Methadone versus other opioids for refractory malignant bone pain: a pilot randomised controlled study.

PURPOSE: Refractory cancer-induced bone pain (CIBP) affects a patient's functional capacity and quality of life, but there is limited evidence to guide opioid choice. We assessed the feasibility, tolerability and possible efficacy of methadone rotation (MR) compared to other opioid rotations (OOR) in this cohort. METHODS: Adults with CIBP and worst pain intensity ≥ 4/10 and/or opioid toxicity graded ≥ 2 on the Common Terminology Criteria for Adverse Events were randomised 1:1 to methadone or another opioid rotation. Standardised assessment tools were used at pre-defined study time points up to 14 days. RESULTS: Of 51 eligible participants, 38 (74.5%) consented, and 29 (76.3%, MR: 14, OOR: 15) completed the fourteen days follow-up post-opioid rotation. Both groups displayed significant reduction in average (MR: d = - 1.2, p = 0.003, OOR: d = - 0.8, p = 0.015) and worst pain (MR: d = - 0.9, p = 0.042, OOR: d = - 0.6, p = 0.048) and total pain interference score (MR: d = - 1.1, p = 0.042, OOR: d = - 0.7, p = 0.007). Oral morphine equivalent daily dose was reduced significantly in MR compared to the OOR group (d = - 0.8, p = 0.05). The incidence of opioid-related adverse events following MR was unchanged but lower in the OOR group (d = 0.9, 95% CI 0.1,1.7, p = 0.022). There were no within-group or between-group differences in satisfaction with analgesia at the end of the study. CONCLUSION: This pilot study demonstrated that MR and OOR in patients with refractory CIBP are feasible, safe and acceptable to patients. Appropriately powered multi-centre randomised controlled studies are needed to confirm the efficacy of MR and OOR in this cohort. TRIAL REGISTRATION: ACTRN12621000141842 registered 11 February 2021.

Bone Pain and Survival Among Patients With Metastatic, Hormone-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG-1216 Trial.

Importance: The presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC). Objective: To compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis. Design, Setting, and Participants: This post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis. Interventions: In the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal. Main Outcomes and Measures: Overall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level. Results: Of the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P = .02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P < .001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P < .001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P < .001). Conclusions and Relevance: In this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

DN4 questionnaire as a useful tool for evaluating the pharmacotherapeutic response to opioid pharmacotherapy in malignant neuropathy.

Objective: Tapentadol is a drug of choice for neuropathic cancer pain. DN4 questionnaire quickly determines neuropathic pain component. The aim of this study is to determine the correlation between neuropathic malignant pain component by applying tapentadol antidolorose pharmacotherapy in combination with palliative radiotherapy of osseous neuropathic metastatic changes in breast cancer patients before and after palliative radiotherapy. Methods: The first patients group comprised 30 patients with primary breast cancer and proved painful bone secondary deposits with neuropathy for which tapentadol was prescribed, and they underwent palliative radiotherapy. The second group comprised 30 patients with primary breast cancer and proved painful bone metastases with neuropathy treated only with palliative antidolorose radiotherapy. Key findings : After two-months-follow up, tapentadol group patients had lower DN4 score values (Z=2,021; p=0.043). Significantly lower number of tapentadol group patients was without neuropathic pain after a three-month-follow up (χ ²=5,711; p=0.017). Significantly greater number of tapentadol group patients had best ECOG score 0 ( χ² =7,486; p=0.023). There was statistically significant positive correlation between tapentadol dose and DN4 score in patients after a month (ρ=0,471; p=0.009) and three months after the radiotherapy completion (ρ=0,610; p<0.001). Tapentadol is an opioid analgesic efficient for neuropathy relief in these patients and DN4 questionnaire is an efficient pharmacotherapy tool.

Optimal production and purification of n.c.a.143Pr as a promising palliative agent for the treatment of metastatic bone pain.

This study proposes the beta-emitting radioisotope 143Pr as a promising candidate for palliative treatment of metastatic bone pain due to its desirable physical decay characteristics. An optimized process was developed for the production and purification of non-carrier-added 143Pr using a medium flux research reactor. Calculations were performed to determine the optimal irradiation time and cooling period for irradiating 1 mg of natural cerium oxide to indirectly produce 143Pr through the decay of 143Ce. Following irradiation and cooling, extraction chromatography was employed to efficiently isolate 143Pr from the irradiated target material. A column containing Ln-resin was used along with nitric acid as the mobile phase and an optional oxidation step with NaBrO3/ascorbic acid to separate 143Pr from impurities such as 143Ce and 141Ce. Radionuclidic purity of over 99.995% was achieved as confirmed through gamma spectroscopy, demonstrating effective separation of 143Pr. Additional quality control analyses established the chemical and radiochemical purity of the purified 143Pr nitrate product. With a half-life of 13.6 days and maximum beta energy of 0.937 MeV, 143Pr exhibits favorable properties for palliative bone pain therapy. This study therefore provides a viable method for producing high-purity 143Pr through the optimized irradiation and purification processes described. Further investigation is warranted to explore potential clinical applications of 143Pr for palliation of metastatic bone cancer pain.

Factors Associated with Discharge Destination in Patients with Bone Metastases.

Background and Objectives: The discharge destination of patients with advanced cancer correlates with their quality of life. Patients with bone metastases often undergo lifestyle changes owing to pain and activity limitations. However, there are few reports on factors related to the discharge destination of patients with bone metastases. This study aimed to elucidate the factors associated with the discharge destination of patients with bone metastases. Methods: This study included 278 patients diagnosed with bone metastases who were admitted to the University of Tsukuba Hospital between April 2015 and March 2020. This study examined discharge destination, occurrence of skeletal-related events (SREs), primary lesions, locations of bone metastases, functional ambulation categories (FAC), age, and length of hospital stay. A binomial logistic regression analysis was conducted to compare the home and non-home discharge groups. Results: Of the 278 patients, 142 were discharged to home, 89 were discharged to somewhere other than home (non-home), and 47 died. The discharge destination was associated with spinal cord compression (SCC) (odds ratio [OR] 3.37, 95% confidence interval [CI] 1.35-8.43), hypercalcemia (OR 6.84, 95% CI 1.09-42.76), and FAC at admission (OR 0.45, 95% CI 0.35-0.58). The admission FAC cut-off value for discharge to home was determined to be 1.5 (area under the curve [AUC] 0.79, sensitivity 77.5%, specificity 68.5%). Conclusions: Factors associated with discharge destination were identified. The walking ability required for discharge to home was FAC 1.5, meaning that the patient needed one person to assist in preventing falls when walking on level ground. A cut-off value for FAC on admission for predicting outcomes was identified, suggesting the importance of gait ability assessment on admission.

The TREK-1 potassium channel is involved in both the analgesic and anti-proliferative effects of riluzole in bone cancer pain.

BACKGROUND: The metastasis of tumors into bone tissue typically leads to intractable pain that is both very disabling and particularly difficult to manage. We investigated here whether riluzole could have beneficial effects for the treatment of prostate cancer-induced bone pain and how it could influence the development of bone metastasis. METHODS: We used a bone pain model induced by intratibial injection of human PC3 prostate cancer cells into male SCID mice treated or not with riluzole administered in drinking water. We also used riluzole in vitro to assess its possible effect on PC3 cell viability and functionality, using patch-clamp. RESULTS: Riluzole had a significant preventive effect on both evoked and spontaneous pain involving the TREK-1 potassium channel. Riluzole did not interfere with PC3-induced bone loss or bone remodeling in vivo. It also significantly decreased PC3 cell viability in vitro. The antiproliferative effect of riluzole is correlated with a TREK-1-dependent membrane hyperpolarization in these cells. CONCLUSION: The present data suggest that riluzole could be very useful to manage evoked and spontaneous hypersensitivity in cancer-induced bone pain and has no significant adverse effect on cancer progression.

Percutaneous Cementation for Improvement of Pain and Function for Osteolytic Pelvic Metastasis: A Systematic Review.

INTRODUCTION: Pelvic metastasis is a common presentation among patients presenting with skeletal metastasis. Image-guided percutaneous cementation of these lesions is becoming increasingly popular for the treatment of these lesions. The objective of this study was to conduct a systematic review that investigates clinical outcomes after percutaneous cementation for pelvic metastasis. METHODS: A systematic review was registered with International Prospective Register of Systematic Reviews and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I to IV clinical studies published in the English language investigating the clinical outcomes after percutaneous cementation for pelvic metastasis were included. RESULTS: Fourteen studies with 579 patients (278 men, 301 women) and 631 metastatic pelvic lesions were included in the study. The mean follow-up range was 0.7 to 26.4 months. Percutaneous cementation alone was performed in 441 patients (76.2%). Supplemental ablative procedures were performed in 77 patients (13.3%), and supplemental internal fixation using cannulated screws was performed in 107 patients (18.5%). Twelve studies with 430 patients (74.2%) reported pain-related and/or functional outcome scores, of which all studies reported overall clinically notable improvement at short-term follow-up. All studies reported periprocedural complications. Local cement leakage was the most common complication (162/631 lesions, 25.7%) followed by transient local pain (25/579 patients, 4.3%). There were no reported cases of major complications. Seven patients (1.2%) underwent re-intervention for persistent symptoms. CONCLUSIONS: Percutaneous cementation may be an effective method for treating pain and function related to pelvic metastasis. The most common complication was cement leakage surrounding the lesion. The rates of major complications were low, and most complications appeared minor and transient. Additional prospective studies are needed to further assess the efficacy of this procedure. LEVEL OF EVIDENCE: IV, systematic review of level I to IV therapeutic studies.

Cinobufotalin Capsule Combined with Zoledronic Acid in the Treatment of Pain Symptoms and Clinical Efficacy in Prostate Cancer Patients with Bone Metastases: A Retrospective Study.

OBJECTIVE: To retrospectively analyse the effects of cinobufotalin capsule combined with zoledronic acid on pain symptoms and clinical efficacy of prostate cancer patients with bone metastases. METHODS: Patients with prostate cancer with bone metastasis admitted to our hospital from January 2021 to December 2022 were selected as study subjects. They were divided into the control group (treated with zoledronic acid) and the combined group (cinobufotalin capsules were added on the control group basis) according to different recorded treatment methods. The efficacies of the two groups after matching, lumbar L1-4 bone mineral density (BMD), serum calcium, serum phosphorus, visual analogue scale (VAS) score and Karnofsky performance status (KPS) score before and after treatment were compared, and adverse reactions were statistically analysed. RESULTS: A total of 102 patients were included in the study, encompassing 52 patients in the combined group and 50 patients in the control group. After 1:1 preference score matching, 64 patients were included in the two groups. No significant difference in baseline data was found between the two groups (p > 0.05). The total effective rate of the combination group was higher than that of the control group (p < 0.05). No significant differences in L1-4 bone mineral density, serum calcium and phosphorus, VAS score and KPS score were observed between the two groups prior to treatment (p > 0.05). After treatment, the L1-4 bone mineral density (BMD) and KPS score of the combined group decreased to less than those of the control group, the VAS score was lower than that of the control group, and the serum calcium and phosphorus level increased but less than that of the control group (p < 0.05). No significant difference in adverse reactions was found between the two groups (p > 0.05). CONCLUSIONS: Cinobufotalin capsule combined with zoledronic acid had ideal efficacy in the treatment of prostate cancer in patients with bone metastasis. This approach could improve their bone density and quality of life, improve their calcium and phosphorus metabolism, reduce their pain symptoms and provide increased safety. It may have an important guiding role in formulating future clinical treatment plans for patients with prostate cancer and bone metastasis.

[Osteosarcoma Secondary to Polyostotoic Fibrous Dysplasia of the Ribs].

Sarcomatous transformation of fibrous dysplasia is extremely rare. We present the case of a 54-yearold man with multiple rib masses, multiple enlarged lymph nodes throughout the body, and multiple osteolytic lesions on computed tomography( CT). A positron emission tomography( PET) scan showed abnormal enhancement in each. A needle biopsy of the right supraclavicular fossa lymph node revealed sarcoidosis. Considering the possibility of malignancy associated with sarcoidosis, a rib tumor resection and mediastinal lymph node biopsy were performed to confirm the diagnosis of the rib lesion. The pathology results showed that the rib mass was a low-grade central osteosarcoma and the mediastinal lymph node was sarcoidosis. The distribution of the lesions was consistent with osteosarcoma secondary to multiple fibrous bone dysplasia. As the osteosarcoma was low grade, the patient was followed up. Three years after surgery, there was no increase in residual disease.

Sweet syndrome with peripheral neuropathy in a patient with metastatic clear cell renal cell carcinoma.

A female patient in her 70s with a newly diagnosed clear cell renal cell carcinoma (ccRCC) with osseous metastasis presented with sudden onset erythematous painful blistering skin lesions on the dorsum of both hands, with associated intermittent fever episodes. Blood tests showed elevated inflammatory marker levels (C reactive protein 257.8 mg/dL, leucocytes 17.79×109/L, with 94% neutrophils). Histologically, there was predominately neutrophil dermal infiltrate without leucocytoclastic vasculitis. The diagnostic criteria of Sweet syndrome were fulfilled. A week later, the patient developed abrupt left-hand palsy, which was confirmed as a medial and ulnar sensorimotor axonal peripheral neuropathy of paraneoplastic origin. The patient was prescribed a course of oral high-dose steroids, which significantly improved the skin lesions. The peripheral nerve palsy improved after 3 months. This case describes the two very rare concurrent paraneoplastic manifestations of ccRCC occurring simultaneously, which have been rarely reported.

Reconstruction of the extensor mechanism using polypropylene mesh in a displaced pathological fracture of the patella affected by giant cell tumour.

A man in his 30s came to our clinic with a year-long history of progressive pain and swelling in his knee. Diagnostic imaging revealed a displaced patellar fracture with an osteolytic, septated lesion and thinned expanded cortex in both fracture fragments. A core needle biopsy confirmed the diagnosis of giant cell tumour. Treatment involved wide excision of the tumour and the use of polypropylene mesh and a peroneal longus tendon autograft to reconstruct the extensor mechanism of the knee joint. One year postoperatively, the patient experienced no pain, demonstrated full range of motion and showed no signs of functional impairment or local tumour recurrence. This case highlights that reconstruction of the extensor mechanism of the knee after tumour excision with synthetic mesh is an affordable, user-friendly and widely accessible method. It can address large defects effectively while minimising the risks of disease transmission and graft lengthening, resulting in satisfactory outcomes.

Comparative Analysis of Stereotactic Radiation Therapy and Conventional Radiation Therapy in Cancer Pain Control: A Systematic Review and Meta-Analysis.

AIMS: Approximately 55% of patients diagnosed with primary or metastatic cancer endure pain directly attributable to the disease. Consequently, it becomes imperative to address pain management through a comparative analysis of stereotactic radiotherapy (SRT) and conventional radiation therapy (CRT), especially in light of the less efficacious improvement achieved solely through pharmacological interventions. MATERIALS AND METHODS: A systematic exploration was undertaken on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies that compare Stereotactic Radiotherapy to Conventional radiation therapy for pain management in individuals with metastatic bone cancer. The analyses were executed utilizing the random-effects model. RESULTS: A cohort of 1152 participants with metastatic bone cancer was analyzed, demonstrating significantly higher complete pain relief in the Stereotactic Radiotherapy group during both early and late follow-up (RR: 1.61; 95% CI: 1.17, 2.23, p-value: 0.004; I2: 0%). Stereotactic Radiotherapy also showed a non-significant increase in the incidence of partial pain relief (RR: 1.07; 95% CI: 0.85, 1.34, p-value: 0.56; I2: 18%). Furthermore, Stereotactic Radiotherapy was associated with a significantly reduced risk of stationary pain throughout follow-up (RR: 0.61; 95%CI: 0.48, 0.76, p-value: <0.0001; I2: 0. The incidence of progressive pain was non-significantly reduced with Stereotactic Radiotherapy during both early and late follow-up (RR: 0.77; 95% CI: 0.50, 1.17, p-value: 0.22; I2: 0%). Secondary outcomes exhibited a non-significant trend favoring Stereotactic Radiotherapy for dysphagia, esophagitis, pain, and radiodermatitis, while a non-significant increase was observed for nausea, fatigue, and vertebral compression fracture. CONCLUSION: In summary, stereotactic radiation therapy (SRT) has improved in achieving complete pain relief while exhibiting a decreased probability of delivering stationary pain compared to conventional radiation therapy (CRT). Nevertheless, it is crucial in future research to address a noteworthy limitation, specifically, the risk of vertebral compression fracture.

Ghrelin Induces the Production of Hypothalamic NPY Through the AMPK-mTOR Pathway to Alleviate Cancer-induced Bone Pain.

BACKGROUND/AIM: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms. MATERIALS AND METHODS: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured. RESULTS: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist. CONCLUSION: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.

Neoplastic pathologic hip fractures are associated with a higher risk of post-operative bleeding and thromboembolic events.

INTRODUCTION: Surgical treatment of hip fractures leads to significant post-operative complications. Although pathologic fractures (PF) are associated with worse outcomes, most studies do not differentiate between etiology (neoplastic and non-neoplastic PF). We seek to compare 30-day complication rates between 1) native hip fractures and neoplastic PF, and 2) neoplastic and non-neoplastic PF. MATERIALS AND METHODS: A total of 127,819 patients with hip fractures and 5104 with PF diagnosed from 2005 to 2021 were retrieved from the NSQIP database. We included 1843 patients with neoplastic PF and 3261 with non-neoplastic PF. Demographics, pre-operative labs and co-morbidities, and post-operative outcomes were analyzed. Propensity-score matching was conducted to control for confounders. RESULTS: Patients with a neoplastic PF had a significantly higher rate of deep venous thrombosis (DVT) (4 % vs 1.2 %, p = 0.001) and pulmonary embolism (PE) (2.4 % vs 0.7 %, p < 0.001), than native hip fractures. Rates of post-operative bleeding were significantly higher in the neoplastic PF group (29.3 % vs 23.9 %, p < 0.001) than non-neoplastic PF. No differences in soft tissue complications were found. When comparing neoplastic and non-neoplastic PF, the former had a higher rate of PE (2.5 % vs 1.0 %, p = 0.015) and post-operative bleeding (27.6 % vs 22.0 %, p = 0.009). Unplanned readmission rates and 30-day mortality rate were also higher in the neoplastic PF group. CONCLUSION: Neoplastic PF of the hip are associated with higher risk of thromboembolic event rates and post-operative bleeding than both native hip fractures and non-neoplastic PF. No differences in rates of soft tissue complications were found between groups.

Effects of palliative intrathecal analgesia on patients with refractory cancer bone pain.

This study examined the effects of intrathecal analgesia (ITA) using an extracorporeal pump with a subcutaneous port system in cancer patients with bone metastasis. Among the patients who died of cancer with bone metastasis at the palliative care unit of our institution, 11 who received ITA were selected. Changes in pain, opioid doses, the palliative prognostic index (PPI), and Eastern Cooperative Oncology Group Performance Scale　after ITA were assessed. Pain, opioid doses, and PPI decreased after ITA (P = 0.002, 0.002, and 0.017). ITA for cancer patients with increased PPI due to refractory cancer bone pain decreased pain, opioid doses, and PPI.(100 words).

Hepatocellular carcinoma and musculoskeletal system: A narrative literature review.

Musculoskeletal alterations in hepatocellular carcinoma (HCC) are less common than liver-related complications. However, they can significantly impact the quality of life and overall prognosis of patients with HCC. The main obstacle in the clinical assessment of HCC-induced musculoskeletal alterations is related to effective and timely diagnosis because these complications are often asymptomatic and unapparent during routine clinical evaluations. This narrative literature review aimed to provide a comprehensive overview of the contemporary literature related to the changes in the musculoskeletal system in patients with HCC, focusing on its clinical implications and underlying etiopathogenetic mechanisms. Osteolytic bone metastases are the most common skeletal alterations associated with HCC, which could be associated with an increased risk of low-trauma bone fracture. Moreover, previous studies reported that osteopenia, sarcopenia, and myosteatosis are associated with poor clinical outcomes in patients with HCC. Even though low bone mineral density and sarcopenia are consistently reported as reliable predictors of pretransplantation and post-transplantation mortality in HCC patients, these complications are frequently overlooked in the clinical management of patients with HCC. Taken together, contemporary literature suggests that a multidisciplinary approach is essential for early recognition and clinical management of HCC-associated musculoskeletal alterations to improve patient prognosis. Further research into the mechanisms and treatment options for musculoskeletal complications is warranted to enhance our understanding and clinical management of this aspect of HCC.

Curcumin analogue NL04 inhibits spinal cord central sensitization in rats with bone cancer pain by inhibiting NLRP3 inflammasome activation and reducing IL-1ß production.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 µg/kg and 489.6 µg/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dose-dependently lowered spinal IL-1ß and IL-18 levels and significantly reduced the expression of IKKß genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKKß expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1ß production, potentially ameliorating pain management in BCP.

Spinal sirtuin 2 attenuates bone cancer pain by deacetylating FoxO3a.

Bone cancer pain (BCP) is refractory to currently used analgesics. Recently, sirtuin 2 (SIRT2) was reported to play a vital role in neuropathic pain but its role in BCP remains unknown. It was hypothesized that spinal SIRT2 attenuates BCP by deacetylating FoxO3a and suppressing oxidative stress. The mouse model of BCP established by injecting tumor cells into the intramedullary space of the femur demonstrated that spinal SIRT2 and FoxO3a were downregulated in BCP development. Intrathecal administration of LV-SIRT2 reduced pain hypersensitivity (mechanical and thermal nociception) in BCP mice. Spinal SIRT2 overexpression upregulated FoxO3a and antioxidant genes (SOD2 and catalase) and inhibited FoxO3a acetylation, phosphorylation, and ubiquitination. Moreover, intrathecal administration of SIRT2 shRNA induced pain hypersensitivity in normal mice. Spinal SIRT2 knockdown downregulated FoxO3a and antioxidant genes and increased FoxO3a acetylation, phosphorylation, and ubiquitination. In summary, spinal SIRT2 increases FoxO3a expression in BCP mice and inhibits oxidative stress by deacetylating FoxO3a and further reducing FoxO3a phosphorylation, ubiquitination, and degradation, leading to BCP relief.