ß-Elemene Improves Morphine Tolerance in Bone Cancer Pain via N-Methyl-D-Aspartate Receptor 2B Subunit-Mediated µ-Opioid Receptor.

Background: Improving morphine tolerance (MT) is an urgent problem in the clinical treatment of bone cancer pain. Considering that ß-Elemene is widely used in the treatment of cancer pain, we explored the effects and mechanism of ß-Elemene in preventing MT of bone cancer pain. Method: Bone cancer pain and chronic MT rat model was established by injecting MADB106 cells and morphine (10 mg/kg). SH-SY5Y cells were treated with morphine (10 µg/mL) for 48 h to establish a cell model. The mechanical withdrawal threshold and thermal withdrawal latency of rats were detected by mechanical allodynia and thermal hyperalgesia tests, respectively. The protein expressions of µ-opioid receptor (MOPR), cyclic adenosine monophosphate (cAMP), N-methyl-D-aspartate receptor subunit 2B (NR2B), phosphorylated-calmodulin-dependent protein kinase II (p-CaMKII), and CaMKII were detected by western blot. The viability of SH-SY5Y cells was determined by the cell counting kit-8 assay. cAMP content in SH-SY5Y cells was measured by a LANCE cAMP kit. Result: Animal experiments showed that MT strengthened over time, while increased ß-Elemene dosage alleviated MT. The viability of SH-SY5Y cells was down-regulated by high-dose ß-Elemene. In the rat and cell models, long-term morphine treatment decreased the expression of MOPR and increased the cAMP and NR2B expressions and p-CaMKII/CaMKII, while ß-Elemene and siNR2B counteracted the effects of morphine treatment. In addition, siNR2B reversed the effects of ß-Elemene on related protein expressions and cAMP content in the cell model. Conclusion: ß-Elemene improved MT in bone cancer pain through the regulation of NR2B-mediated MOPR.

[Early intervention of bone-nearby acupuncture combined with electroacupuncture on morphine tolerance in bone cancer pain rats and its effect on the expression of HDAC and MOR in dorsal root ganglia].

OBJECTIVE: To observe the effect of early intervention of bone-nearby acupuncture (BNA) combined with electroacupuncture (EA) on the expression of histone deacetylase1(HDAC1), histone deacetylase 2 (HDAC2) andµ-opioid recepter (MOR) in dorsal root ganglia (DRG) of bone cancer pain-morphine tolerance (BCP-MT) rats, and to explore its possible mechanism. METHODS: A total of 35 SD rats were randomized into a sham BCP group (n=6), a BCP group (n=7), a MT group (n=7), a BNA+EA group (n=8) and a shame BNA group (n=7). Except of the sham BCP group, cancer cell inoculation operation at left tibia was given in the other 4 groups to establish the bone cancer pain model. In the MT group, the BNA+EA group and the shame BNA group, intraperitoneal injection of morphine hydrochloride was given to establish the morphine tolerance model. After the operation, bone-nearby acupuncture combined with electroacupuncture was applied at "Zusanli" (ST 36) and "Kunlun" (BL 60) in the BNA+EA group, with dilatational wave, 2 Hz/100 Hz in frequency, 0.5 to 1.5 mA in intensity. Intervention in the shame BNA group was applied at the same time and acupoints as those in the BNA+EA group, the needles were pierced the skin without any electrical stimulation. The needles were retained for 30 min, once a day for continuous 7 days in both BNA+EA and shame BNA groups. Before and 10, 11, 15, 22 days after the operation, the left paw withdrawal threshold (PWT) was measured in the 5 groups. The levels of HDAC1, HDAC2 and MOR in DRG were detected by Western blot. RESULTS: Ten days after the cancer cell inoculation operation, the PWT of the BCP, MT, BNA+EA and sham BNA groups was decreased compared with the sham BCP group (P<0.01). Eleven days after the operation, the PWT of the MT, BNA+EA and sham BNA groups was increased compared with the BCP group (P<0.01). Twenty-two days after the operation, the difference was no significant between the BCP group and MT group (P>0.05); the PWT of the BNA+EA group was increased compared with the MT and sham BNA group (P<0.01). In the BCP group, the DRG levels of HDAC1 and HDCA2 were increased, while the level of MOR was decreased compared with the sham BCP group (P<0.05, P<0.01). In the MT group, the DRG level of HDAC1 was increased compared with the BCP group (P<0.05). In the BNA+EA group, the DRG level of HDAC1 was decreased compared with the MT group and the sham BNA group (P<0.01, P<0.05), while the level of MOR was increased (P<0.01). CONCLUSION: Early intervention of bone-nearby acupuncture combined with electroacupuncture can relieve the morphine tolerance in bone cancer pain rats, it may relate to down-regulating the expression of HDAC1 and up-regulating the expression of MOR in the dorsal root ganglia.

Assessment of risk factors for occurrence or worsening of acetabular fracture following percutaneous cementoplasty of acetabulum malignancies.

PURPOSE: To evaluate the clinical, radiological and periprocedural features associated with the occurrence or worsening of acetabular fracture (OWAF) following percutaneous cementoplasty of the acetabulum (PCA) in cancer patients. METHOD: All patients who underwent PCA in our comprehensive cancer center for an acetabular metastasis between January 2008 and December 2015 were included. Clinical features, characteristics of the metastasis on computed tomography (CT-scan) (location [roof, quadrilateral surface, anterior and posterior columns], number of locations, matrix, extra/intra-articular fractures, extra-osseous or subchondral extensions) and of the procedure (extra- or intra-articular cement leakage (IACL), percentage of filling of each location, complications) were reported as well as prior, concomitant or post-PCA treatments. The endpoint was OWAF on CT-scan during post-PCA follow-up. Log-rank tests and Cox models were used to identify prognostic factors. RESULTS: 140 PCA were identified in 129 patients (11 bilateral procedures, median age: 66.6). Eighteen (18/140, 12.9%) had an initial articular fracture. IACL was seen in 12/140 (8.6%) PCA. The only feature associated with IACL was a pre-existing articular fracture (p = 0.009). Of the 111 patients with imaging follow-ups, 18 (16.2%) showed OWAF. In multivariate analysis, the presence of cement filling (even partial) of all acetabular metastatic locations was the only feature predictive of OWAF-free survival (hazard ratio = 3.8, p = 0.031). CONCLUSIONS: Injecting cement in all areas affected by acetabular metastases could prevent OWAF. Because survival following PCA is not negligible, completing an insufficient first PCA could help preserve patients' quality of life.

Qualitative study exploring patients experiences of being diagnosed and living with primary bone cancer in the UK.

OBJECTIVE: The aim of this study is to explore the experiences of patients with primary bone cancer. DESIGN: Qualitative study design using semistructured interviews and focus groups. SETTING: Hospitals across the UK and recruitment through UK sarcoma charities and support groups. METHODS: Semistructured telephone/face-to-face interviews and focus groups with a purposive sample of 26 participants. Data were analysed using Framework Analysis. PARTICIPANTS: Patients (n=26) with primary bone cancer aged 13-77 years. The majority were male (69%), white (85%); diagnosed within 4 years (54%); and had lower limb sarcoma (65%). Ten participants had undergone an upper/lower limb amputation (39%). RESULTS: The health-related quality-of-life domains of physical, emotional and social well-being and healthcare professionals' role were the overarching themes of analysis. The physical domain anchored patient experiences. The intensity and length of treatment, the severity of side-effects, the level of disability after surgery and the uncertainty of their prognosis had an impact on patient's self-image, confidence, mood and identity, and caused disruption to various aspects of the patients' social life, including their relationships (emotional and sexual) and participation in work/school and leisure activities. Adaptation was influenced by the way patients dealt with stress and adversity, with some finding a new outlook in life, and others struggling with finding their 'new normal'. Family and friends were the main source of support. Healthcare professional's expertise and support was critical. Rehabilitation services had a considerable role in patient's physical and emotional well-being, but inequitable access to these services was apparent. CONCLUSIONS: This study described the impact of primary bone cancer on patients' well-being and adjustment over time with the identification of influencing factors of better/worse experiences. It showed that impact was felt after end of treatment and affected patients at different life stages. Holistic models of survivorship care are needed.

[Photodynamic intramedullary bone stabilization of pathological fractures]. / Fotodynamische intramedulläre Knochenstabilisierung bei pathologischen Frakturen.

Pathological fractures of long tubular bones are stabilized with conventional implants. Essentially, plates and intramedullary nails are used for stabilization and are two different techniques, which compete with each other with respect to the surgical treatment. A large number of such means of osteosynthesis are commercially available but are primarily focused on acute fractures in otherwise biologically healthy bones. The pathological fracture or the treatment of impending pathological fractures due to metastatic osteolysis differs from the treatment of healthy bones in some fundamental aspects. The characteristics of pathological fractures make the development of new technologies that meet the specific needs of both the patient and the surgeon desirable. A new approach in treatment is stabilization of internal long bone fractures by the use of a cylindrical balloon implant, which is introduced into the bone via a small proximal or distal hole and then filled and expanded to a much larger diameter with a liquid monomer. The curing process is initiated with the application of blue light forming a rigid implant by polymerization (IlluminOss™). Many of the well-known disadvantages of conventional implants can be eliminated with this technology. Specifically, with respect to the irregular shape of the natural medullary canal it is possible to completely fill the medullary canal of the tubular bone. The filling of the canal provides torsional stability without the use of interlocking screws. Similarly, the use of the balloon technique enables minimally invasive surgery and furthermore permits the additive use of conventional metallic plates whenever necessary. The new balloon techniques show high primary stability in the treatment of pathological shaft fractures. In particular cases, the addition of a supplemental plate osteosynthesis is recommended.

Acupuncture for pain caused by prostate cancer: Protocol for a systematic review.

BACKGROUND: Prostate cancer is a male malignant tumor disease with high prevalence in recent years. Patients with advanced prostate cancer are more likely to have bone metastasis and strong bone pain, and even lead to pathological fracture, which has a serious impact on the quality of life of patients. Acupuncture has good clinical efficacy in treating pain caused by prostate cancer. This review hopes to adopt meta-analysis to evaluate the efficacy and safety of acupuncture in the treatment of pain caused by prostate cancer and provides evidence for its application in clinical practice. METHODS AND ANALYSIS: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet, Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to November 2018. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata 13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of epididymitis. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of acupuncture for pain caused by prostate cancer. Owing to the fact that all of the data used in this systematic review and meta-analysis have been published, this review does not require ethical approval. Furthermore, all data will be anonymously analyzed during the review process trial. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018111550.

Home care with acupuncture increased the quality of life in a patient with advanced cancer with neuropathic pain induced by bone metastasis: a case report.

A 66-year-old female patient was diagnosed with hepatocellular carcinoma accompanied by neuropathic pain induced by a metastatic tumor that compromised root and spinal canal. Although her pain was relieved following medical treatment, breakthrough pain occurring 1-2 times a day was still distressing. Neuropathic pain in her right lower limb caused discomfort and irritability and decreased her quality of life. We had limited options to adjust her prescription drug regime, due to the side effect of these drugs. Although acupuncture therapy was only performed at her home once a week, the efficacy was outstanding. The patient did not report any further instances of breakthrough pain, and she did not require additional bolus morphine. She could comfortably live in her familiar surroundings with her family and did not require any emergency room visits or admission into the hospital during the last month of her life. She had excellent quality of life in the terminal period of her life, and could even participate in a family function during this time. The present case report suggests that acupuncture may have a role in treating neuropathic pain induced by bone metastasis in patients with advanced cancer across clinical and in-home settings.

The Effect of Acupressure on Pain in Cancer Patients With Bone Metastasis: A Nonrandomized Controlled Trial.

BACKGROUND: Pain is a serious and common problem in bone metastases. For this purpose, complementary and supportive practices are also applied along with medical treatment. This study was conducted for the purpose of evaluating the effect of acupressure on pain in cancer patients with bone metastasis. METHODS: The study was conducted in a nonrandomized controlled trial with patients who applied to the radiotherapy unit of an oncology hospital. The data of the study were collected by using a questionnaire and the Visual Analog Scale. A total of 8 acupressure sessions, which lasted for approximately 10 minutes each (with warming and acupressure periods), was applied to the intervention group. The data were analyzed by using χ2 test, paired t test, and Pearson's correlation coefficient. RESULTS: It was determined that the pain mean score of the intervention group was 7.6 ± 1.9 before the acupressure and decreased to 6.8 ± 1.9 after the acupressure and this result was statistically significant. On the other hand, no significant difference was determined in the pain mean score of the control group. CONCLUSIONS: Acupressure is applicable for cancer patients with bone metastasis by nursing staff after receiving brief training and may make a difference in relieving pain of the patients. Further well-designed trials should be conducted.

Brachytherapy with iodine 125 seeds for bone metastases.

OBJECTIVE: To evaluate the treatment safety and efficacy of iodine 125 (I125) seeds implantation in patients with bone metastases and assess the availability of quality of life (QOL) as an index for efficacy evaluation. PATIENTS AND METHODS: The study enrolled 98 patients with 133 bone metastases from July 2010 to January 2016, who had undergone computed tomography-guided brachytherapy with I125 seeds. Brief pain inventory was administered to assess the degree of pain at the preoperative (W0) and postoperative 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks (W2, W4, W8, W12, and W24). Drug use, QOL score, and complications were also assessed. RESULTS: Postoperative pain scores were significantly decreased and maintained for a long term. Numerical rating scale score at W0 was 7.3 ± 1.6, which was decreased to 4.5 ± 1.7 (P < 0.01), 3.7 ± 1.3 (P < 0.01), 2.5 ± 1.1 (P < 0.01), 1.9 ± 0.9 (P < 0.01), and 1.3 ± 0.5 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. After standardized transformation, the dose of morphine for patients at W0 was 175.2 ± 24.5 mg, which was decreased to 91.2 ± 21.7 mg (P < 0.01), 89.4 ± 24.6 mg (P < 0.01), 89.4 ± 24.6 mg (P < 0.01), 72.8 ± 14.8 mg (P < 0.01), and 56.7 ± 11.3 mg (P < 0.01) at W2, W4, W8, W12, and W24, respectively. The efficiency reached 65.3%, 85.1%, 91.2%, 95.2%, and 92.7% at postoperative W2, W4, W8, W12, and W24, respectively. QOL score at W0 was 17.4 ± 3.3, which increased to 23.2 ± 4.5 (P < 0.01), 28.6 ± 7.6 (P < 0.01), 43.2 ± 9.1 (P < 0.01), 45.6 ± 10.3 (P < 0.01), and 47.6 ± 9.8 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. CONCLUSION: Brachytherapy with I125 seeds was safe and effective for treating bone metastases, offering a potential alternative to external-beam radiotherapy. QOL could be applied to evaluate the efficacy of I125 seeds implantation for treating bone metastases.

[Change of paradigm in the surgical treatment of metastatic diseases of bone. Part I. Bony metastases of the extremities and pelvis]. / Paradigmaváltás a csontmetasztázisok sebészetében. I. Végtagi és medencelokalizációjú áttétek.

According to the statistical data of tumor registries the incidence of cancer has increased in the last decade, however the mortality shows only a slight change due to the new and effective multimodal treatments. The aim of our overview article is to present the changes in the survival of the metastatic patients, and to demonstrate which factors influence their prognosis. The improvement of survival resulted in a more active surgical role both in metastases of the bone of the extremities and the pelvis. We present a diagnostic flow chart and current options for the reconstruction of the different regions of the bone and skeleton, and we will discuss their potential advantages, disadvantages and complications. It is evident that apart from the impending and pathological fracture surgery it is not the first choice of treatment but rather a palliative measure. The aim of surgery is to alleviate pain, to regain mobility and improve quality of life. If possible minimal invasive techniques are performed, as they are less demanding and allow fast rehabilitation for the patient, and they are solutions that last for a lifetime. In optimal conditions radical curative surgery can be performed in about 10 to 15 per cent of the cases, and better survival is encouraging. Orv Hetil. 2017; 158(40): 1563-1569.

Hormonas tiroideas, TSH, cáncer de tiroides y hueso en mujeres pre y postmenopáusicas / Thyroid hormones, TSH, thyroid cancer and bones in pre- and postmenopausal women

En los últimos años se han realizado progresos en el conocimiento de la regulación del desarrollo del esqueleto y del mantenimiento de la masa ósea del adulto por el eje hipotálamo-hipófisis-tiroides. Se han hecho estudios sobre el efecto de las hormonas tiroideas sobre el osteoblasto, osteoclasto y el condrocito, que han implicado un mejor conocimiento genético y fisiológico de la acción celular de estas hormonas. Recientemente se han propuesto posibles intervenciones de las deiodinasas D2 en la osteoporosis, e incluso se ha señalado la relación entre la densidad mineral ósea, la calidad del hueso y el riesgo de fracturas con las hormonas tiroideas en mujeres postmenopáusicas normales, lo que sugiere un papel de estas hormonas, incluso dentro del rango de la normalidad tiroidea, en estas patologías. Por otro lado, la incidencia del cáncer diferenciado de tiroides, modelo experimental in vivo de la supresión de la hormona tiroidea por la terapia preventiva de recidivas, ha aumentado significativamente. Existen guías clínicas para su manejo, pero es evidente que los posibles efectos secundarios derivados requieren una precisa indicación ajustada al balance riesgo-beneficio de la dosificación de las hormonas tiroideas, prescritas a largo plazo, especialmente en los casos de baja agresividad tumoral, edad avanzada e incluso en pacientes frágiles. Las pacientes con elevado riesgo, deben ser referidas para una densitometría ósea, para considerar el tratamiento de futuras fracturas. La prevención de osteoporosis, en particular en la mujer postmenopáusica, es altamente conveniente y debe incluir dieta adecuada en calcio y suplementación de vitamina D si es necesario. No existe aún un consenso sobre el tratamiento de la osteoporosis en la paciente con cáncer de tiroides y tratamiento supresor, pero los criterios indicados para la osteoporosis postmenopáusica en general parecen aplicables (AU)

In recent years, progress has been made in regulating skeletal development and maintenance of bone mass of the adult by the hypothalamus-pituitary-thyroid axis. Studies have been carried out into the effect of thyroid hormones on the osteoblasts, osteoclast and the chondrocyte. This research has led to better genetic knowledge into the physiology of the cellular action of these hormones. Recently, possible D2 deodinase interventions in osteoporosis have been proposed. The link between bone mineral dignity, bone quality and the risk of fractures with thyroid hormones in normal postmenopausal women suggest a role for these hormones, even within the range of normal thyroid, in these diseases. On the other hand, the incidence of differentiated thyroid cancer, experimental in vivo thyroid hormone suppression by therapy, recurrent disease, has increased significantly. There are management guides, but it is clear that the secondary derivatives require a precise balance-adjusted indication, risk-benefit ratio of thyroid hormone dosage, prescribed long term, especially in cases of low tumor aggressiveness, advanced age and even in fragile patients. High risk patients should be referred for a bone densitometry, to consider treating future fractures. Prevention of osteoporosis, particularly in postmenopausal women, is highly desirable and should include adequate diet in calcium and vitamin D supplementation if necessary. There is still no consensus on osteoporosis treatment in the patient with thyroid cancer and suppressive treatment, but the indicated criteria for postmenopausal osteoporosis seem to be applicable in general (AU)

Simultaneous inhibition of NMDA and mGlu1/5 receptors by levo-corydalmine in rat spinal cord attenuates bone cancer pain.

Bone cancer pain is a challenge for its not completely clarified mechanism and broad clinical morbidity. Therefore, novel and more effective drugs are urgent needed for improvement of patients' quality of life. Glutamate receptors have been associated with the development of the central sensitization of chronic pain. Inhibition of N-methyl-d-aspartate (NMDA) and metabotropic glutamate (mGlu) receptors can effectively attenuate bone cancer pain, respectively. Herein, our results indicated that levo-Corydalmine (l-CDL), a compound from Corydalis yanhusuo W.T. Wang, which has been used in traditional Chinese medicine for pain relief could effectively attenuate bone cancer pain induced by tibia bone cavity tumor cell implantation (TCI) through simultaneously inhibiting the NMDA and mGlu1/5 receptors in rat spinal cord without notable side effects. Both intragastric and intrathecal administration of l-CDL significantly alleviated the mechanical hypersensitivity induced by TCI in rats, and the analgesic effect of l-CDL could be reversed by intrathecal administration of NMDA receptor agonist NMDA and mGlu1/5 receptor agonist DHPG but not AMPA receptor agonist AMPA. l-CDL could also selectively suppress NMDA and DHPG induced rapid rise in Ca2+ oscillations in primary cultures neurons of spinal cord in vitro. The antinociception of l-CDL were partially mediated by the reduced phosphorylation of PKC γ and ERK1/2 in spinal cord of TCI rats in a NMDA and mGlu1/5 dependent manner. In conclusion, these results suggested that l-CDL attenuates TCI induced bone cancer pain through simultaneously inhibiting the NMDA and mGlu1/5 receptors and the downstream PKC γ, ERK1/2 signaling pathways in the spinal cord.

Effects of circadian rhythms and treatment times on the response of radiotherapy for painful bone metastases.

BACKGROUND: Previous studies have observed how the time of radiotherapy delivery can impact toxicities and outcomes. The goal of this study was to determine whether treatment time influenced radiotherapy response for bone metastases. METHODS: Patients who received radiation treatment to painful bone metastases from January 2000 to December 2010 were included in our analysis. Demographic and treatment information including performance status, primary site, treatment dose and fraction, and response were collected prospectively. Treatment times were extracted from patient medical records. Patients were allocated to 8:00 AM-11:00 AM, 11:01 AM-2:00 PM, or 2:01 PM-5:00 PM cohorts based on their treatment times. To compare treatment response between the three cohorts, the Fisher exact test was used. A two-sided P value of <0.05 was considered statistically significant. Analysis was repeated with males and females separately. RESULTS: A total of 194 patients were included. The median age was 68 years and 55.5% of patients responded to treatment. The dose and fraction of radiation received differed significantly between treatment cohorts using all allocation methods. Females in the 11:01 AM-2:00 PM cohort exhibited a significantly higher response rate (P=0.02) and differing proportions of response types (P=0.03) compared to the 8:00 AM- 11:00 AM and 2:01 PM-5:00 PM cohorts when allocated using all treatment times. No significant differences in response were seen between cohorts when all patients were analysed together or analysed for males only. CONCLUSIONS: Treatment time may affect response in female patients receiving radiotherapy for painful bone metastases. Subsequent chronotherapy studies in radiation should investigate these gender differences.

Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain.

Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer-related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain.

Tanshinone IIA Exerts an Antinociceptive Effect in Rats with Cancer-induced Bone Pain.

BACKGROUND: Cancer-induced bone pain (CIBP) is a common chronic pain characterized by 2 components, ongoing pain and breakthrough pain. Tanshinone IIA (TSN IIA) is a bioactive constituent of the traditional Chinese medicine Danshen, which has been reported to have an antinociceptive effect on neuropathic and inflammatory pain through downregulation of the late proinflammatory cytokine high-mobility group protein B1 (HMGB1). OBJECTIVE: To assess the antinociceptive effect of TSN IIA on CIBP. STUDY DESIGN: A randomized, double-blind, controlled animal trial was performed. SETTING: University lab in China. METHODS: A rat CIBP model was established by injecting Walker 256 mammary gland carcinoma cells into the intramedullary cavity of the tibia. Both ongoing pain, e.g., flinching and guarding, and breakthrough pain, e.g., limb use and von Frey threshold, were evaluated. The effects of intraperitoneally administered TSN IIA on pain behavior and the expression levels of spinal HMGB1, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were determined. The effect of TSN IIA on the electrically evoked response of spinal wide-dynamic range (WDR) neurons was performed in vivo. RESULTS: TSN IIA dose-dependently inhibited cancer-induced ongoing pain and breakthrough pain. The expression levels of spinal HMGB1 and other inflammatory factors (IL-1beta, TNF-alpha, and IL-6) were increased in the rat model, but they were suppressed by TSN IIA in a dose-dependent manner. Moreover, TSN IIA significantly inhibited the neuronal responses of WDR neurons in spinal deep layers. LIMITATIONS: Further studies are warranted to ascertain how TSN IIA attenuates cancer-induced ongoing pain. CONCLUSIONS: Our results indicate that TSN IIA attenuates cancer-induced ongoing pain and breakthrough pain, possibly via suppression of central sensitization in CIBP rats. Therefore, we have provided strong evidence supporting TSN IIA as a potential and effective therapy for relieving CIBP. KEY WORDS: Cancer-induced bone pain, high-mobility group protein B1, Tanshinone IIA, ongoing pain, breakthrough pain.

Evaluation of Bone Cancer Pain Induced by Different Doses of Walker 256 Mammary Gland Carcinoma Cells.

BACKGROUND: Cancer pain is a complex medical syndrome. Understanding its underlying mechanisms relies on the use of animal models which can mimic the human condition. A crucial component of this model is the quantity of tumor cells; however, the exact relationship between the doses of tumor cells on bone cancer pain is yet unknown. OBJECTIVE: We explored the relationship of different doses of Walker 256 carcinoma cells using a bone cancer pain model in rats, and evaluated its success and stability. STUDY DESIGN: Experimental animal study using a comparative design. SETTING: Experimental Animal Center and Tumor Institute of Traditional Chinese Medicine. METHODS: We constructed the bone cancer pain model by implanting Walker 256 carcinoma cells into the right tibia of Sprague-Dawley (SD) rats (150 - 170 g). Spontaneous pain, mechanical threshold, and paw withdrawal latency (PWL) were measured and x-ray, bone mineral density (BMD), histological, interleukin-1 beta (IL-1beta) mRNA, carboxyterminal telopeptide of type I collagen (ICTP), and bone alkaline phosphatase (BAP) were analyzed for bone pain model evaluation. RESULTS: The results showed that: (1) the 3 doses (3×105, 3.5×105, 4×105) of Walker 256 carcinoma cells can induce bone cancer pain from day 7 to day 21 after implantation into the right tibia of SD rats; (2) compared to the control group, 3×105, 3.5×105, and 4×105 Walker 256 carcinoma cells produced different pain manifestations, where the 3.5×105 dose of Walker 256 carcinoma cells resulted in the greatest bone cancer pain response; (3) the 3.5×105 dose induced the lowest mortality rate in rats; (4) Walker 256 carcinoma cells (3×105, 3.5×105, and 4×105) resulted in a significant decrease in the general condition and body weight of rats, where the 3.5×105 and 4×105 doses of carcinoma cells produced a greater effect than 3×105 dose of carcinoma cells; (5) progressive spontaneous pain, PWL, and mechanical threshold were exacerbated by 3.5×105 and 4×105 doses of carcinoma cells; (6) implantation of 3.5×105 and 4×105 doses of carcinoma cells induced progressive bone destruction and decrease in BMD; (7) ICTP and BAP were significantly increased following the implantation of 3.5×105 and 4×105 doses of carcinoma cells; (8) IL-1beta mRNA was significantly up-regulated in the spinal cord of rats implanted with 3.5×105 and 4×105 doses of carcinoma cells. LIMITATIONS: One limitation of this study was the small sample size; therefore, additional research is needed to provide better validation. Another limitation is the unavailability of small animal Micro computed tomography (CT), which is a more advanced and precise technique in determining bone marrow density than the x-ray imaging system we used. In addition, ethology experiments during late-stage tumor progression can be more objective. CONCLUSION: This study provides evidence that implantation of 3.5×105 and 4×105 dose of Walker 256 carcinoma cells produced the greatest effects in relation to the bone cancer pain model in SD rats, and 3.5×105 dose induced the lowest mortality rate. KEY WORDS: Bone cancer pain model, Walker 256 carcinoma cells, different doses.

Electrochemotherapy in the Treatment of Bone Metastases: A Phase II Trial.

INTRODUCTION: Bone metastatic disease is a major cause of pain and decreased quality of life in patients with cancer. In addition to systemic therapy and pain control with narcotic analgesics, standard local treatments include palliation with radiation therapy and surgery. However, 20-30 % of patients do not respond to conventional treatments, increasing the interest in alternative therapies. We present the results of a new minimally invasive technique in the treatment of bone metastases. METHODS: Twenty-nine patients affected by painful bone metastases were treated with electrochemotherapy (ECT) from July 2009 to July 2011; the mean age was 60 years (range 37-87); 21 patients received a previous ineffective local treatment; the appendicular skeleton was affected in 15 patients while in 14 patients other sites were involved. ECT was performed using the Cliniporator Vitae under fluoroscopy or CT guidance depending on the site of the lesion. Clinical response was assessed using VAS scale and objective tumour response was evaluated according to the MD Anderson criteria for bone metastases. RESULTS: All patients well tolerated the procedure and no intraoperative or postoperative complications were observed. At a mean follow-up of 7 months, 24 patients were available for evaluation. 84 % of the patients (20 out of 24) referred improvement of pain ≥50 % with reduction of narcotics consumption. Radiographic evaluation after 3 months in 20 evaluable patients, showed "partial response" in 1 patient, "stable disease" in 17 and "progression" in two cases. DISCUSSION: Results reported in this study demonstrated ECT to be safe and feasible in the treatment of painful bone metastases even when other previous treatments were ineffective. Pain and disease progression control was achieved in the majority of the patients with consequent improvement of quality of life. CONCLUSION: ECT should be considered a new feasible tool in the treatment of bone metastases in place or in combination with standard treatments; further developments are required to extend the use of this technique to spine metastases.

Effect of music therapy on pain behaviors in rats with bone cancer pain.

PURPOSE: To investigate the effects of music therapy on the pain behaviors and survival of rats with bone cancer pain and analyze the mediating mechanism of mitogen activated protein kinase (MAPK) signal transduction pathway. METHODS: Male Wistar rats aged 5-8 weeks and weighing 160-200 g were collected. The rat models of colorectal cancer bone cancer pain was successfully established. Animals were divided into experimental and control group, each with 10 rats. The animals in the observation group were given Mozart K448 sonata, sound intensity of 60 db, played the sonata once every 1 hr in the daytime, stopped playing during the night, and this cycle was kept for 2 weeks. On the other hand, rats in the control group were kept under the same environment without music. RESULTS: Animals in the experimental group consumed more feed and gained significant weight in comparison to the control group. The tumor volume of the experimental group was significantly smaller than that of the control group (p<0.05). After 1-2 weeks of treatment, spontaneous foot withdrawal reflection caused by pain in the experimental group was significantly lower than that in the control group, heat pain threshold and free walking pain scoring in the experimental group were also significantly higher as compared with the control group (p<0.05). The expression of p38á and p38ß in animals' spinal cord and dorsal root ganglion was significantly lower in the experimental group than in the control group (p< 0.05). CONCLUSION: Music therapy may improve the pain behaviors in rats with bone cancer pain, which might be related with low expression of p38á and p38ß in the MAPK signal transduction pathway.

Use of denosumab in a dialysis patient with bone metastases from breast cancer and hepatorenal polycystic disease: a case report.

Cancer patients with severe renal dysfunction represent a challenge for the physician. This is the first case report on the use of denosumab in a dialysis patient with bone metastases. We present the clinical case of a 45-year-old woman who had hepatorenal polycystic disease, diagnosed during childhood, and stage IV chronic kidney failure at the time of breast cancer diagnosis. Three years after surgery plus adjuvant hormonal therapy she suffered a further worsening of renal function, requiring dialysis, and very advanced bone metastasis in the hip with severe pain. As pamidronate was the only bone agent available in the center, she received it for 4 months (before a dialysis session), during which time the bone metastases stabilized. In March 2014, the patient switched to denosumab (which had become available in the center), and continued with hormone therapy. Seven months after denosumab initiation, the patient had almost complete pain relief, and the bone metastases exhibited radiological improvement. The tolerability was excellent, without any related adverse event. There were no changes in albumin-adjusted serum calcium, serum phosphorus, and intact parathyroid hormone, except for a transient and mild hypocalcemia at 3 months and an increase in intact parathyroid hormone levels, which required adjustment of vitamin D analog dose. Denosumab can be administered to prevent skeletal-related events in patients with bone metastasis from solid tumors and severely impaired renal function, even in those requiring dialysis. In this particular patient, the safety was good.