Control and Treatment of Bone Cancer: A Novel Theoretical Study

The human body has symmetric bones.This paper uses control engineering concepts to design a suitable controller to synchronize two symmetric bones of the human body to control and treat bone cancer.A Nonsingular Terminal Sliding Mode Control(NTSMC)method will be employed to design the proposed control inputs.The control inputs can be the chemical drugs that can be used to treat bone cancer.The dynamical equations of bone cancer will be used to apply the designed control method and test it.For testing the designed controller,Simulink/MATLAB software will be used.The proposed controller is chattering-free,robust against uncertainties and external disturbances,and finite-time stable in the control engineering view.Bone cancer will be treated for almost one year using the proposed control method.

Application of additively manufactured 3D scaffolds for bone cancer treatment:a review

Bone cancer is a critical health problem on a global scale,and the associated huge clinical and economic burdens are still rising.Although many clinical approaches are currently used for bone cancer treatment,these methods usually affect the normal body functions and thus present significant limitations.Meanwhile,advanced materials and additive manufacturing have opened up promising avenues for the development of new strategies targeting both bone cancer treatment and post-treatment bone regeneration.This paper presents a comprehensive review of bone cancer and its current treatment methods,particularly focusing on a number of advanced strategies such as scaffolds based on advanced functional materials,drug-loaded scaffolds,and scaffolds for photothermal/magnetothermal therapy.Finally,the main research challenges and future perspectives are elaborated.

In vivo analysis of post-joint-preserving surgery fracture of 3D-printed Ti-6Al-4V implant to treat bone cancer

Cancer growth in the bone due to its random shape disables bone strength and thus changes its capacity to support body weight or muscles,which can crucially affect the quality of human life in terms of normal walking or daily activities.For successful patient recovery,it is necessary to remove the cancer-affected minimal bone area and quickly replace it with a biocompatible metal implant within less than 2 weeks.An electron beam-melted Ti-6Al-4V implant was designed and applied in a patient to preserve the natural knee joint close to the bone tumor.The developed implant fits the bone defect well,and the independent ambulatory function of the natural knee joint was restored in the patient within six weeks after surgery.A delayed fracture occurred six months after the successful replacement of cancer-affected bone with Ti-6Al-4V implant at the proximal meshed junction of the implant because of a minor downward slip.Microstructural,mechanical,and computational analyses were conducted for the fractured area to find the main reason for the delayed fracture.Our findings pertaining to the mechanical and material investigation can help realize the safe implantation of the three-dimensionally printed titanium implant to preserve the natural joints of patients with massive bone defects of the extremities.

JNK in Spinal Cord Facilitates Bone Cancer Pain in Rats through Modulation of CXCL1

In patients with advanced cancer, cancer-induced bone pain（CIBP） is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase（JNK） and chemokine（C-X-C motif） ligand 1（CXCL1） have been shown to participate in several chronic pain processes, we investigated the role of JNK and CXCL1 in CIBP and the relationship between them. A rat bone cancer pain model was established by intramedullary injection of Walker 256 rat gland mammary carcinoma cells into the left tibia of Sprague-Dawley rats. As a result, intramedullary injection of Walker 256 carcinoma cells induced significant bone destruction and persistent pain. Both phosphorylated JNK1（p JNK1） and p JNK2 showed time-dependent increases in the ipsilateral spinal cord from day 7 to day 18 after tumor injection. Inhibition of JNK activation by intrathecal administration of SP600125, a selective p JNK inhibitor, attenuated mechanical allodynia and heat hyperalgesia caused by tumor inoculation. Tumor cell inoculation also induced robust CXCL1 upregulation in the ipsilateral spinal cord on day 18 after tumor injection. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody showed a stable analgesic effect. Intrathecal administration of SP600125 reduced CXCL1 increase in the spinal cord, whereas inhibition of CXCL1 in the spinal cord showed no influence on JNK activation. Taken together, these results suggested that JNK activation in spinal cord contributed to the maintenance of CIBP, which may act through modulation of CXCL1. Inhibition of the p JNK/CXCL1 pathway may provide a new choice for treatment of CIBP.

Effects of p38 MAPK inhibitor on the rat pain behavior and proinflammatory cytokines in a metastatic bone cancer pain model

Objective： To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone cancer pain induced by breast cancer cells. Methods： Eleven rats were used to establish the models of bone cancer pain, six rats were treated by intrathecal SB203580 injection, and the other 5 were as the controls. The paw withdrawal latency （PWL）, histology and the spinal levels of IL-1β and TNF-α were detected. Results： All the 11 rats presented evident bone destruction and thermal hyperalgesia after intra-tibial injection of breast cancer cells. No effect of SB203580 on the bone destruction was observed. However, following intrathecal injection of SB203580, the left PWLs （12.12± 1.26 s at 16 days and 12.99 ± 1.65 s at 19 days） were significant higher than that of controls （9.05 ± 1.08 s at 16 days and 8.55 ± 1.60 s at 19 days）, P 〈 0.05. Meanwhile, inkathecal injection of SB203580 evidently reduced the levels of spinal IL-1β and TNF-α. Conclusion： Intrathecal injection of SB203580 in a rat model of bone cancer pain cannot prevent the tibial destruction but significantly depress the thermalgia sensitivity, which might result from inhibiting inkacellular p38 MAPK signaling transduction, and thereby reducing the release of the proinflammatory cytokines.

Incidence and mortality of primary bone cancers in China, 2014

Objective: In this study, we aimed to estimate the updated incidence and mortality of primary bone cancers based on population-based cancer registration data in 2014, collected by the National Central Cancer Registry of China(NCCRC).Methods: In 2017, 339 registries' data were qualified based on data quality criteria set down by the NCCRC.Cases of primary bone cancers were retrieved from the national database. We estimated numbers of primary bone cancer cases and deaths in China using age-specific rates and corresponding national population stratified by area,sex, age-group(0, 1-4, 5-9, 10-14, …, 85+). Chinese standard population in 2000 and Segi's World population were applied for the calculation of age-standardized incidence and mortality rates.Results: In 2014, 24,000 primary bone cancer cases and 17,200 deaths attributable to primary bone cancers were estimated to have occurred in China. The crude incidence rate of primary bone cancers was 1.76/100,000, with agestandardized incidence rate by Chinese standard population(ASIRC) and by World standard population(ASIRW)being 1.35/100,000 and 1.32/100,000, respectively. The crude mortality rate of primary bone cancers was1.26/100,000, with age-standardized mortality rate by Chinese standard population(ASMRC) and by World standard population(ASMRW) being 0.88/100,000 and 0.86/100,000, respectively. Age-specific incidence curve was bimodally distributed with age, with the first peak occurring in the second decade of the life and the second peak in the elderly. Males had higher crude and age-standardized rates for both incidence and mortality compared with females. Both crude and age-standardized incidence rates were higher in rural areas than in urban areas, so were the crude and age-standardized mortality rates.Conclusions: This population-based study presents the most recently available estimates on primary bone cancers in China, revealing that the males are 1.34 times as much as females suffering from primary bone cancers and the adolescents in puberty and the elderly are predominantly affected groups by these cancers. High-quality cancer registration data are a prerequisite for undertaking further study for gaining insight into the causes and risk factors for primary bone cancers in China.

Bone Cancer Mortality in Inner Mongolia from 2008 to 2012

Objective: The aim of our study was to assess bone cancer mortality and the related social factors in Inner Mongolia in China. Methods: We obtained data from the Centers for Disease Control in Inner Mongolia from five monitoring points of the Death Registry System in Inner Mongolia from 2008 to 2012. We calculated the crude mortality rate for bone cancer. The χ2 test was used to examine differences in bone cancer mortality rates between sexes and years. Unconditional logistic regressions were applied to analyze the effect of socio-demographic characteristics by sex. Results: Between 2008 and 2012, the crude mortality rate of bone cancer was 1.12/100000 (95% confidence interval = 1.02-1.21). The bone cancer mortality was 2.24 in men and 1.25 in women, resulting in a male-female ratio of 1.8. No between-year difference in the mortality rate was observed between 2008 and 2012 (men: χ2 = 4.65, P = 0.325;women: χ2 = 2.21, P = 0.698). In general, mortality increased with increasing age. People with a lower education level exhibited an increased risk of bone cancer among both men and women. Jobs involving extensive manual labor decreased the likelihood of bone cancer mortality, and the odds ratio was higher for men than women (0.6 vs. 0.45). Unmarried people had a higher risk for bone cancer than married people. Conclusion: The mortality rate of bone cancer was not significantly different between men and women from 2008 to 2012. The risk of bone cancer increased with age among both sexes. Unmarried people and those with a low education status had an elevated risk of bone cancer, whereas employment in a field involving extensive manual labor appeared to be a protective factor against bone cancer.

Profile of Secondary Bone Cancer in Brazzaville

Objectives: To report an epidemiology study and prognosis for metastatic bone tumor. Methodology: It was a descriptive, transversal study on records of patients hospitalized in Rheumatology and Oncology-Radiotherapy departments of the University Teaching Hospital of Brazzaville, Congo from 1 January 2005 to 31 July 2011 (7 years and 6 months). The diagnosis of bone metastasis was made because of the existence of bone pain, or pathological fracture, or bone swelling and a bone-condensing or mixed or osteolytic radiological image. The anatomo-pathological evidence was made after biopsy of the bone lesion or primary cancer. 3687 patients were hospitalized for active cancer, among them 81 had documented bone metastasis. Results: There were 60 men (74.1%) and 21 women (25.9%) with a sex ratio of 2.85. The average age was 53 years, ranging from 3 to 80 years. 75% of patients were more or equal to 50 years old at the discovery of the bone metastasis. Bone pain was the main mode of discovery (67.9% of cases). However, in 6.2% of cases, it was discovered incidentally. The metastasis was bone condensing in 50.7% of cases, osteolytic in 40.7% and mixed in 8.6%. They were unifocal in 25.9% and multifocal in 74.1% of cases. The Primary cancer most frequently found was that of the prostate in 55.6% of cases, breast in 20.7% and rhabdomyosarcoma in 4.9%. In 6.2% of cases, the primary site of cancer was unknown. The average survival was 25 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The discovery of metastasis remains a major evolutionary step of cancer.

Profile of Secondary Bone Cancer in Lomé(Togo)

Objectives: To determine the epidemiological, clinical and paraclinical profile of bone metastases cancer. Patients and Methods: It was a retrospective study performed on a series of cases, admitted in Rheumatology department of the University Teaching Hospital of Lomé, Togo from October 1989 to December 2008. The diagnosis of bone metastasis was made because of the existence of inflammatory bone pain, or pathological fracture, or bone swelling and a bone condensing or mixed or osteolytic radiological image. The anatomopathological evidence was made after biopsy of the bone lesion or primary cancer. 2018 patients were hospitalized in rheumatology, and among them 77 had documented bone metastasis. Results: There were 53 men (68.8%) and 24 women (31.2%) with a sex ratio of 2.2. The mean age was 56.6 ± 12.6 years, ranging from 21 to 82 years. The primary cancer most frequently found was that of the prostate, representing 57.1% of bone metastasis and breast in 15.6%. The main manifestations of patients with bone metastases were inflammatory bone pain (76.6%) and alteration of general condition (75.3%). The spine was the main area of pain (64.9%). The metastasis was bone condensing in 48.1% of cases, osteolytic in 40.3% and mixed in 11.6%. The average survival was 22 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The diagnosis of the primary tumor is often made at the stage of metastasis in black Africa.

The effects of Yishen Qutong granula on pain sensitization and bone destruction of rats with bone cancer pain

Objective:To study the effects of Yishen Qutong granula on pain sensitization and bone destruction of rats with bone cancer pain.Methods:Walker256 cells were passaged in ascites and injected into the tibia of female Wistar rats to prepare the bone cancer pain model.On the 14th day after model establishment,60 rats were randomly divided into model group,sham-operated group,Yishen Qutong granula low,middle,high dose group and tramadol hydrochloride positive control group.After continuous administration for 14 days,the mechanical pain threshold,thermal threshold and weight-bearing difference of both hind limbs were observed.Results:Compared with the model group,Yishen Qutong groups increased the mechanical pain threshold,thermal pain threshold and reduced the weight difference of both hind limbs(P<0.05).Compared with the positive drug group,there was no significant difference in increasing the mechanical pain threshold and thermal pain threshold of rats in the medium dose group of Yishen Qutong(P>0.05),and Yishen Qutong granula significantly reduced the weight-bearing difference of hind limbs in all groups(P<0.05).Conclusion:Yishen Qutong granula can relieve pain sensitization and alleviate bone damage in rats with bone cancer pain.

A theragenerative bio-nanocomposite consisting of black phosphorus quantum dots for bone cancer therapy and regeneration

Recently,the term theragenerative has been proposed for biomaterials capable of inducing therapeutic approaches followed by repairing/regenerating the tissue/organ.This study is focused on the design of a new theragenerative nanocomposite composed of an amphiphilic non-ionic surfactant(Pluronic F127),bioactive glass(BG),and black phosphorus(BP).The nanocomposite was prepared through a two-step synthetic strategy,including a microwave treatment that turned BP nanosheets(BPNS)into quantum dots(BPQDs)with 5±2 nm dimensions in situ.The effects of surfactant and microwave treatment were assessed in vitro:the surfactant distributes the ions homogenously throughout the composite and the microwave treatment chemically stabilizes the composite.The presence of BP enhanced bioactivity and promoted calcium phosphate formation in simulated body fluid.The inherent anticancer activity of BP-containing nanocomposites was tested against osteosarcoma cells in vitro,finding that 150μg mL^(-1)was the lowest concentration which prevented the proliferation of SAOS-2 cells,while the counterpart without BP did not affect the cell growth rate.Moreover,the apoptosis pathways were evaluated and a mechanism of action was proposed.NIR irradiation was applied to induce further proliferation suppression on SAOS-2 cells through hyperthermia.The inhibitory effects of bare BP nanomaterials and nanocomposites on the migration and invasion of bone cancer,breast cancer,and prostate cancer cells were assessed in vitro to determine the anticancer potential of nanomaterials against primary and secondary bone cancers.The regenerative behavior of the nanocomposites was tested with healthy osteoblasts and human mesenchymal stem cells;the BPQDs-incorporated nanocomposite significantly promoted the proliferation of osteoblast cells and induced the osteogenic differentiation of stem cells.This study introduces a new multifunctional theragenerative platform with promising potential for simultaneous bone cancer therapy and regeneration.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Contribution of Bone Scintigraphy in the Metastatic Extension Assessment of Prostate Cancer: A Study of 288 Cases in the Nuclear Medicine Department of Idrissa Pouye General Hospital, Dakar

Introduction: Prostate cancer is the most frequently diagnosed male malignancy and the fifth leading cause of cancer death in men worldwide. Since the advent of screening methods such as Prostate Specific Antigen (PSA) assay, digital rectal examination (DRE) and prostate biopsy, its incidence has increased significantly. The aim of our study was to analyse aspects of bone scintigraphy (BS) as part of the metastatic extension assessment of prostate cancer in Senegal. Patients and Methods: This was a retrospective descriptive and analytical study, running from January 1er 2022 to August 31 2023. Patients with histologically confirmed prostate cancer were included. Whole-body scans (WBS) were performed using a dual-head SPECT gamma camera (Mediso Nucline TM Spirit DH-V type), 3 hours after intravenous injection of 8 MBq/kg (555 to 740 MBq) of 99mTc-HMDP. Results: A total of 288 patients with a mean age of 68.37 ± 7.79 years were included. The median total PSA level was 97.6 ng/ml, with 144 patients having a level greater than or equal to 20 ng/ml. All patients had adenocarcinoma, and the Gleason score was available in 202 (70.13%) patients, 75.75% of whom had a score greater than or equal to 7. BS was contributory in 70.48% of cases, with 30.90% positive and 39.58% negative. The result was inconclusive in 85 patients (29.51%). The mean PSA for patients with a positive scan was 190.2 ng/ml and 40.6 ng/ml for those with a negative scan. Multiple metastatic lesions predominated (87.35% of cases). Metastatic lesions occurred preferentially in the axial skeleton, with a proportion of 68% versus 32% in the appendicular skeleton. Classification of bone metastases according to the SOLOWAY score revealed grade I (62.07%), grade II (35.63%) and grade IV (2.30%). Conclusion: In Senegal, prostate cancer is generally diagnosed in men of advanced age. The presence of bone metastases is frequent in its evolution, transforming a curable localized disease into a generalized disease with a compromised prognosis. Bone scintigraphy remains an essential part of the initial work-up and evaluation of response to treatment.

Place of Bone Scintigraphy in the Assessment of Extension and Follow-Up of Breast Cancer in Senegal: Study of 165 Cases in the Nuclear Medicine Department of Idrissa Pouye General Hospital (Dakar)

Introduction: Breast cancer is the most common cancer in women worldwide, accounting for an estimated 22% of all female cancers. It is the leading cause of cancer mortality in women, almost all of which is due to metastases, with 73% of metastases occurring in the bone. In oncology, metastable technetium 99-labelled methylene bisphosphonate bone scintigraphy (BS) remains the standard examination for detecting and assessing the extent of bone metastases. The aim of this study was to assess the role of BS in the evaluation and follow-up of breast cancer in Senegal. Methodology: This was a retrospective study of breast cancer patients who underwent bone scintigraphy with 99mTc-HMDP in the nuclear medicine department of Idrissa Pouye General Hospital (IPGHO), from July 2009 to June 2022. Results: We enrolled 165 patients, mean age 46.79 years (27 - 87 years). BS was performed in 94.37% of cases for post-therapeutic monitoring and in 5.63% for pre-therapeutic assessment. Results were contributory in 131 patients (92.25%), of whom 72 cases (50.70%) were normal and 59 cases (41.55%) positive or presenting bone metastases;and non-contributory or doubtful in 11 cases (7.75%). Secondary bone locations were multiple in 57 cases (96.61%) and single or solitary in 2 cases (3.39%). The scintigraphic appearance of bone metastases was hyper-fixative in 58 cases (98.31%) and mixed in 1 case (1.69%). Bone lesions were quantified using the Soloway’s grading classification. Conclusion: BS with 99mTc-labelled bisphosphonates remains the examination of choice for skeletal exploration, in the detection and extension of bone metastases in breast cancer. Performance has been enhanced by the development of SPECT coupled with CT (SPECT-CT).

Impacts of radiation therapy on quality of life and pain relief in patients with bone metastases

Bone metastases(BM)are a common complication in advanced cancer patients,significantly contributing to morbidity and mortality due to their ability to cause pain,fractures,and spinal cord compression.Radiation therapy(RT)is vital in managing these complications by targeting metastatic lesions to ease pain,improve mobility,and reduce the risk of skeletal-related events such as fractures.Evidence supports the effectiveness of RT in pain relief,showing its ability to provide significant palliation and lessen the need for opioid painkillers,thereby enhancing the overall quality of life(QoL)for patients with BM.However,optimizing RT outcomes involves considerations such as the choice of radiation technique,dose fractionation schedules,and the integration of supportive care measures to mitigate treatment-related side effects like fatigue and skin reactions.These factors highlight the importance of personalized treatment planning tailored to individual patient needs and tumor characteristics.This mini-review aims to provide comprehensive insights into the multifaceted impacts of RT on pain management and QoL enhancement in BM patients,with implications for refining clinical practices and advancing patient care through the synthesis of findings from various studies.

Correlation of PSA Level and ISUP Grade Group with Scintigraphic Bone Metastases Detection in 36 Prostate Cancer Patients

Background: We need population-specific clinical features that can predict bone metastases as an affordable therapeutic decision-making tool in newly diagnosed prostate cancer patients as scintigraphy or positron emission tomography are not available and as no such study had ever been performed in our country. Objective: To determine biologic and pathologic criteria that can predict the scintigraphic detection of bone metastases in our prostate cancer patients. Patients and Method: We analyzed with student’s t test and logistic regression the PSA level, the ISUP grade and the scintigraphic data retrospectively collected in newly diagnosed prostate cancer patients. Results: In ten years, 36 prostate cancer patients were sent to the Korle Bu Teaching Hospital in Accra (Ghana) for bone scintigraphy (mean age = 63.9 years;55.6%, 19.4% and 25.0% ISUP grade ≤ 2, 3 or ≥4). Among 28 patients who had performed the bone scintigraphy, 6 (21.4%) presented bone metastases, 22 (78.6%) had no bone metastasis. The mean PSA level was 36.7ng/mL in the non-metastatic patients and 97.7 ng/mL in the metastatic patients. The difference in PSA level between the 2 groups was significative (p = 0.041). 63.6% of the non-metastatic cancers versus 16.7% of the metastatic cancers were ISUP grade 2 or less. Inversely, 36.4% of the non-metastatic cancers versus 83.3% of the metastatic cancers were ISUP grade 3 or more. The difference was significative in the ISUP grade 2 or less (p = 0.035), was significative in the ISUP grade group 3 or more (p = 0.035). Metastasis was more likely in prostate cancer patients with PSA equal 30 ng/mL or more and ISUP grade 3 or more (83.3%) than in prostate cancer patients with PSA less than 30 ng/mL and ISUP grade less than 3 (16.7%) [OR = 13.7;CI 95% (1.59;31.0);p = 0.035]. Conclusion: The scintigraphic detection of bone metastases is low in patients with PSA < 30 ng/mL and ISUP grade < 3. This can be helpful in curative therapy decision making for prostate cancer when nuclear medicine or other metastases detection tools are lacking.

Modulation of Na_v1.8 by Lysophosphatidic Acid in the Induction of Bone Cancer Pain

Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.

Increased circulating rather than spinal cytokines accompany chronic pain behaviors in experimental bone cancer and arthritis

Aim:Peripheral cytokines contribute to arthritis and bone cancer pain through sensory nerve actions.However,increased spinal cytokine and glial filament expression,coined neuroinflammation,has also been proposed to play a part in chronic pain.Therefore,spinal cord,dorsal root ganglia and circulating cytokines were compared in murine arthritis and bone cancer models in relationship to behavioral signs of pain.Methods:Exploratory behaviors were studied after intra-articular complete Freund’s adjuvant or bone intramedullary sarcoma cell injection.Nervous tissue and blood cytokine expression were determined by real-time polymerase chain reaction(PCR)and multiplex immunoassays,respectively.Results:PCR analysis did not reveal any hallmark of spinal neuroinflammation in spontaneously-behaving mice with cartilage or bone lesions.However,imposed paw stimulation during joint inflammation increased spinal interleukin-1β(IL-1β)expression.Spontaneous paw guarding during rearing was displayed by animals with joint inflammation and bone destruction and was accompanied by increased circulating IL-6 and monocyte chemoattractant protein-1,respectively.In addition,dorsal root ganglia were found to constitutively express receptors for this chemotactic cytokine.Conclusion:Our findings indicate that spinal neuroinflammation is not a necessary condition for chronic pain and suggest that circulating cytokine action in dorsal root ganglia may contribute to experimental joint inflammation and bone cancer pain.

Molecular pathogenesis of bone metastases in breast cancer: Proven and emerging therapeutic targets

Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.

Predictive Value of Serum Bone Sialoprotein and Prostate-specific Antigen Doubling Time in Patients with Bone Metastasis of Prostate Cancer

Summary： This study aimed to evaluate the diagnostic and prognostic significance of serum bone sialoprotein （BSP） and prostate-specific antigen doubling time （PSADT） in patients with bone metastasis （BM） from prostate cancer （PC）. A total of 116 patients with PC, 120 patients with benign prostatic hyperplasia （BPH） and 120 healthy controls were enrolled in this study. PC patients were divided into bone metastasis （BM） group （n=56） and non-bone metastasis （NBM） group （n=60）. Serum BSP was detected by Sandwich ELISA. Severity of bone pain was evaluated using visual analogue score （VAS）. Serum f-PSA and t-PSA levels were measured by using electrochemiluminescence immunoassay （ECLIA）. PSADT was calculated according to the formula： PSADT=lg（2）/[log（PSA2）--log（PSA1）]. The mean serum BSP level in PC patients with BM was significantly higher than in PC patients without BM, BPH patients and controls （P〈0.001 for all）. Pearson＇s analysis showed that serum BSP level was posi- tively correlated with VAS in PC patients with BM （P〈0.05）. Receiver operating characteristics （ROC） analysis demonstrated that BSP discriminated patients with BM from those without BM at the cutoff value of 33.26 ng/mL. The sensitivity and specificity were 78.21% and 79.28%, respectively. The opti- mal cutoff value of PSADT was 131 days, with sensitivity of 85.69% and specificity of 85.36%. Kap- lan-Meier analysis revealed that subjects with higher BSP levels/shorter PSADT had a shorter BM-free period than those with lower BSP levels/longer PSADT. Serum BSP and PSADT are useful biomarkers for the diagnosis of BM from PC, and can be regarded as independent factors for predicting the progno- sis of BM from PC. Combined determination of BSP and PSADT can improve accuracy and positive rate of BM from PC significantly.