Altered Functional Connectivity in Pain-Related Brain Regions and Its Correlation with Pain Duration in Bone Metastasis with Cancer Pain.

Bone metastatic pain is thought to be a severe type of cancer pain that has refractory characteristics and a long duration. This study is aimed at exploring the brain functional connectivity (FC) pattern in lung cancer patients with bone metastatic pain. In this study, 27 lung cancer patients with bone metastatic pain (CP+), 27 matched lung cancer patients without pain-related complaints (CP-), and 27 matched healthy controls (HC) were recruited. All participants underwent fMRI data acquisition and clinical assessments. One-way ANOVA or a Mann-Whitney U test was applied to compare clinical data according to data distribution. Seventeen hypothesis-driven pain-related brain regions were selected as regions of interest (ROIs). FC values among pain-related brain regions across the three groups were computed by using ROI-ROI functional connectivity analysis. ANCOVA with a post hoc test was applied to compare FC differences among the three groups. p < 0.05 indicated statistical significance. Correlation analysis was conducted to explore the potential relationship between the FC values and clinical characteristics. Except for years of education, no significant differences were revealed among the three groups in age, gender, or neuropsychological assessment. In the CP+ group, FC alterations were mainly concentrated in the dorsal lateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), secondary somatosensory cortex (SII), and amygdala compared to the CP- group. Among these brain regions with statistical differences, FC between the right DLPFC and the right ACC showed a positive correlation with the duration of cancer pain in the CP+ group. In addition, in the CP- group, altered FC was found in the bilateral SII, ACC, and thalamus compared to the HC group. Altered FC in pain-related brain regions may be a brain pattern of bone metastatic pain and may be associated with the long duration of cancer pain.

Neuroablative surgical treatments for pain due to cancer.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

Breast cancer survivors living with chronic neuropathic pain show improved brain health following mindfulness-based stress reduction: a preliminary diffusion tensor imaging study.

PURPOSE: The present study explores the benefits of an 8-week mindfulness-based stress reduction (MBSR) program to white matter integrity among breast cancer survivors experiencing chronic neuropathic pain (CNP). METHODS: Twenty-three women were randomly assigned to either a MBSR treatment group (n = 13) or a waitlist control group (n = 10). Participants were imaged with MRI prior to and post-MBSR training using diffusion tensor imaging. RESULTS: Compared with controls, the MBSR group showed a significant increase in fractional anisotropy (FA), particularly in the left subcortical regions including the uncinate fasciculus, amygdala, and hippocampus, as well as in the external capsule and in the left sagittal stratum. No decreases to FA were found in any brain regions following MBSR training. The FA values also negatively correlated with the pain severity and pain interference scores from the BRIEF pain questionnaire. CONCLUSIONS: The present findings demonstrate that MBSR training may enhance the integrity of cerebral white matter that coincides with a reduction in pain perception. Further research with a larger sample size is required. IMPLICATIONS FOR CANCER SURVIVORS: This study highlights the potential for MBSR, as a non-pharmacological intervention, to provide both brain health improvement and pain perception relief for female breast cancer survivors experiencing CNP.

Pulsed Radiofrequency of the Sacral Roots Improves the Success Rate of Superior Hypogastric Plexus Neurolysis in Controlling Pelvic and Perineal Cancer Pain.

BACKGROUND: Superior hypogastric plexus neurolytic (SHP-N) block is the mainstay management for pelvic cancer pain of visceral origin when oral opioids fail due to inefficacy or intolerance to side effects. Unfortunately, SHP-N has the potential to control pelvic pain in 62%-72% of patients at best, because chronic pelvic pain may assume additional characteristics other than visceral. OBJECTIVE: Combining SHP-N with pulsed radiofrequency (PRF) of the sacral roots might block most of the pain characteristics emanating from the pelvic structures and improve the success rate of SHP-N in controlling pelvic and perineal cancer pain. STUDY DESIGN: This study was a prospective randomized controlled clinical trial. SETTINGS: The research took place in the interventional pain unit of a tertiary center in the university hospital. METHODS: Fifty-eight patients complaining of cancer-related chronic pelvic and perineal pain were randomized to either the PRF + SHP group (n = 29), which received SHP-N combined with PRF of the sacral roots S2-4, or the SHP group (n = 29), which received SHP-N alone. The outcome variables were the percentage of patients who showed a > 50% reduction in their Visual Analog Scale (VAS) pain score, the VAS pain score, and global perceived effect evaluated during a 3-month follow-up period. RESULTS: The percentage of patients who showed a > 50% reduction in their VAS pain score was significantly higher in the SHP + PRF group compared to the SHP group when assessed at one month (92.9% [n = 26] vs 57.7% [n = 15]; P = .003) and 3 months (85.7% [n = 24) vs 53.8% [n = 14]; P = .01) post procedure, respectively. However, no significant difference was observed between the 2 groups at the 6-month evaluation (SHP + PRF [57.1% (n = 16)] vs SHP [50% (n = 13)]; P = .59). There was a statistically significant reduction of VAS in the SHP + PRF group in comparison to the SHP group at one month (2.8 ± 0.9 vs 3.5 ± 1.2 [mean difference, -0.7 (95% confidence interval [CI], -1.29 to -0.1), P = .01]), 2 months (2.8 ± 0.9 vs 3.5 ± 1.2 [mean difference, -0.64 (95% CI, -1.23 to -0.05), P = .03]), and 3 months (2.7 ± 1 vs 3.4 ± 1.2 [mean difference, -0.67 (95% CI, -1.29 to -0.05)], P = .03]) post procedure, respectively; however, the 2 groups did not significantly differ at 2 weeks, 4, 5, and 6 months post procedure. Regarding postprocedural analgesic consumption, there were trends towards reduced opioid consumption at all postprocedural measured time points in the SHP+PRF group compared to the SHP group; these differences reached statistical significance at 2 months (median, 30 [interquartile range (IQR), 0.00-30] vs median, 45 [IQR, 30-90]; P = .046) and 3 months (median, 0.00 [IQR, 0.00-30] vs median, 30 [IQR, 0.00-67.5]; P = .016) post procedure, respectively. LIMITATIONS: The study follow-up period is limited to 6 months only. CONCLUSIONS: SHP-N combined with PRF of the sacral roots (S2, 3, 4) provided a better analgesic effect than SHP-N alone for patients with chronic pelvic and perineal pain related to pelvic cancer. TRIAL REGISTRY: ClinicalTrials.gov. NCT03228316. KEY WORDS: Pelvic pain, pulsed radiofrequency, sacral roots, superior hypogastric plexus.

Computed tomography-guided paravertebral doxorubicin injection for refractory pain in patients with spinal metastases: Two case reports.

RATIONALE: Diagnosing and treating refractory cancer pain have become standardized and effective procedures with guidance from the Expert Consensus on Refractory Cancer Pain released in 2017 by the Committee of Rehabilitation and Palliative Care of China. Doxorubicin has been used for perineural injection in the treatment of chronic non-cancer pain owing to its retrograde sensory ganglion resection effect. Our study reports a new fourth-ladder treatment for cancer pain: CT-guided paravertebral doxorubicin injection for patients with refractory cancer pain caused by paraspinal metastasis. PATIENT CONCERNS: A 48-year-old female and a 47-year-old male patients suffered from refractory cancer pain over the past months. They had both undergone surgical tumor resection, chemotherapy, and precision radiotherapy but result in limited analgesic effect. The daily oral morphine dosage was around 60 to 100 mg and rescue analgesic methods had been used at the time. DIAGNOSES: Refractory cancer pain in 2 patients with renal cancer and hepatobiliary adenocarcinoma. INTERVENTIONS: The patients both received computed tomography (CT)-guided 1 mL of 0.5% doxorubicin paravertebral injection at each affected nerve root segments. OUTCOMES: The Visual Analog Scale and Douleur Neuropathique four Questions were used for 6-month follow-up, and the analgesic requirement was also recorded. The patients enjoyed satisfactory analgesia for up to 6 months without adverse reaction. In addition, the oral opioid analgesic doses were significantly reduced after the neurolytic block. LESSONS: The CT-guided paravertebral doxorubicin injection was an effective fourth-step analgesic interventional technology that allowed our 2 patients with refractory cancer pain to maintain satisfactory analgesia. This analgesia method taken at an appropriate stage, according to the latest analgesic concept, results in good analgesia and opioid use reduction. Also, with the imaging guidance, only a small amount of neurolytic agent is needed to achieve analgesia in a precise and safe way.

Painful Inguinal Angiomyomatous Hamartoma Responsive to Conservative Pain Management: A Case Report.

Angiomyomatous hamartoma (AMH) is a rare and benign mixed-tissue tumor of the lymphatic system. The majority of AMH tumors are removed surgically for cosmetic reasons or during workup of lymphadenopathy. There are few reported cases of this condition in the literature; AMH does not cause pain, and there are no published reports of AMH recurring after surgical excision. Here, we report a unique case of inguinal AMH recurring after surgical excision and causing a painful compression neuropathy. Our report also describes the patient's successful but transient response to nonsurgical pain management.

Interventional Pain Treatments in the Management of Oncologic Patients With Thoracic Spinal Tumor-Related Pain: A Case Series.

BACKGROUND: Advanced tumors of the thoracic spine are difficult to treat and can lead to complex pain syndromes. Following conventional oncologic treatments, pharmacologic therapy may be insufficient to manage pain. Minimally invasive interventional procedures offer alternatives to treat malignant thoracic spinal pain. METHODS: Thirteen patients with metastatic disease and poorly controlled thoracic axial and/or radicular pain were identified via a retrospective chart review. Patients were either treated with radiation, surgery, chemotherapy, or a combination of these. Then, the patients were organized into groups based on their diagnoses, anatomical disease locations, symptoms, prior treatments, and interventional pain procedures offered. RESULTS: All cases of intercostal nerve, costotransverse junction, erector spinae plane, and paravertebral blocks resulted in pain relief without any reported complications. A patient who received a thoracic epidural injection had a complete resolution of pain when combined with radiation therapy 2 weeks after the injection. One patient who underwent repeat thoracic epidural injections eventually had an intrathecal pump placement, resulting in reduced opioid usage. Finally, 1 patient who received a thoracic medial branch block with a relief of thoracic axial pain reported greater pain relief with a medial branch nerve cryoablation. CONCLUSION: We propose a treatment algorithm to manage patients with thoracic spinal tumor-related pain. Interventional thoracic axial procedures may be safe and efficacious pain treatments for patients with cancer.

Longitudinal FDG-PET scan study of brain changes in mice with cancer-induced bone pain and after morphine analgesia.

Morphine is the most commonly used drug for treating physical and psychological suffering caused by advanced cancer. Although morphine is known to elicit multiple supraspinal analgesic effects, its behavioral correlates with respect to the whole-brain metabolic activity during cancer-induced bone pain have not been elucidated. We injected 4T1 mouse breast cancer cells into the left femur bone marrow cavity of BALB/c mice. All mice developed limb use deficits, mechanical allodynia, and hypersensitivity to cold, which were effectively suppressed with morphine. Serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed for each mouse before cancer induction (0 day), after cancer-induced bone pain was established (14 days), and during effective morphine treatment (16 days). The longitudinal FDG-PET imaging analysis demonstrated that cancer-induced bone pain increased glucose uptake in the insular cortex and hypothalamus and decreased the activity of the retrosplenial cortex. Morphine reversed the activation of the insular cortex and hypothalamus. Furthermore, morphine activated the amygdala and rostral ventromedial medulla and suppressed the activity of anterior cingulate cortex. Our findings of hypothalamic and insular cortical activation support the hypothesis that cancer-induced bone pain has strong inflammatory and affective components in freely moving animals. Morphine may provide descending inhibitory and facilitatory actions in the treatment of cancer-induced bone pain in a clinical setting.

Focal breast pain: imaging evaluation and outcomes.

OBJECTIVES: To determine the number and characteristics of cancers detected and the optimal imaging evaluation in women presenting with focal breast pain (FBP). MATERIALS AND METHODS: We performed a retrospective review of 4720 women who underwent imaging for FBP from 2001 to 2013. Women 18 and over with one or two foci of breast pain and no concurrent breast symptoms were included. 944 patients met criteria. We recorded the imaging work-up, presence and type of finding at the site of pain, BI-RADS® assessment, and pathological outcomes. Subsequent imaging and clinical follow up was recorded. RESULTS: Imaging evaluation consisted of sonogram alone in 286 women, mammogram alone in 231 women, and both in 427 women. 113 women had an imaging finding at the site of pain; 103 were designated benign or probably benign. 12 biopsies of corresponding findings were performed: 9 benign, 1 invasive lobular carcinoma, 1 invasive ductal carcinoma, 1 ductal carcinoma in situ. All three malignancies were seen mammographically; 2 had an ultrasound correlate. At initial evaluation, 4 incidental breast cancers were diagnosed remote from the site of FBP. All were seen on mammogram and 2 of 4 had an ultrasound correlate. On follow up evaluation, 9 cancers were diagnosed at the site of pain and 13 incidental cancers were diagnosed. CONCLUSION: FBP is rarely associated with malignancy. Targeted ultrasound may be deferred in women 40 and older with FBP, no other clinical findings, and a negative mammogram.

Ce-141-labeled DOTMP: A theranostic option in management of pain due to skeletal metastases.

Owing to its favorable radioactive decay characteristics (T1/2  = 32.51 d, Eß [max] = 434.6 keV [70.5%] and 580.0 keV [29.5%], Eγ  = 145.4 keV [48.5%]), 141 Ce could be envisaged as a theranostic radionuclide for use in nuclear medicine. The present article reports synthesis and evaluation of 141 Ce complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP) as a potent theranostic agent targeting metastatic skeletal lesions. Ce-141 was produced with 314 ± 29 MBq/mg (n = 6) specific activity and >99.9% radionuclidic purity (n = 6). Around 185 MBq dose of [141 Ce]Ce-DOTMP was synthesized with 98.6 ± 0.5% (n = 4) radiochemical yield under optimized conditions of reaction, and the preparation showed adequately high in vitro stability. Biodistribution studies in normal Wistar rats demonstrated significant skeletal localization and retention of injected activity (2.73 ± 0.28% and 2.63 ± 0.22% of injected activity per gram in femur at 3 hours and 14 days post-injection, respectively) with rapid clearance from non-target organs. The results of biodistribution studies were corroborated by serial scintigraphic imaging studies. These results demonstrate the potential utility of 141 Ce-DOTMP as a theranostic molecule for personalized patient care of cancer patients suffering from painful metastatic skeletal lesions.

Prospective administration of anti-nerve growth factor treatment effectively suppresses functional connectivity alterations after cancer-induced bone pain in mice.

Cancer-induced bone pain is abundant among advanced-stage cancer patients and arises from a primary tumor in the bone or skeletal metastasis of common cancer types such as breast, lung, or prostate cancer. Recently, antibodies targeting nerve growth factor (NGF) have been shown to effectively relieve neuropathic and inflammatory pain states in mice and in humans. Although efficacy has been shown in mice on a behavioral level, effectiveness in preventing pain-induced functional rearrangements in the central nervous system has not been shown. Therefore, we assessed longitudinal whole-brain functional connectivity using resting-state functional magnetic resonance imaging in a mouse model of cancer-induced bone pain. We found functional connectivity between major hubs of ascending and descending pain pathways such as the periaqueductal gray, amygdala, thalamus, and cortical somatosensory regions to be affected by a developing cancer pain state. These changes could be successfully prevented through prospective administration of a monoclonal anti-NGF antibody (mAb911). This indicates efficacy of anti-NGF treatment to prevent pain-induced adaptations in brain functional networks after persistent nociceptive input from cancer-induced bone pain. In addition, it highlights the suitability of resting-state functional magnetic resonance imaging readouts as an indicator of treatment response on the basis of longitudinal functional network changes.

Decitabine attenuates nociceptive behavior in a murine model of bone cancer pain.

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain, and as patients with cancer are living longer, new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in preclinical models of postsurgical and soft-tissue oral cancer pain by inducing an upregulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2 µg/g, intraperitoneally) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of ß-endorphin in the cell supernatant, which reduced the number of responsive dorsal root ganglia neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Activation of the P2X7 receptor in midbrain periaqueductal gray participates in the analgesic effect of tramadol in bone cancer pain rats.

Background Cancer pain is a well-known serious complication in metastatic or terminal cancer patients. Current pain management remains unsatisfactory. The activation of spinal and supraspinal P2X7 receptors plays a crucial role in the induction and maintenance mechanisms of various kinds of acute or chronic pain. The midbrain periaqueductal gray is a vital supraspinal site of the endogenous descending pain-modulating system. Tramadol is a synthetic, centrally acting analgesic agent that exhibits considerable efficacy in clinically relieving pain. The purpose of this study was to determine whether the activation of P2X7 receptor in the ventrolateral region of the periaqueductal gray (vlPAG) participates in the analgesic mechanisms of tramadol on bone cancer pain in rats. The bone cancer pain rat model was established by intratibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The analgesic effects of different doses of tramadol (10, 20, and 40 mg/kg) were assessed by measuring the mechanical withdrawal threshold and thermal withdrawal latency values in rats by using an electronic von Frey anesthesiometer and radiant heat stimulation, respectively. Alterations in the number of P2X7 receptor-positive cells and P2X7 protein levels in vlPAG were separately detected by using immunohistochemistry and Western blot assay. The effect of intra-vlPAG injection of A-740003 (100 nmol), a selective competitive P2X7 receptor antagonist, on the analgesic effect of tramadol was also observed. Results The expression of P2X7 receptor in the vlPAG on bone cancer pain rats was mildly elevated, and the tramadol (10, 20, and 40 mg/kg) dose dependently relieved pain-related behaviors in bone cancer pain rats and further upregulated the expression of P2X7 receptor in the vlPAG. The intra-vlPAG injection of A-740003 pretreatment partly but significantly antagonized the analgesic effect of tramadol on bone cancer pain rats. Conclusions The injection of tramadol can dose dependently elicit analgesic effect on bone cancer pain rats by promoting the expression of the P2X7 receptor in vlPAG.

Nuclear factor kappa B regulated monocyte chemoattractant protein-1/chemokine CC motif receptor-2 expressing in spinal cord contributes to the maintenance of cancer-induced bone pain in rats.

BACKGROUND: Chemokine, monocyte chemoattractant protein-1 (MCP-1), is a potential factor to cause cancer-induced bone pain (CIBP). NF-κB signaling is very important in mediating the expression of chemokines and may have a role in CIBP. However, the mechanism is still unclear. This study investigates the role of NF-κB in CIBP by regulating MCP-1/chemokine CC motif receptor-2 (CCR2) signaling pathway. METHODS: A rat CIBP model was established by injecting Walker-256 cells into the tibia medullary cavity. Nine days later, animals were intrathecally administrated with MCP-1 neutralizing antibody, CCR2 antagonist (RS504393), or NF-кB inhibitor (BAY11-7081). Mechanical paw withdrawal threshold was used to assess pain behavior and sciatic functional index, and radiographic images were adopted to evaluate the damage of nerve and bone. The spinal cords were harvested for Western blot and quantitative reverse transcription polymerase chain reaction. The distribution of MCP-1, CCR2, and NF-кB was detected by double immunofluorescent staining. RESULTS: CIBP caused remarkable bone destruction, injury of sciatic and femoral nerve, and persistent (>15 days) mechanical allodynia in rats. Tumor cell inoculation upregulate MCP-1 and NF-кB in activated neurons as well as CCR2 in neurons and microglia of the spinal cord. MCP-1 antibody, RS504393, and BAY11-7081 partially reversed CIBP-induced mechanical allodynia, and CIBP regulated the expression levels of pro-inflammatory cytokines, tumor necrosis factor-α and interferon-γ, and anti-inflammatory cytokine, interleukin 4, and BAY11-7081 lowered CIBP-induced MCP-1 and CCR2 expressions in a dose-dependent manner. CONCLUSION: In conclusion, NF-кB signaling pathway regulates the expressions of MCP-1/CCR2-induced inflammatory factors in the spinal cord of CIBP rats.

Supraclavicular Brachial Plexus Neurolysis for a Malignant Peripheral Nerve Sheath Tumor: A Case Report.

The perineural administration of alcohol or phenol results in protein denaturation and, consequently, neurolysis. This can produce long-lasting analgesia, with a duration of 3-6 months. Although neurolytic blocks for the brachial plexus have been described in multiple review articles and textbooks, they are rarely performed. As such, little is known about the efficacy and adverse effect profile of this commonly described treatment. In this article, we report the outcomes of a patient who underwent a left brachial plexus neurolytic block for the management of upper limb pain arising from a malignant peripheral nerve sheath tumor.

CT guided neurolytic blockade of the coeliac plexus in patients with advanced and intractably painful pancreatic cancer.

BACKGROUND AND AIMS: Pain caused by infiltrating pancreatic cancer is complex in nature and may therefore be difficult to treat. In addition to conventional analgesics, neurolytic blockade of the coeliac plexus is often recommended. However, different techniques are advocated, and procedures vary, and the results may therefore be difficult to compare. Therefore strong evidence for the effect of this treatment is still lacking, and more studies are encouraged. Our aim was to describe our technique and procedures using a Computer Tomograph (CT) guided procedure with a dorsal approach and present the results. METHODS: The procedures were performed in collaboration between a radiologist and an anaesthesiologist. All patients had advanced pancreatic cancer. The patients were placed in prone position on pillows, awake and monitored. Optimal placement of injection needles was guided by CT, and the radiologist injected a small dose of contrast as a control. When optimal needle position, the anaesthesiologist took over and completed the procedure. At first 40 mg methylprednisolone was injected to prevent inflammation. Thereafter a mixture of 99% ethanol diluted to 50% by ropivacaine 7.5 mg/mL to a total amount of 20-30 mL per needle was slowly injected. Repeated aspiration was performed during injection to avoid intravasal injection. Pain treatment and pain score was recorded and compared before and after the treatment. RESULTS: Eleven procedures in 10 patients were performed. Age 49-75, mean 59 years. Median rest life time was 36 days (11-140). Significant reduction of analgesics was observed 1 week after the procedure, and most patients also reported reduction of pain. No serious side effects were observed. CONCLUSIONS: CT guided neurolytic celiac plexus blockade is a safe and effective treatment for intractable pain caused by advanced pancreatic cancer. Not all patients experience a significant effect, but the side effects are minor, and the procedure should therefore be offered patients experiencing intractable cancer related pain.

Tumoricidal effect and pain relief after concurrent therapy by strontium-89 chloride and zoledronic acid for bone metastases.

OBJECTIVE: The purpose of this study was to investigate the palliative and tumoricidal effects of concurrent therapy of strontium-89 chloride (89SrCl2) and zoledronic acid (ZA) for painful bone metastases. SUBJECTS AND METHODS: Fifty-one patients with painful bone metastases prostate cancer (n=17), lung cancer (n=13), breast cancer (n=12), other cancers (n=9) were treated. Bone metastases was confirmed in all patients by technetium-99m hydroxymethylene diphosphonate (99mTc-HMDP) bone scintigraphy. The numeric rating scale (NRS) and performance status (PS) were used to assess the degree of pain and patients' physical condition. The extent of bone metastases was assessed with imaging modalities including CT, MRI and/or 99mTc bone scintigraphy before treatment and 2 or 3 months after. RESULTS: The pain relief response of 89SrCl2 with ZA for bone metastases was 94% (48/51) from 1 to 3 months after treatment. The tumoricidal effect of concurrent therapy by 89SrCl2 with ZA for painful bone metastases was 8/22 as shown by imaging modalities and the rate of non-progressive disease (non-PD) was 19/22. Pain due to bone metastases assessed with the NRS was significantly improved (P<0.001) in many types of primary cancer, including prostate, breast and lung cancers. CONCLUSION: Concurrent therapy of 89SrCl2 with ZA may offer not only pain relief, but also a tumoricidal effect for painful bone metastases.

Spinal PKC activation - Induced neuronal HMGB1 translocation contributes to hyperalgesia in a bone cancer pain model in rats.

Bone cancer pain (BCP) remains a serious complication of malignancy, which is an intractable clinical problem due to the gap in knowledge of its underlying mechanisms. Recent studies have demonstrated that the major involvement of neuroinflammation, particularly high-mobility group box 1 (HMGB1), which was identified as a late mediator of inflammation, in a number of pain conditions. However, the underlying mechanisms and functions of HMGB1 release in spinal cord, and its contributions to the development of BCP as well, are poorly understood. In the present study, we examined the theory that PKC activation lead to nuclear translocation and cytosolic HMGB1 secretion, which subsequently induces spinal neuro inflammatory responses (cytokine release) causing hyperalgesia. Our results showed that PKC activation and HMGB1 release in spinal neurons as well as mechanical allodynia in BCP rats, were all attenuated by intrathecal administration of the PKC inhibitor Gö6983 and aggravated by its activator PMA. Intrathecal administration of anti-HMGB1 antibody also alleviated hypersensitivity caused by BCP. Meanwhile, phospho-PKC and cellular HMGB1 were found co-localized in neurons, but not in microglia and astrocytes, of the spinal dorsal horns of tumor-bearing rats. Additionally, we found that HMGB1 translocation from nuclei to cytoplasm may be the consequence of PKC translocation into the nuclei, which occurred 9 days after tumor inoculation. Total p-HMGB1 as well as nuclear and cytoplasmic HMGB1 expression levels were tested in response to broad-spectrum PKC inhibitor Gö6983 or activator PMA in BCP rats. Together, these findings suggest that bone cancer related hyperalgesia is driven by PKC induced phosphorylation of HMGB1, which results in its translocation from the nucleus, and releasing from the cytosol of the dorsal horn, and the activation of spinal pro-inflammatory mediators.