The specificity and sensitivity of provocative maneuvers are relatively high when three or more tests are positive, though recent studies have questioned the predictive value of single or even batteries of provocative tests. Medical imaging is indicated only to rule out red flags for potentially serious conditions. The diagnostic value of SI joint infiltration with local anesthetic remains controversial due to the potential for false-positive and false-negative results. Treatment of SI joint pain ideally consists of a multidisciplinary approach that includes conservative measures as first-line therapies (eg, pharmacological treatment, cognitive-behavioral therapy, manual medicine, exercise therapy and rehabilitation treatment, and if necessary, psychological support). Intra- and extra-articular corticosteroid injections have been documented to produce pain relief for over 3 months in some people. Radiofrequency ablation (RFA) of the L5 dorsal ramus and S1-3 (or 4) lateral branches has been shown to be efficacious in numerous studies, with extensive lesioning strategies (eg, cooled RFA) demonstrating the strongest evidence. The reported rate of complications for SI joint treatments is low. CONCLUSIONS: SI joint pain should ideally be managed in a multidisciplinary and multimodal manner. When conservative treatment fails, corticosteroid injections and radiofrequency treatment can be considered.

3. Pain originating from the lumbar facet joints.

INTRODUCTION: Pain originating from the lumbar facets can be defined as pain that arises from the innervated structures comprising the joint: the subchondral bone, synovium, synovial folds, and joint capsule. Reported prevalence rates range from 4.8% to over 50% among patients with mechanical low back pain, with diagnosis heavily dependent on the criteria employed. In well-designed studies, the prevalence is generally between 10% and 20%, increasing with age. METHODS: The literature on the diagnosis and treatment of lumbar facet joint pain was retrieved and summarized. RESULTS: There are no pathognomic signs or symptoms of pain originating from the lumbar facet joints. The most common reported symptom is uni- or bilateral (in more advanced cases) axial low back pain, which often radiates into the upper legs in a non-dermatomal distribution. Most patients report an aching type of pain exacerbated by activity, sometimes with morning stiffness. The diagnostic value of abnormal radiologic findings is poor owing to the low specificity. SPECT can accurately identify joint inflammation and has a predictive value for diagnostic lumbar facet injections. After "red flags" are ruled out, conservatives should be considered. In those unresponsive to conservative therapy with symptoms and physical examination suggesting lumbar facet joint pain, a diagnostic/prognostic medial branch block can be performed which remains the most reliable way to select patients for radiofrequency ablation. CONCLUSIONS: Well-selected individuals with chronic low back originating from the facet joints may benefit from lumbar medial branch radiofrequency ablation.

4. Painful diabetic polyneuropathy.

INTRODUCTION: Pain as a symptom of diabetic polyneuropathy (DPN) significantly lowers quality of life, increases mortality and is the main reason for patients with diabetes to seek medical attention. The number of people suffering from painful diabetic polyneuropathy (PDPN) has increased significantly over the past decades. METHODS: The literature on the diagnosis and treatment of diabetic polyneuropathy was retrieved and summarized. RESULTS: The etiology of PDPN is complex, with primary damage to peripheral nociceptors and altered spinal and supra-spinal modulation. To achieve better patient outcomes, the mode of diagnosis and treatment of PDPN evolves toward more precise pain-phenotyping and genotyping based on patient-specific characteristics, new diagnostic tools, and prior response to pharmacological treatments. According to the Toronto Diabetic Neuropathy Expert Group, a presumptive diagnosis of "probable PDPN" is sufficient to initiate treatment. Proper control of plasma glucose levels, and prevention of risk factors are essential in the treatment of PDPN. Mechanism-based pharmacological treatment should be initiated as early as possible. If symptomatic pharmacologic treatment fails, spinal cord stimulation (SCS) should be considered. In isolated cases, where symptomatic pharmacologic treatment and SCS are unsuccessful or cannot be used, sympathetic lumbar chain neurolysis and/or radiofrequency ablation (SLCN/SLCRF), dorsal root ganglion stimulation (DRGs) or posterior tibial nerve stimulation (PTNS) may be considered. However, it is recommended that these treatments be applied only in a study setting in a center of expertise. CONCLUSIONS: The diagnosis of PDPN evolves toward pheno-and genotyping and treatment should be mechanism-based.

6. Persistent spinal pain syndrome type 2.

INTRODUCTION: Persistent Spinal Pain Syndrome (PSPS) refers to chronic axial pain and/or extremity pain. Two subtypes have been defined: PSPS-type 1 is chronic pain without previous spinal surgery and PSPS-type 2 is chronic pain, persisting after spine surgery, and is formerly known as Failed Back Surgery Syndrome (FBSS) or post-laminectomy syndrome. The etiology of PSPS-type 2 can be gleaned using elements from the patient history, physical examination, and additional medical imaging. Origins of persistent pain following spinal surgery may be categorized into an inappropriate procedure (eg a lumbar fusion at an incorrect level or for sacroiliac joint [SIJ] pain); technical failure (eg operation at non-affected levels, retained disk fragment, pseudoarthrosis), biomechanical sequelae of surgery (eg adjacent segment disease or SIJ pain after a fusion to the sacrum, muscle wasting, spinal instability); and complications (eg battered root syndrome, excessive epidural fibrosis, and arachnoiditis), or undetermined. METHODS: The literature on the diagnosis and treatment of PSPS-type 2 was retrieved and summarized. RESULTS: There is low-quality evidence for the efficacy of conservative treatments including exercise, rehabilitation, manipulation, and behavioral therapy, and very limited evidence for the pharmacological treatment of PSPS-type 2. Interventional treatments such as pulsed radiofrequency (PRF) of the dorsal root ganglia, epidural adhesiolysis, and spinal endoscopy (epiduroscopy) might be beneficial in patients with PSPS-type 2. Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic, intractable neuropathic limb pain, and possibly well-selected candidates with axial pain. CONCLUSIONS: The diagnosis of PSPS-type 2 is based on patient history, clinical examination, and medical imaging. Low-quality evidence exists for conservative interventions. Pulsed radiofrequency, adhesiolysis and SCS have a higher level of evidence with a high safety margin and should be considered as interventional treatment options when conservative treatment fails.

1. Lumbosacral radicular pain.

INTRODUCTION: Patients suffering lumbosacral radicular pain report radiating pain in one or more lumbar or sacral dermatomes. In the general population, low back pain with leg pain extending below the knee has an annual prevalence that varies from 9.9% to 25%. METHODS: The literature on the diagnosis and treatment of lumbosacral radicular pain was reviewed and summarized. RESULTS: Although a patient's history, the pain distribution pattern, and clinical examination may yield a presumptive diagnosis of lumbosacral radicular pain, additional clinical tests may be required. Medical imaging studies can demonstrate or exclude specific underlying pathologies and identify nerve root irritation, while selective diagnostic nerve root blocks can be used to confirm the affected level(s). In subacute lumbosacral radicular pain, transforaminal corticosteroid administration provides short-term pain relief and improves mobility. In chronic lumbosacral radicular pain, pulsed radiofrequency (PRF) treatment adjacent to the spinal ganglion (DRG) can provide pain relief for a longer period in well-selected patients. In cases of refractory pain, epidural adhesiolysis and spinal cord stimulation can be considered in experienced centers. CONCLUSIONS: The diagnosis of lumbosacral radicular pain is based on a combination of history, clinical examination, and additional investigations. Epidural steroids can be considered for subacute lumbosacral radicular pain. In chronic lumbosacral radicular pain, PRF adjacent to the DRG is recommended. SCS and epidural adhesiolysis can be considered for cases of refractory pain in specialized centers.

Progression of Site-Specific Recurrence of Pancreatic Cancer and Implications for Treatment.

OBJECTIVE: This study aimed to analyze post-recurrence progression in context of recurrence sites and assess implications for post-recurrence treatment. BACKGROUND: Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within two years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of post-recurrence progression and survival remains. METHODS: This retrospective analysis included surgically treated PDAC patients at the NYU-Langone Health (2010-2021). Sites of recurrence were identified at time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox-regression analyses were applied to assess survival outcomes. RESULTS: Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95%CI:12.6 to 16.5). First site of recurrence was local in 43.9% patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, while 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared to other sites (16.9 months vs. 8.49 months, P=0.003). In local recurrence, 21 (33.3%) patients were alive after one year without progression to secondary sites. This was associated with a CA19-9 of <100U/ml at time of primary diagnosis (P=0.039), nodal negative disease (P=0.023), and well-moderate differentiation (P=0.042) compared to patients with progression. CONCLUSION: Except for lung recurrence, post-recurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.

Paclitaxel With or Without Cixutumumab as Second-Line Treatment of Metastatic Esophageal or Gastroesophageal Junction Cancer: A Randomized Phase II ECOG-ACRIN Trial.

BACKGROUND: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers. METHODS: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated. RESULTS: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56. CONCLUSION: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388).

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial.

BACKGROUND: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later. METHODS: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. RESULTS: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture. CONCLUSIONS: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.

Outcomes after primary tumor resection of metastatic pancreatic neuroendocrine tumors: An analysis of the National Cancer Database.

INTRODUCTION: There is no consensus regarding the role of primary tumor resection for patients with metastatic pancreatic neuroendocrine tumors (panNET). We assessed surgical treatment patterns and evaluated the survival impact of primary tumor resection in patients with metastatic panNET. METHODS: Patients with synchronous metastatic nonfunctional panNET in the National Cancer Database (2004-2016) were categorized based on whether they underwent primary tumor resection. We used logistic regressions to assess associations with primary tumor resection. We performed survival analyses with Kaplan-Meier survival functions, log-rank test, and Cox proportional hazard regression within a propensity score matched cohort. RESULTS: In the overall cohort of 2613 patients, 68% (n = 839) underwent primary tumor resection. The proportion of patients who underwent primary tumor resection decreased over time from 36% (2004) to 16% (2016, p < 0.001). After propensity score matching on age at diagnosis, median income quartile, tumor grade, size, liver metastasis, and hospital type, primary tumor resection was associated with longer median overall survival (OS) (65 vs. 24 months; p < 0.001) and was associated with lower hazard of mortality (HR: 0.39, p < 0.001). CONCLUSION: Primary tumor resection was significantly associated with improved OS, suggesting that, if feasible, surgical resection can be considered for well-selected patients with panNET and synchronous metastasis.

Safety of Scrambler Therapy: A Systematic Review of Complications and Adverse Effects.

OBJECTIVE: The objective was to qualitatively synthesize all reported cases of complications, adverse effects, side effects, or harms arising from the use of scrambler therapy (ST). METHODS AND DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The PubMed, Embase, Scopus, Web of Science, United States National Library of Medicine clinical trials registry, and Cochrane Central Register of Controlled Trials databases were searched from database inception to December 10, 2021. Case reports/series, abstracts, retrospective studies, and prospective studies (e.g., open-label trials, randomized controlled trials) pertaining to ST and any description of a complication, adverse effect, side effect, or harm were screened. The search protocol was developed a priori and registered via the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021291838). RESULTS: A total of six RCTs, 19 prospective open-label trials, and 11 case series / case reports met the inclusion criteria, comprising 1,152 total patients. Two patients experienced contact dermatitis, and one patient reported minor ecchymosis that resolved without intervention. This yielded a composite complication rate of 0.26% (3/1,152). There were zero reported serious adverse events. CONCLUSIONS: When used in accordance with the treatment protocols described by the United States Food and Drug Administration and device manual, ST is associated with a reported composite complication rate that is orders of magnitude lower than those of invasive neuromodulation devices. ST neuromodulation is a safe alternative for patients who cannot undergo invasive neuromodulation device implantation because of either risk or preference.

Fear Avoidance Beliefs in Upper-Extremity Musculoskeletal Pain Conditions: Secondary Analysis of a Prospective Clinical Study on Digital Care Programs.

BACKGROUND: Fear-avoidance beliefs (FAB) have been associated with poorer prognosis and decreased adherence to exercise-based treatments in musculoskeletal (MSK) pain. However, the impact of high FAB on adherence and outcomes in upper extremity MSK (UEMSK) pain is poorly explored, particularly through exercise-based digital care programs (DCP). OBJECTIVE: Assess the adherence levels, clinical outcomes and satisfaction in patients with UEMSK pain and elevated FAB after a fully remote multimodal DCP. Associations between FABQ-PA and clinical outcomes were conducted. METHODS: Secondary analysis of an ongoing clinical trial. Participants with UEMSK pain (shoulder, elbow, and wrist/hand) and elevated FAB-physical activity (FABQ-PA ≥ 15) were included. Adherence (completion rate, sessions/week, total exercise time) and mean change in clinical outcomes-disability (QuickDASH), numerical pain score, FABQ-PA, anxiety (GAD-7), and depression (PHQ-9)-between baseline and end-of-program were assessed. Associations between FABQ-PA and clinical outcomes were conducted. RESULTS: 520 participants were included, with mean baseline FABQ-PA of 18.02 (SD 2.77). Patients performed on average 29.3 exercise sessions (2.8 sessions/week), totalizing 338.2 exercise minutes. Mean satisfaction was 8.5/10 (SD 1.7). Significant improvements were observed in all clinical outcomes. Higher baseline FAB were associated with higher baseline disability (P < .001), and smaller improvements in disability (P < .001) and pain (P = .001). Higher engagement was associated with greater improvements in FABQ-PA (P = .043) and pain (P = 0.009). CONCLUSIONS: This study provides evidence of the potential benefits of a structured and multimodal home-based DCP in the management of UEMSK pain conditions in patients with elevated FAB in a real-world context.

Sympathetic Blocks as a Predictor for Response to Ketamine Infusion in Patients with Complex Regional Pain Syndrome: A Multicenter Study.

BACKGROUND: Ketamine infusions are frequently employed for refractory complex regional pain syndrome (CRPS), but there are limited data on factors associated with treatment response. Sympathetic blocks are also commonly employed in CRPS for diagnostic and therapeutic purposes and generally precede ketamine infusions. OBJECTIVES: We sought to determine whether demographic and clinical factors, and technical and psychophysical characteristics of sympathetic blocks are associated with response to ketamine infusion. METHODS: In this multi-center retrospective study, 71 patients who underwent sympathetic blocks followed by ketamine infusions at 4 hospitals were evaluated. Sympathetically maintained pain (SMP) was defined as ≥ 50% immediate pain relief after sympathetic block and a positive response to ketamine was defined as ≥ 30% pain relief lasting over 3 weeks. RESULTS: Factors associated with a positive response to ketamine in univariable analysis were the presence of SMP (61.0% success rate vs 26.7% in those with sympathetically independent pain; P = .009) and post-block temperature increase (5.66 ± 4.20 in ketamine responders vs 3.68 ± 3.85 in non-responders; P = .043). No psychiatric factor was associated with ketamine response. In multivariable analysis, SMP (OR 6.54 [95% CI 1.83, 23.44]) and obesity (OR 8.75 [95% 1.45, 52.73]) were associated with a positive ketamine infusion outcome. CONCLUSIONS: The response to sympathetic blocks may predict response to ketamine infusion in CRPS patients, with alleviation of the affective component of pain and predilection to a positive placebo effect being possible explanations.

Fentanyl-induced respiratory depression in rodents is inhibited by bioabsorbable, subcutaneous naltrexone implants at 3.5 months.

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants inhibit respiratory depression after an IV injection of fentanyl. Bioabsorbable implants fabricated from two different release-controlling polymers, poly-D-L-lactide (PDLLA) and polycaprolactone (PCL), alone (placebo) or containing NTX, were subcutaneously implanted in Sprague Dawley rats. After 3.5 months of implantation, the rodents were administered an IV bolus of fentanyl through the tail vein. The placebo implant rats received a dose of 4 micrograms (mcg) - (10 mcg/kg/dose), while the NTX implanted animals received a dose of 8 mcg (20 mcg/kg/dose). The minimum active dose of fentanyl that caused a > 50 ± 2% depression in the respiration rate in the placebo implanted rodents was 4 mcg. The respiration rate of the placebo implanted rats dropped from 208 ± 14 breaths/minute at predose, to 84 ± 12 breaths/minute (p = 0.0003) at 2 min. In contrast, all NTX implanted animals easily tolerated twice the dose of 8 mcg of fentanyl without any significant reduction in respiration rate. The mean respiration rate = increased from 164 ± 22 breaths/minute at predose to 178 ± 17 breaths/minute (p = 0.24) at 2 min. The mean plasma concentrations of NTX, 3.5 months after implantation, ranged from 7.4 (±1.1) ng/mL to 80.3 (±37.5) ng/mL. Bioabsorbable implants containing NTX effectively blocked fentanyl-induced respiratory depression in rodents as compared with placebo implants, 3.5 months after implantation.