Bone-targeted therapies to reduce skeletal morbidity in prostate cancer / 亚洲男科学杂志(英文版)

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.

Subcutaneous extravasation of Sr-89: usefulness of bremsstrahlung imaging in confirming Sr-89 extravasation and in the decision making for the choice of treatment strategies for local radiation injuries caused by Sr-89 extravasation

A male patient in his 20s presented at our clinic with pain caused by bone metastases of the primitive neuroectodermal tumor, and Sr-89 was administrated to palliate the pain. After receiving the injection, the patient complained of a slight burning pain at the catheterized area. Slight reddening and small circular swelling [diameter, 0.5 cm] were observed at the catheterized area. Sr-89 extravasation was suspected. To estimate the amount of subcutaneous Sr-89 leakage, bremsstrahlung imaging was immediately performed. We speculated that the skin-absorbed dose from the subcutaneous Sr-89 leakage was 1.78 Gy. The mildest clinical sign of local radiation injury was erythema. The received dose was higher than 3 Gy, and the time of onset was from 2 to 3 weeks. In our patient, local radiation injuries [LRIs] did not occur. Though requiring further verification, subsequent bremsstrahlung imaging and estimation of the skin-absorbed dose from the subcutaneous Sr-89 leakage are useful in confirming Sr-89 extravasation and in the decision making for the choice of treatment strategies for LRIs caused by Sr-89 extravasation

Experimental and clinical study on treatment of hypertrophic scars with (90)Sr radiation / 中华烧伤杂志

<p><b>OBJECTIVE</b>To analyze the potential mechanism of preventive and therapeutic effects of (90)Sr on hypertrophic scar, and to observe its clinical effect.</p><p><b>METHODS</b>Fibroblasts isolated from human hypertrophic scar were cultured in vitro and radiated by (90)Sr with the dose varying from 0 Gy (control group) to 5 Gy (LD group), 10 Gy (MD group), and 15 Gy (HD group). The cell cycle and apoptosis rate were determined by flow cytometry at post radiation hour (PRH) 24, 48, and 72. The concentration of type I collagen in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). Therapeutic effects of (90)Sr radiation were evaluated among 348 patients with hypertrophic scars, 40 patients with keloids, and 114 patients for scar prevention after surgical operation. The number of fibroblasts after HE staining was compared among normal skin tissue, hypertrophic scar, and hypertrophic scar treated with (90)Sr radiation. Data were processed with one-way analysis of variance and q test.</p><p><b>RESULTS</b>(1) Apoptotic rates in MD and HD groups at PRH 48 were higher than those at PRH 24, and the apoptotic rate was similar between MD group and HD group at PRH 72. Apoptotic rate in LD group at PRH 48 was significantly higher than that at PRH 24, but it decreased rapidly at PRH 72, which was significantly lower than those in MD and HD groups (with F values all equal to 916.711, P values all below 0.01). (2) At PRH 24, cell ratios of each phase in LD and HD groups were similar, and cell ratio of S phase in HD group [(48.1 ± 1.0)%] was higher than those in the other three groups (with F values all equal to 200.277, P values all below 0.01). At PRH 72, cell ratio of S phase in MD and HD groups was respectively (85.7 ± 5.2)%, (73.0 ± 8.4)%, implying that cells were blocked in S phase, and the values were all higher than those in control and LD groups (with F values all equal to 111.105, P values all below 0.01). (3) At the same time point, the concentration of type I collagen decreased along with the increase of radiation dose (with F values from 5044.449 to 8234.432, P values all below 0.01). With the same radiation dose, the concentration of type I collagen increased along with prolongation of time (with F values from 333.395 to 2973.730, P values all below 0.01). (4) Clinical observation showed the (obvious) effective rate of radiation for pathological scars and that for scar prevention after surgical operation added up to 88.45%. The number of fibroblasts per 200 times visual field in patients after (90)Sr radiation (86 ± 20) was less than that in patients without treatment [(198 ± 65), F = 208.405, P < 0.05].</p><p><b>CONCLUSIONS</b>The effect of (90)Sr radiation on fibroblasts and extracellular matrix can contribute to inhibition of scar formation, and the clinical effect is significant.</p>

Preliminary application of strontium-89 for the treatment of bone metastases from prostate cancer / 生物医学工程学杂志

Bone metastases are a major problem in the clinical management of patients with prostate cancer. Despite the use of analgesic for the relief of such pain, the outcomes are not often satisfactory. Strontium-89 (89Sr) is a pure beta-emitting radioisotope to be avidly concentrated in the areas of high osteoblastic activity. The aim of this study was to evaluate the efficacy of 89Sr in the therapy for bone metastases of prostate carcinoma. 116 patients received intravenous injection of 89Sr at the dose of 3mCi (111MBq). All patients underwent physical examination and Karnofsky's Performance Score (KPS) evaluation before and after administration; the analgesic effects were evaluated by scores of pain. The complete response (CR) was defined as scores of pain > 75%; no response (NR) was defined as scores of pain < 25% the remaining was partial response (PR). The changes of bone metastases were screened by CT, MRI and 99mTc-MDP bone scintigraphy according to the standards of WHO. After the treatment with 89Sr, the total response rate was 80.2%. In the 116 cases, 21 cases (18.1%) displayed complete response and 72 cases (62.1%) displayed partial response, but 23 cases (19.2%) showed no response. The mean score on Karnfsky's performance status (KPS) was 20.0% higher. About 1/3 cases exhibited an obvious decrease in the number of metastases, and some foci disappeared. Thirteen cases (12%) showed a greater decrease in prostate-specific antigen (PSA) value. 89Sr chloride is an effective and safe therapy of the bone metastases from prostate cancer.

Strontium-89 for bone metastases from prostate cancer: an update / 中华男科学杂志

Strontium-89 (Sr-89) is a pure emitter with maximum beta energy of 1.46 MeV, average beta energy of 0.58 MeV, and a physical half-life of 50.5 days. It is rapidly taken up by bone and preferentially retained at the sites of osseous metastases. Its biological half-life is >50 days at the metastatic sites, but about 14 days only in the normal bone. The dose of its absorption in the tumor-bearing bone ranges from 21 +/- 4 to 231 +/- 56 cGy/MBq, 2-25 times higher than in the normal bone. Strontium-89 therapy is an effective palliative treatment of bone metastases from prostate cancer, with analgesic effectiveness in 80%.

Strontium-89: a desirable therapeutic for bone metastases of prostate cancer / 中华男科学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of strontium-89 (89Sr) in the treatment of painful bone metastases of prostate cancer.</p><p><b>METHODS</b>A total of 116 patients with painful bone metastases of prostate cancer received bilateral orchiectomy and incretion, followed by intravenous injection of 89Sr at the dose of 1.48-2.22 MBq (40-60 microCi)/kg. The clinical effects were evaluated by follow-up analysis.</p><p><b>RESULTS</b>After the 89Sr treatment, appetite and sleep were evidently improved in 33.6% and 56.0% of the patients respectively, the applied dose of anodyne reduced in 61.2%, pain alleviated in 83.6%, with an absolute palliation rate of 24.1%. Pain relief started at 3-21 (10.2 +/- 6.5) days and lasted 3-12 (5.3 +/- 2.2) months. Flare ache occurred in 31.9% of the patients. Compared with pre-treatment, the mean score on Karnofsky's performance status (KPS) was 20.0% higher, and the WBC count decreased to 3.0-3.9 x 10(6)/L in 18.1% of the patients. Whole body bone scintigraphy of 53 followed-up patients showed that 39 (73.6%) of them exhibited an obvious decrease in the number of metastases, 10 (18.9% remained in a stabilized state and only 4 (7.5% deteriorated.</p><p><b>CONCLUSION</b>89Sr, capable of inhibiting bone metastasis, palliating pain and improving the quality of life with few adverse effects, can be used as a desirable therapeutic for painful bone metastases of prostate cancer.</p>

Therapeutic efficacy of strontium-89-chloride for bone metastatic tumors without bone pain / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the safety and efficacy of strontium-89-chloride for management of bone metastases in patients without bone pain.</p><p><b>METHODS</b>Fifty-four patients without painful bone metastases were given a single intravenous dose (1.48-2.22 MBq/kg) of strontium-89-chloride, which was repeated once or twice at the interval between 3 and 6 months.</p><p><b>RESULTS</b>The total response rate was 74.0% in these, and the response rate was significantly lower in patients with focal size>2 cm than in those with focal size<or=2 cm (33.3% vs 66.6%, chi2=14.9, P<0.01). The side effects of strontium-89-chloride included mainly thrombocytopenia and neutropenia, mostly mild and reversible without interventions.</p><p><b>CONCLUSION</b>Strontium-89-chloride is effective and safe for treatment of nonpainful bone metastases.</p>

Changes of immunologic parameters in patients with simple bone metastases treated with 89SrCl2 / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the influence of (89)SrCl(2) (strontium-89 chloride) on immune functions in patients with simple bone metastases.</p><p><b>METHODS</b>Twenty-five patients diagnosed as simple bone metastases with un-detectable primary tumors were treated with (89)SrCl(2). The CD4(+), CD8(+), CD4(+)/CD8(+) lymphocyte subsets were assessed before and after (89)SrCl(2) treatment. Twenty normal individuals served as controls.</p><p><b>RESULTS</b>The CD4(+), CD8(+) and CD4(+)/CD8(+) in the control group were (38.83 +/- 8.95)%, (32.19 +/- 8.51)% and 1.29 +/- 0.47, respectively. In patients, they were (31.12 +/- 8.12)%, (41.75 +/- 10.91)% and 0.84 +/- 0.22 before treatment, and (36.21 +/- 8.71)%, (35.08 +/- 10.14)% and 1.19 +/- 0.27 after treatment, respectively (P < 0.05). The patients were divided into treatment effective and non-effective groups by pain score. Before treatment, the immunologic parameters in the two groups had no significant differences (P > 0.05). After treatment, the frequencies of CD4(+) and CD8(+) subsets, CD4(+) to CD8(+) ratios and the number of metastatic foci in the effective group were (37.81 +/- 5.18)%, (33.17 +/- 6.38)%, 1.33 +/- 0.31 and 6.64 +/- 3.11, respectively, while in the treatment non-effective group, they were (32.09 +/- 5.72)%, (39.99 +/- 5.38)%, 0.82 +/- 0.22 and 9.87 +/- 3.46, respectively (P < 0.05).</p><p><b>CONCLUSION</b>The immune functions in patients with simple bone metastases are inhibited. Treatment with (89)SrCl(2) may improve their immunity to certain extent. The degree of recovery in the treatment effective patients was better than that in the treatment non-effective cases.</p>

89SrCl2 in the treatment of cancer patients with bone metastasis and pain / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the clinical value of (89)SrCl(2) (Ke xing Inc, Shanghai) as a palliative therapy modality for cancer patients with bone metastasis.</p><p><b>METHODS</b>In 504 cancer patients with painful limitation of movement due to bony metastasis, a dose of 1.48-2.22 MBq/kg (40-60 uCi/kg) iv infusion of (89)SrCl(2) was given.</p><p><b>RESULTS</b>In 97 patients (19.2%) there was no improvement in pain and life quality, 298 patients (59.1%) showed mild to moderate improvement (moderately effective), 109 patients (21.6%) became free of pain and were subsequently fully ambulatory (markedly effective). The pain relief appeared from D1-D46 after (89)SrCl(2) administration, most frequently from D5-D14. The palliative effect could last for about 56 days to 13 months. Repeated bone scans of some patients showed that the metastatic foci in the bone became smaller or even disappeared gradually after the administration of (89)SrCl(2). Approximately 55% of patients experienced grade I approximately III bone marrow depression attributable to (89)SrCl(2), which would return to the pre-treatment level within 3 approximately 9 months.</p><p><b>CONCLUSION</b>(89)SrCl(2) is effective and safe for the relief of bone pain and improvement of quality of life in cancer patients with painful bony metastasis.</p>

Effect of beta radiation on TGF-beta1 and bFGF expression in hyperplastic prostatic tissues / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate the transforming growth factor beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) expressions in benign prostatic hyperplasia (BPH) and the effect of beta-radiation.</p><p><b>METHODS</b>TGF-beta1 and bFGF expression was studied by means of an immunohistochemical method in nine normal prostatic (NP) tissues, 15 hyperplastic prostatic tissues and 35 hyperplastic prostatic tissues treated with 90Sr/90Y.</p><p><b>RESULTS</b>The TGF-beta1 expression in the epithelium and stroma of normal prostatic tissues was 68.2 % +/- 10.5 % and 29.7 % +/- 4.6 %, respectively, while it was 64.8 % +/- 9.3 % and 28.6 % +/- 4.1 %, respectively, in hyperplastic prostatic tissues. Compared with the controls, TGF-beta1 expression in the epithelia and stroma of BPH treated with 90Sr/90Y increased significantly (P <0.01). The bFGF expression in epithelia and stroma of normal prostatic tissues was 17.4 % +/- 3.7 % and 42.5 % +/- 6.8 %, respectively, and was 46.3 % +/- 8.2 % and 73.2 % +/- 12.1 %, respectively, in hyperplastic prostatic tissues. Compared with the controls, expressions of bFGF in the epithelia and stroma of BPH treated with a 90Sr/90Y prostatic hyperplasia applicator decreased significantly (P <0.01).</p><p><b>CONCLUSION</b>Exposure of beta-rays had noticeable effects on BPH tissues, enhancing TGF-beta1 expression and inhibiting bFGF expression.</p>

Experimental model of the morphological and morphometric aspects of tissue repair in skin wounds submitted to beta radiation emitted by Strontium -90 in rats

O objetivo deste trabalho é relatar o uso do modelo experimental para investigação dos efeitos da radiação Beta do Estrôncio-90 no processo de reparação tecidual de feridas provocadas em ratos. Utilizamos 48 animais da linhagem EPM-1 Wistar, distribuídos em dois grupos que receberam a radiação em dias alternados (Grupo A) e diariamente (Grupo B). Cada grupo foi subdividido em quatro, cada um com 6 ratos, para estudo no 3º, 7º, 14º e 21º dias de pós-operatório. Realizou-se duas incisões no dorso de cada animal, suturou-se em seguida, sendo que a de situação cranial foi irradiada e a caudal serviu para controle. Nas datas determinadas, as feridas controle e irradiada foram observadas macroscopicamente e retiradas para preparo do estudo histológico comparativo ao microscópico óptico. Realizou-se em seguida, análise morfométrica para contagem de leucócitos, fibroblastos e fibras colágenas, submetidos a estudo estatístico.

Clinical observation on treatment of multiple bone metastatic tumor of mammary cancer by combination therapy of 89Sr and Chinese herbal medicine / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To compare the clinical curative effects between 89Sr and its combination with the Guliu recipe (GLR, a Chinese herbal medicine) in treating multiple bone metastatic tumor of mammary cancer (MBM-MC).</p><p><b>METHODS</b>By adopting the random sampling and grouping method, 89Sr alone (Sr) and 89Sr combined with CHM (Sr-GLR) were used in treating 86 and 40 patients with MBM-MC respectively. The efficacy of therapy were appraised according to the degree of ostalgia relieving and quality of life (QOF) in patients, and the effect of treatment on focal bone metabolism and bone marrow hematopoietic function were compared.</p><p><b>RESULTS</b>The effective rate of Sr and Sr-GLR in relieving ostalgia was 83.72% and 95.00%, respectively (P > 0.05), the QOF improving and stabilizing rate of them 80.23% and 95.00% (P < 0.05), the effective rate on focal bone metabolism 59.30% and 52.50% (P > 0.05) and their hemo-toxicity 28.00% and 30.00% (P > 0.05).</p><p><b>CONCLUSION</b>Sr-GLR is a combination therapy in treating MBM-MC with good effect, it could raise the patient's QOF, enhance the ostalgia relieving effect without increasing the hemo-toxicity of treatment.</p>

90Sr-90Y biokinetics at incorporation determine the radiation burden to bone marrow.

The decay characteristics of 90Sr-90Y ensure that the mother and daughter nuclides exist in radioactive equilibrium, unless they get discriminated on the basis of their chemical properties, as it happens during metabolism. Although bone is the ultimate organ of deposition, the two nuclides arrive at this target organ over different biokinetic pathways. As 90Y is not excreted, it goes through transient deposition in the liver before being secondarily deposited in bone. This leads to a temporary radioactive excess of 90Y in bone. Since the decay energy of 90Y is by a factor of about 4 higher than that of 90Sr, the initial radiation burden to the bone marrow is primarily due to 90Y. This was estimated in rats by implanting LiF thermoluminescence dosimeters (TLD) in the marrow cavity of the femur. By calibrating the TLD against a known source of 90Sr-90Y, the absorbed dose rates and cumulative doses were determined as a function of time after incorporation. Two routes of administration were employed and their influence on the radiation burden is also shown.

The role of natural killer cells in the early period of infection in murine cutaneous leishmaniasis

In order to study the role of natural killer (NK) cells during the early period of Leishmania infection, BALB/c mice were selectively and permanently depleted of NK cells by injection with 90Sr and subsequently infected with Leishmania (Leishmania) amazonensis (HSJD-1 strain). 90Sr is known to selectively deplete NK cells, leaving an intact T- and B-cell compartment and preserving the ability to produce both interferon alpha and IL-2. This method of depletion has advantages when compared with depletion using anti-NK cell monoclonal antibodies because the effect is permanent and neither activates complement nor provokes massive cell death. In the present study, after one month of treatment with 90Sr, the depletion of NK cells was shown by a more than ten-fold reduction in the cytotoxic activity of these cells: 2 x 106 spleen cells from NK-depleted animals were required to reach the same specific lysis of target cells effected by 0.15 x 106 spleen cells from normal control animals. The histopathology of the skin lesion at 7 days after Leishmania infection showed more parasites in the NK cell-depleted group. This observation further strengthens a direct role of NK cells during the early period of Leishmania infection

Estudo histológico e morfométrico da reparaçäo de feridas cutâneas, provocadas em ratos, submetidas à radiaçäo beta do estrôncio-90 / Histologic and morphometric study on the healing of skin wounds in rats subwitted to Beta irradiation of Stroncium-90

O objetivo deste trabalho foi investigar os efeitos da radiaçäo Beta do Estrôncio-90 no processo de reparaçäo tecidual de feridas provocadas em ratos. Utilizamos 24 animais da linhagem EPM-1 Wistar distribuídos em 4 grupos. Receberam a radiaçäo em dias alternados e sua análise foi feita aos 3, 7, 14 e 21 dias de pós-operátorio. Realizou-se duas incisöes no dorso de cada animal, suturou-se em seguida, sendo que a de situaçäo cranial foi irradiada e a caudal serviu para controle. Nas àreas determinadas, as feridas controle e irradiada foram observadas macroscopicamente e retiradas para preparo do estudo histológico comparativo ao microscópio óptico. Realizou-se, em seguida, análise morfométrica para contagem de leucócitos, fibroblastos e fibras colágenas, submetidas a estudo estatístico. Da análise dos resultados, pode-se concluir que, em geral, a radiaçäo Beta do Estrôncio-90 provocou um aumento no número de leucócitos, uma diminuiçäo no número de fibroblastos e näo alterou o número de fibras colágenas, quando comparou-se a ferida irradiada à controle nos tempos do experimento

Characterization of tear film protein in rabbits following exposure to SR90 B-radiation

Purpose To assess the changes in tear composition in rabbits following exposure to Sr90 beta - radiation. Methods The damage induced by beta - radiation from Sr90 applicator, at doses of 20 Gy, 40 Gy and 60 Gy in weekly sitting of 10 Gy to treated left eye and the right untreated one of 25 there-month-old New Zealand white rabbits was assessed. An additional ten rabbits were used as a control. Tears collected after 24 hours were measured for protein content and lysozyme concentration. The lysozyme molecular structure was studied through the use of column chromatography; cellogel paper electrophoresis and radial diffusion technique was utilized for the demonstrated doses. The delayed effects of beta-radiation on tear lysozyme after one and three months' post exposure was also studied. All samples were analyzed six times and the mean result obtained. Results The radiation damage process increased by increasing the exposure doses and this phenomenon still propagated after the study delay periods which reported no remarks for repair. A significant decrease in the lysozyme concentration for the treated and untreated eyes was observed after the dose of 60 Gy [-61.46%] for the treated eye and [-70.64%] for the untreated one. Conclusions Although irradiation has proved to be a valuable tool in controlling eye disease, with excellent survival rates, nevertheless, side effects of radiation form serious limitations for the applicabilities of this technique

Tratamiento del dolor por metástasis óseas en el cáncer de próstata y mama con Estroncio 89 / Pain treatment for bone metastase in prostate and breast cancer with Stronium 89

Se estudiaron los efectos de la inyección endovenosa del radioisótopo Estroncio 89, sobre la Escala de categoría numérica en reposo, Escala de categoría numérica en actividad (dinámico), Escala de Karnofsky, consumo de DAINES, opioides, y sobre sus efectos en los valores de PCA (Antígeno Prostático) Fosfatasa Alcalina, Fosfatemia, Calcemia, recuento de blancos, rojos y plaquetas y recuento de metástasis óseas, en 10 pacientes portadores de cáncer de próstata (8) y cáncer de mama (2). Se realizaron controles semanales de todos los parámetros durante 14 semanas, excepto el recuento de metástasis que se realizó en 2 oportunidades. En los resultados encontramos una disminución estadísticamente significativa en la Escala numérica en reposo, en la Escala numérica en actividad (Dinámico), y en la Escala de Karnofsky a partir de la 5ta. semana. El consumo de DAINES, mostró una tendencia descendente, siendo el consumo de opioides reducido a niveles significativos. Los glóbulos rojos, glóbulos blancos y plaquetas, descendieron luego de la 8va. semana, detectándose aumento del PCA (Antígeno Prostático) y la Fosfatasa Alcalina. Los números de metástasis no se modificaron. Se describen las características del fármaco, mecanismo de acción, dosificación, contraindicaciones y sus efectos adversos. Se discuten las distintas alternativas de tratamiento del dolor por metástasis óseas: hormonoterapia, cirugía, quimioterapia, radioterapia, farmacología. Se concluye que este procedimiento es una alternativa válida para disminuir consumo de analgésicos, aumentar la calidad de vida factible de realizar a pesar de haber sido irradiado el paciente, sin efectos secundarios, excepto por disminución de valores hemáticos no graves.

Use of beta radiation to control I.O.P.

The use of ophthalmic applicator containing Strontium-90 beta ray was used to bring about a change in I.O.P. by its effect on the ciliary body. The change in I.O.P. depends on the degree of damage done to the ciliary body. The study showed that the change in I.O.P. was directly proportional to the intensity of beta rays application - higher the dose of beta radiation more was the damage and more the reduction in I.O.P.