Secondary bone cancer is where malignant cells have spread to the bones from other parts of the body. This is different to cancer that actually started in the bones (primary bone cancer). Virtually all types of cancer can spread to bone. Bone metastases are particularly common in people with breast, lung or prostate cancer. Bone metastases are usually multiple, they cause pain and can can lead to other symptoms such as hypercalcemia (abnormally high levels of calcium in the blood).
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PubMed Central search for free-access publications about Bone Cancer (secondary) MeSH term: Bone Neoplasms US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
This list of publications is regularly updated (Source: PubMed).
Jin X, Zhu Z, Shi Y Metastasis mechanism and gene/protein expression in gastric cancer with distant organs metastasis. Bull Cancer. 2014; 101(1):E1-12 [PubMed] Related Publications
Metastasis is the most fatal characteristics of malignancy tumor, which accounted for more than 90% of tumor-related mortality. Distant organ or tissue metastasis is a sign of poor prognosis in patients with gastric cancer. Tumor cells metastasis is a very complex process including tumor cell transformation, growth, angiogenesis, invasion, dissemination and survival in the circulation, and subsequent adhesion and colonization the secondary organ or tissue. The origin of tumor cell, genetic variation, the circulatory mode and the physiological structure of the metastatic organ determines the specific sites of distant metastasis. In theory, the metastatic lesion is originated from their primary tumor, so they should have the same molecular profile with the primary tumor. But this view has been confirmed to be wrong in various tumors, including gastric cancer. The gene expression of primary gastric cancer and its metastasis have differences, which may contribute to the early diagnosis and individualized treatment of metastasis. However, the heterogeneity of tumor cells is still unclear in different metastasis lesion of gastric cancer, which will be a major focus of future research. In this review, we discuss the basic principles of cancer metastasis, the unique physiological characteristics of the various metastasis organs and the expression of different functions of gene/protein in primary and metastasis of gastric cancer. In addition, we also discuss the diagnosis, prognosis and treatment in various organ metastasis of gastric cancer.
Di Franco R, Falivene S, Ravo V, et al. Management of painful bone metastases: our experience according to scientific evidence on palliative radiotherapy. Anticancer Res. 2014; 34(2):1011-4 [PubMed] Related Publications
AIM: Our aim was to evaluate retrospectively the role of the radiotherapy in the multi-disciplinary management of pain due to bone metastases. PATIENTS AND METHODS: A total of 305 patients received radiotherapy with or without bisphosphonate and antalgic drugs. Tolerability and efficacy were evaluated using a Numerical Rating Scale, Pain Intensity Difference evaluation scale related to administration of the drug, a 5-point verbal scale of the patients' general impression. RESULTS: We found differences in some patient subgroups: pain reduction was significantly more evident in patients treated with a single-fraction radiotherapy scheme. Overall, 68% of patients experienced an improvement in pain control using concomitant drugs during radiotherapy. CONCLUSION: Our study underlines the role of radiotherapy in the management of metastatic bone pain. The use of rapid-onset opioids to prevent predictable pain is a crucial step in managing radiotherapy. An interdisciplinary approach is recommended.
Shahid M, Saunders T, Jeys L, Grimer R The outcome of surgical treatment for peri-acetabular metastases. Bone Joint J. 2014; 96-B(1):132-6 [PubMed] Related Publications
We reviewed the outcome of patients who had been treated operatively for symptomatic peri-acetabular metastases and present an algorithm to guide treatment. The records of 81 patients who had been treated operatively for symptomatic peri-acetabular metastases between 1987 and 2010 were identified. There were 27 men and 54 women with a mean age of 61 years (15 to 87). The diagnosis, size of lesion, degree of pelvic continuity, type of reconstruction, World Health Organization performance status, survival time, pain, mobility and complications including implant failure were recorded in each case. The overall patient survivorship at five years was 5%. The longest lived patient survived 16 years from the date of diagnosis. The mean survival was 23 months (< 1 to 16 years) and the median was 15 months. At follow-up 14 patients remained alive. Two cementoplasties failed because of local disease progression. Three Harrington rods broke: one patient needed a subsequent Girdlestone procedure. One 'ice-cream cone' prosthesis dislocated and was subsequently revised without further problems. We recommend the 'ice-cream cone' for pelvic discontinuity and Harrington rod reconstruction for severe bone loss. Smaller defects can be safely managed using standard revision hip techniques.
Chow E, van der Linden YM, Roos D, et al. Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol. 2014; 15(2):164-71 [PubMed] Related Publications
BACKGROUND: Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. METHODS: We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. FINDINGS: Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). INTERPRETATION: In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. FUNDING: Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.
Takanen S, Bangrazi C, Caiazzo R, et al. Multiple bone metastases from glioblastoma multiforme without local brain relapse: a case report and review of the literature. Tumori. 2013 Sep-Oct; 99(5):e237-40 [PubMed] Related Publications
Extracranial metastases from glioblastoma multiforme (GBM) are a very rare event, even if an increasing incidence has been documented. We report the case of a young woman with primary GBM who developed bone metastases without local brain relapse. Because of persistent headache and visual disturbances, in March 2011 the patient underwent magnetic resonance imaging (MRI) evidencing a temporoparietal mass, which was surgically resected. Histology revealed GBM. She was given concomitant chemoradiotherapy according to the Stupp regimen. After a 4-week break, the patient received 6 cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days. In December 2011 she complained of progressive low back pain, and MRI showed multiple bone metastases from primary GBM, confirmed by histology. Cases of metastatic GBM in concurrence with a primary brain tumor or local relapse are more common in the literature; only a few cases have been reported where extracranial metastases from GBM occurred without any relapse in the brain. Here we report our experience.
Messina M, Ricci F, Spina B, Boccardo F Single skull metastasis 15 years after primary treatment of prostate cancer and with undetectable PSA levels: a case report and review of the literature. Tumori. 2013 Sep-Oct; 99(5):e220-4 [PubMed] Related Publications
Prostate cancer is the first cause of skull metastases in men, accounting for 12-18% of all cases. This condition is generally a late event in the course of the disease, involving patients with disseminated lesions. Quite rarely is skull involvement the first and single site of distant recurrence. We report the case of a patient who developed a single skull lesion 15 years after primary treatment of prostate cancer, in the presence of undetectable PSA levels. Pathological assessment performed after resection of the lesion revealed a metastasis from prostate carcinoma. Basing on this experience the appearance of craniofacial pain or a nerve deficit in patients with a history of prostate cancer should alert the clinician to exclude distant recurrence of disease, even in the presence of undetectable PSA levels and even if many years have elapsed since the treatment of the primary tumor. Knowledge of these manifestations will reduce any diagnostic delay and lead to the effective delivery of appropriate treatment.
Dröge LH, Hinsche T, Canis M, et al. Fractionated external beam radiotherapy of skull base metastases with cranial nerve involvement. Strahlenther Onkol. 2014; 190(2):199-203 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Skull base metastases frequently appear in a late stage of various tumor entities and cause pain and neurological disorders which strongly impair patient quality of life. This study retrospectively analyzed fractionated external beam radiotherapy (EBRT) as a palliative treatment approach with special respect to neurological outcome, feasibility and acute toxicity. PATIENTS AND METHODS: A total of 30 patients with skull base metastases and cranial nerve disorders underwent EBRT with a mean total dose of 31.6 Gy. Neurological status was assessed before radiotherapy, during radiotherapy and 2 weeks afterwards categorizing orbital, parasellar, middle fossa, jugular foramen and occipital condyle involvement and associated clinical syndromes. Neurological outcome was scored as persistence of symptoms, partial response, good response and complete remission. Treatment-related toxicity and overall survival were assessed. RESULTS: Before EBRT 37 skull base involvement syndromes were determined with 4 patients showing more than 1 syndrome. Of the patients 81.1 % responded to radiotherapy with 10.8 % in complete remission, 48.6 % with good response and 21.6 % with partial response. Grade 1 toxicity of the skin occurred in two patients and grade 1 hematological toxicity in 1 patient under concurrent chemoradiotherapy. Median overall survival was 3.9 months with a median follow-up of 45 months. CONCLUSION: The use of EBRT for skull base metastases with symptomatic involvement of cranial nerves is marked by good therapeutic success in terms of neurological outcome, high feasibility and low toxicity rates. These findings underline EBRT as the standard therapeutic approach in the palliative setting.
Chu T, Teng J, Jiang L, et al. Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation. Biochem Biophys Res Commun. 2014; 443(3):962-8 [PubMed] Related Publications
Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC.
Olsen DL, Anderson SR Metastatic plasmacytoid urothelial carcinoma: a case report and review of the literature. Acta Cytol. 2014; 58(1):108-12 [PubMed] Related Publications
Plasmacytoid urothelial carcinoma is a rare form of invasive urothelial carcinoma first described in 1991 by Sahin et al. [Acta Cytol 1991;35:277-280]. Since this original publication, over 70 cases of plasmacytoid urothelial carcinoma have been described. A small number of cytologic descriptions have been published, including cases involving cerebrospinal fluid cytology, bladder washings and urine cytology. To our knowledge, we describe the first fine needle aspiration of metastatic plasmacytoid urothelial carcinoma in a 75-year-old man who presented with a pathologic fracture of the L4 vertebral body. One of the diagnostic pitfalls in the cytologic evaluation of this rare malignancy is the positive staining with CD138. While CD138 is a marker for plasma cell differentiation, it is also positive in plasmacytoid urothelial carcinoma. In addition to recognizing the cytomorphologic details, a full immunohistochemical panel is helpful in properly characterizing this entity. A brief discussion of long-term prognosis and treatment benefit is provided.
Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014; 15(1):114-22 [PubMed] Related Publications
BACKGROUND: Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone. METHODS: This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820. FINDINGS: Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13%] vs 85 [corrected] [12%]), joint pain (41 [corrected] [6%] vs 38 [5%]), infection (31 [5%] vs 23 [corrected] [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]). INTERPRETATION: Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions. FUNDING: Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022).
Ota N, Kato K, Iwano S, et al. Comparison of ¹⁸F-fluoride PET/CT, ¹⁸F-FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study. Br J Radiol. 2014; 87(1034):20130444 [PubMed] Related Publications
OBJECTIVE: We compared the efficacies of ¹⁸F-fluoride positron emission tomography (¹⁸F-fluoride PET)/CT, ¹⁸F-fludeoxyglucose PET (¹⁸F-FDG PET)/CT, and ⁹⁹mTc bone scintigraphy [planar and single photon emission CT (SPECT)] for the detection of bone metastases in patients with differentiated thyroid carcinoma (DTC). METHODS: We examined 11 patients (8 females and 3 males; mean age 6 standard deviation, 61.968.7 years) with DTC who had been suspected of having bone metastases after total thyroidectomy and were hospitalized to be given ¹³¹I therapy. Bone metastases were verified either when positive findings were obtained on both ¹³¹I scintigraphy and CT or when MRI findings were positive if MRI was performed. RESULTS: Metastases were confirmed in 24 (13.6%) of 176 bone segments in 9 (81.8%) of the 11 patients. The sensitivities of ¹⁸F-fluoride PET/CT and ⁹⁹mTc bone scintigraphy (SPECT) were significantly higher than those of ¹⁸F-FDG PET/CT and ⁹⁹mTc bone scintigraphy (planar) (p,0.05). The accuracies of ¹⁸F-fluoride PET/CT and mTc bone scintigraphy (SPECT) were significantly higher than that of ⁹⁹mTc bone scintigraphy (planar) (p,0.05). CONCLUSION: The sensitivity and accuracy of ¹⁸F-fluoride PET/CT for the detection of bone metastases of DTC are significantly higher than those of ⁹⁹mTc bone scintigraphy (planar). However, the sensitivity and accuracy of ⁹⁹mTc bone scintigraphy (planar) are improved near to those of ¹⁸F-fluoride PET/CT when SPECT is added to a planar scan. The sensitivity of ¹⁸F-FDG PET/CT is significantly lower than that of 18F-fluoride PET/CT or ⁹⁹mTc bone scintigraphy (SPECT).
Blake ML, Tometsko M, Miller R, et al. RANK expression on breast cancer cells promotes skeletal metastasis. Clin Exp Metastasis. 2014; 31(2):233-45 [PubMed] Related Publications
RANK ligand (RANKL), acting through its cognate receptor RANK, is a key factor for bone remodeling and metastasis by regulating the differentiation, survival and activation of osteoclasts. RANKL is also crucial for the development of mouse mammary glands during pregnancy and has been recently linked to the etiology of breast cancer via its direct activity on RANK-expressing normal or transformed breast epithelial cells, leading to increased mitogenesis, enhanced regenerative potential of mammary stem cells, and increased invasion and migration. We demonstrate that higher RANK expression in MDA-MB-231 breast cancer cells (MDA-231-RANK cells) is sufficient to confer a significantly greater metastatic growth rate in the bone compared with MDA-MB-231 cells which do not express high levels of RANK. Blockade of osteoclastic bone resorption, achieved with treatment by either RANKL inhibition or zoledronic acid, did reduce skeletal tumor progression of MDA-231-RANK cells suggesting that the vicious cycle contributes to metastatic growth. However, RANKL inhibition reduced skeletal growth of MDA-231-RANK tumors to a significantly greater extent than zoledronic acid, indicating that skeletal growth of RANK-positive tumors is also driven by direct RANKL effects. RANKL stimulated the expression of multiple genes associated with cell invasive behavior, including several matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature. These data indicate that RANKL provokes breast cancer bone metastases via two distinct, but potentially overlapping mechanisms: stimulation of tumor-associated osteoclastogenesis and stimulation of RANK-expressing tumor cells.
Raphael B, Hwang S, Lefkowitz RA, et al. Biopsy of suspicious bone lesions in patients with a single known malignancy: prevalence of a second malignancy. AJR Am J Roentgenol. 2013; 201(6):1309-14 [PubMed] Related Publications
OBJECTIVE: The probability that a suspicious bone lesion in a patient with one known malignancy is actually due to a second, previously unknown primary malignancy has been reported to be 2-8%. We sought to determine this prevalence as well as that of benign diagnoses in a larger number of patients in a tertiary cancer center. MATERIALS AND METHODS: The medical records of 482 consecutive patients (254 women and 228 men) with only one known primary malignancy each (excluding nonmelanoma skin cancer) and who underwent biopsy of a suspicious bone lesion were retrospectively reviewed. The results of bone biopsy were classified as benign, metastasis of the known primary malignancy, due to a second primary malignancy, or nondiagnostic or indeterminate. RESULTS: In 103 of 482 (21%) patients, bone biopsy results were benign, 316 (66%) were due to metastases of the known malignancy, 15 (3%) were due to a second malignancy, and 48 (10%) were nondiagnostic or indeterminate. Second malignancies included osteosarcoma (n = 4); soft-tissue sarcoma (n = 2); lymphoma (n = 2); plasma cell malignancy (n = 2); and lung cancer, thyroid cancer, renal cancer, chondrosarcoma, and carcinoma of unknown primary (n = 1 each). CONCLUSION: In 3% of patients with one known malignancy and a suspicious bone lesion, the lesion was due to a previously unknown second malignancy; in 21% of patients, the lesion was benign. Bone biopsy is recommended in the management of patients with one known cancer and a suspicious bone lesion only if the presence of a second malignancy would alter clinical management.
O'Hurley G, Prencipe M, Lundon D, et al. The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases. Prostate. 2014; 74(3):306-13 [PubMed] Related Publications
BACKGROUND: Castration-resistant prostate cancer (CRPC) represents a challenge to treat with no effective treatment options available. We recently identified serum response factor (SRF) as a key transcription factor in an in vitro model of castration resistance where we showed that SRF inhibition resulted in reduced cellular proliferation. We also demonstrated an association between SRF protein expression and CRPC in a cohort of castrate-resistant transurethral resections of the prostate (TURPS). The mechanisms regulating the growth of CRPC bone and visceral metastases have not been explored in depth due to the paucity of patient-related material available for analysis. In this study, we aim to evaluate SRF protein expression in prostate cancer (PCa) metastases, which has not previously been reported. METHODS AND RESULTS: We evaluated the nuclear tissue expression profile of SRF by immunohistochemistry in 151 metastatic sites from 42 patients who died of advanced PCa. No relationship between SRF nuclear expression and the site of metastasis was observed (P = 0.824). However, a negative association between SRF nuclear expression in bone metastases and survival from (a) diagnosis with PCa (P = 0.005) and (b) diagnosis with CRPC (P = 0.029) was seen. These results demonstrate that SRF nuclear expression in bone metastases is associated with survival, with patients with the shortest survival showing high SRF nuclear expression and patients with the longest survival having low SRF nuclear expression. CONCLUSION: Our study indicates that SRF is a key factor determining patients' survival in metastatic CRPC and therefore may represent a promising target for future therapies.
Menezes JD, Cappellari PF, Capelari MM, et al. Mandibular metastasis of adenocarcinoma from prostate cancer: case report according to epidemiology and current therapeutical trends of the advanced prostate cancer. J Appl Oral Sci. 2013 Sep-Oct; 21(5):490-5 [PubMed] Free Access to Full ArticleRelated Publications
Prostate cancer represents the most frequent non-cutaneous neoplasia in males. This type of neoplasia can develop peculiar patterns of evolution, presenting, in many cases, precocious relapses and metastasis. Bone metastasis in the mouth is extremely rare, and represents 1% of all malignant mouth neoplasias. The aim of the present study is to report a clinical case of bone metastasis in the mandibular region associated with a tumoral prostate adenocarcinoma, as well as to discuss connected aspects about diagnosis, prognosis and integrated treatment of this condition.
Chang AL, Solomon JA, Hainsworth JD, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014; 70(1):60-9 [PubMed] Related Publications
BACKGROUND: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. OBJECTIVE: We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. METHODS: This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. LIMITATIONS: Abbreviated follow-up time because of study termination upon FDA approval was a limitation. CONCLUSION: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
Issack PS, Kotwal SY, Lane JM Management of metastatic bone disease of the acetabulum. J Am Acad Orthop Surg. 2013; 21(11):685-95 [PubMed] Related Publications
Metastatic acetabular disease can be severely painful and may result in loss of mobility. Initial management may consist of diphosphonates, narcotic analgesics, radiation therapy, protected weight bearing, cementoplasty, and radiofrequency ablation. Patients with disease affecting large weight-bearing regions of the acetabulum and with impending failure of the hip joint are unlikely to gain much relief from nonsurgical treatment and interventional procedures. The profound osteopenia of the acetabulum, limited healing potential of the fracture, and projected patient life span and function necessitate surgical techniques that provide immediate stable fixation to reduce pain and restore ambulatory function. Current reconstructive procedures, including cemented total hip arthroplasty, the saddle or periacetabular endoprosthesis, and porous tantalum implants, are based on the quality of remaining acetabular bone as well as the patient's level of function and general health. Well-executed acetabular reconstructions can provide durable hip joints with good pain relief and function.
Martinez LM, Vallone VB, Labovsky V, et al. Changes in the peripheral blood and bone marrow from untreated advanced breast cancer patients that are associated with the establishment of bone metastases. Clin Exp Metastasis. 2014; 31(2):213-32 [PubMed] Related Publications
Bone metastasis is an incurable complication of breast cancer affecting 70-80 % of advanced patients. It is a multistep process that includes tumour cell mobilisation, intravasation, survival in the circulation, extravasation, migration and proliferation in the bone marrow/bone. Although novel findings demonstrate the bone marrow microenvironment significance in bone metastatic progression, a majority of studies have focused on end-stage disease and little is known about how the pre-metastatic niche arises in the bone marrow/bone tissues. We demonstrated a significant increase in patients' peripheral blood plasma ability to induce transendothelial migration of MCF-7 cells compared with healthy volunteers. Moreover, high RANKL, MIF and OPG levels in patients' peripheral blood could play a role in the intravasation, angiogenesis, survival and epithelial-mesenchymal transition of circulating tumour cells. Also, we observed a significant increase in patients' bone marrow plasma capacity to induce transendothelial migration of MDA-MB231 and MCF-7 cells compared with healthy volunteers. Furthermore, patients' bone marrow mesenchymal stem cells could control the recruitment of tumour cells, modifying the MCF-7 and MDA-MB231 cell migration. In addition, we found a significantly higher MDA-MB231 cell proliferation when we used patients' bone marrow plasma compared with healthy volunteers. Interestingly, PDGF-AB, ICAM-1 and VCAM-1 levels in patients' bone marrow were significantly higher than the values of healthy volunteers, suggesting that they could be involved in the cancer cell extravasation, bone resorption and cancer cell proliferation. We believe that these results can reveal new information about what alterations happen in the bone marrow of advanced breast cancer patients before bone colonisation, changes that create optimal soil for the metastatic cascade progression.
Vela I, Morrissey C, Zhang X, et al. PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer. Clin Exp Metastasis. 2014; 31(2):199-211 [PubMed] Related Publications
The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.
Marlow R, Honeth G, Lombardi S, et al. A novel model of dormancy for bone metastatic breast cancer cells. Cancer Res. 2013; 73(23):6886-99 [PubMed] Related Publications
Mortality of patients with breast cancer is due overwhelmingly to metastatic spread of the disease. Although dissemination is an early event in breast cancer, extended periods of cancer cell dormancy can result in long latency of metastasis development. Deciphering the mechanisms underlying cancer cell dormancy and subsequent growth at the metastatic site would facilitate development of strategies to interfere with these processes. A challenge in this undertaking has been the lack of models for cancer cell dormancy. We have established novel experimental systems that model the bone microenvironment of the breast cancer metastatic niche. These systems are based on 3D cocultures of breast cancer cells with cell types predominant in bone marrow. We identified conditions in which cancer cells are dormant and conditions in which they proliferate. Dormant cancer cells were able to proliferate upon transfer into supportive microenvironment or upon manipulation of signaling pathways that control dormancy. These experimental systems will be instrumental for metastasis studies, particularly the study of cellular dormancy.
Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: A population-based analysis. Prostate. 2014; 74(2):210-6 [PubMed] Related Publications
BACKGROUND: There is few data on what constitutes the distribution of metastatic sites in prostate cancer (PCa). The aim of our study was to systematically describe the most common sites of metastases in a contemporary cohort of PCa patients. METHODS: Patients with metastatic PCa were abstracted from the Nationwide Inpatient Sample (1998-2010). Most common metastatic sites within the entire population were described. Stratification was performed according to the presence of single or multiple (≥ 2 sites) metastases. Additionally, we evaluated the distribution of metastatic sites amongst patients with and without bone metastases. RESULTS: Overall, 74,826 patients with metastatic PCa were identified. The most common metastatic sites were bone (84%), distant lymph nodes (10.6%), liver (10.2%), and thorax (9.1%). Overall, 18.4% of patients had multiple metastatic sites involved. When stratifying patients according to the site of metastases, only 19.4% of men with bone metastases had multiple sites involved. Conversely, among patients with lymph nodes, liver, thorax, brain, digestive system, retroperitoneum, and kidney and adrenal gland metastases the proportion of men with multiple sites involved was 43.4%, 76.0%, 76.7%, 73.0%, 52.2%, 60.9%, and 76.4%, respectively. When focusing exclusively on patients with bone metastases, the most common sites of secondary metastases were liver (39.1%), thorax (35.2%), distant lymph nodes (24.6%), and brain (12.4%). CONCLUSIONS: Although the majority of patients with metastatic PCa experience bone location, the proportion of patients with atypical metastases is not negligible. These findings might be helpful when planning diagnostic imaging procedures in patients with advanced PCa.
Mariani P, Servois V, De Rycke Y, et al. Liver metastases from breast cancer: Surgical resection or not? A case-matched control study in highly selected patients. Eur J Surg Oncol. 2013; 39(12):1377-83 [PubMed] Related Publications
AIM: To determine whether, in a highly selected patient population, medical treatment combined with surgical resection of liver metastases from breast cancer is associated with improved survival compared with medical treatment alone. PATIENTS AND METHODS: Between 1988 and 2007, 100 liver resections for metastatic breast cancer were performed at Institut Curie, 51 of which met the criteria for inclusion in this case-control study. With the exception of bone metastases, patients with other distant metastasis sites were excluded. Surgery was only performed in patients with stable disease or disease responding to medical treatment evaluated by imaging evaluation. Surgical cases were individually matched with 51 patients receiving medical treatment only. All patients had 4 or fewer resectable liver metastases. The study group was matched with the control group for age, year of breast cancer diagnosis, time to metastasis, TNM stage, hormone receptor status and breast cancer tumour pathology. RESULTS: Univariate analysis confirmed a survival advantage for patients lacking bone metastases and axillary lymphadenopathy at the time of breast cancer diagnosis and for surgically treated patients. Multivariate analysis indicated that surgery and the absence of bone metastases were associated with a better prognosis. A multivariate Cox model adapted for paired data showed a RR = 3.04 (CI: 1.87-4.92) (p < 0.0001) in favour of surgical treatment. CONCLUSION: Surgical resection of liver metastases from primary breast cancer appears to provide a survival benefit for highly selected patients.
Chang MA, Morgado M, Warren CR, et al. p62/SQSTM1 is required for cell survival of apoptosis-resistant bone metastatic prostate cancer cell lines. Prostate. 2014; 74(2):149-63 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND: Bone marrow stromal cell (BMSC) paracrine factor(s) can induce apoptosis in bone metastatic prostate cancer (PCa) cell lines. However, the PCa cells that escape BMSC-induced apoptosis can upregulate cytoprotective autophagy. METHODS: C4-2, C4-2B, MDA PCa 2a, MDA PCa 2b, VCaP, PC3, or DU145 PCa cell lines were grown in BMSC conditioned medium and analyzed for mRNA and/or protein accumulation of p62 (also known as sequestome-1/SQSTM1), Microtubule-associated protein 1 light chain 3B (LC3B), or lysosomal-associated membrane protein 1 (LAMP1) using quantitative polymerase chain reaction (QPCR), Western blot, or immunofluorescence. Small interfering RNA (siRNA) was used to determine if p62 is necessary PCa cell survival. RESULTS: BMSC paracrine signaling upregulated p62 mRNA and protein in a subset of the PCa cell lines. The PCa cell lines that were insensitive to BMSC-induced apoptosis and autophagy induction had elevated basal p62 mRNA and protein. In the BMSC-insensitive PCa cell lines, siRNA knockdown of p62 was cytotoxic and immunostaining showed peri-nuclear clustering of autolysosomes. However, in the BMSC-sensitive PCa cell lines, p62 siRNA knockdown was not appreciably cytotoxic and did not affect autolysosome subcellular localization. CONCLUSIONS: A pattern emerges wherein the BMSC-sensitive PCa cell lines are known to be osteoblastic and express the androgen receptor, while the BMSC-insensitive PCa cell lines are characteristically osteolytic and do not express the androgen receptor. Furthermore, BMSC-insensitive PCa may have evolved a dependency on p62 for cell survival that could be exploited to target and kill these apoptosis-resistant PCa cells in the bone.
Cummings MC, Simpson PT, Reid LE, et al. Metastatic progression of breast cancer: insights from 50 years of autopsies. J Pathol. 2014; 232(1):23-31 [PubMed] Related Publications
There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array-based comparative genomic hybridization for six cases(##) . 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non-axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down-regulation during progression in a non-random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.
Ricci E, Mattei E, Dumontet C, et al. Increased expression of putative cancer stem cell markers in the bone marrow of prostate cancer patients is associated with bone metastasis progression. Prostate. 2013; 73(16):1738-46 [PubMed] Related Publications
BACKGROUND: The number of cells positive for the α-6 and α-2 integrin subunits and the c-Met receptor in primary tumors and bone biopsies from prostate cancer patients has been correlated with metastasis and disease progression. The objective of this study was to quantify disseminated tumour cells present in bone marrow in prostate cancer patients using specific markers and determine their correlation with metastasis and survival. METHODS: Patients were included at different stage of prostate cancer disease, from localised to metastatic castration-resistant prostate cancer. Healthy men were used as a control group. Bone marrow samples were collected and nucleated cells separated. These were stained for CD45, α-2, α-6 integrin subunits and c-Met and samples were processed for analysis and quantification of CD45-/α2+/α6+/c-met + cells using flow cytometry. Clinical and pathological parameters were assessed and survival measured. Statistical analyses were made of associations between disease specific parameters, bone marrow flow cytometry data, prostate-specific antigen (PSA) progression free survival and bone metastases progression free survival. RESULTS: For all markers, the presence of more than 0.1% positive cells in bone marrow aspirates was significantly associated with the risk of biochemical progression, the risk of developing metastasis and death from prostate cancer. CONCLUSIONS: Quantification of cells carrying putative stem cell markers in bone marrow is a potential indicator of disease progression. Functional studies on isolated cells are needed to show more specifically their property for metastatic spread in prostate cancer.
Chung Y, Koom WS, Ahn YC, et al. A survey of patterns of practice on palliative radiation therapy for bone metastasis in Korea. J Cancer Res Clin Oncol. 2013; 139(12):2089-96 [PubMed] Related Publications
PURPOSE: The aim of this study was to understand the practice patterns of palliative radiation therapy for bone metastasis in Korea among Korean radiation oncologists by survey and to determine the decision factors affecting the prescription of radiation therapy fractionation schedules. METHODS: An Internet-based survey was performed from October 5 to October 23, 2009, among 177 active full members of the Korean Society for Radiation and Oncology (KOSRO). The survey questionnaire included general information about the respondent, three types of clinical scenario, depending on the life expectancy of the patients, and the decision factors that affected the prescription of a radiation therapy schedule. RESULTS: The most prescribed schedule was 30 Gy in 10 fractions regardless of the life expectancy of the patient. Also, it was found that a single fraction was seldom prescribed routinely in Korea. An increasing number prescribed fewer than 10 fractions as the life expectancy shortened; however, the prescription rate of a single fraction was still low. The general performance (and/or accompanying diseases) of patients and the life expectancy were the most considered factors in deciding the prescription of radiation therapy. CONCLUSIONS: Despite the abundant evidence supporting the equivalence of single- and multi-fraction radiation therapy, still, most Korean radiation oncologists continue to prescribe multi-fraction schedules depending on the general performance and life expectancy of the patients. Thus, we confirmed that there was a gap between evidence and practice, and treatment prescriptions can be strongly affected by decision factors other than published literature results.
Maass N, Harbeck N, Mundhenke C, et al. Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. J Cancer Res Clin Oncol. 2013; 139(12):2047-56 [PubMed] Related Publications
PURPOSE: Everolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment. PATIENTS AND METHODS: We evaluated everolimus in a double-blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8 weeks of everolimus 10 mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation. RESULTS: Eighty-nine patients were enrolled in 4 years. Thirty-nine patients with SD after 8 weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95 % CI 16.7-40.3) versus 12.6 weeks (95 % CI 7.1-17.9) with placebo [HR 0.554 (95 % CI 0.282-1.09) p = 0.0818], adjusted for endocrine therapy [HR 0.464 (95 % CI 0.226-0.954) p = 0.037]. TTP in everolimus responders (n = 6) was 86 weeks. CONCLUSION: The RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long-term benefit from everolimus if they do not progress within 8 weeks of treatment.
Romanos O, Solomou E, Georgiadis P, et al. Magnetic resonance imaging and image analysis of post - radiation changes of bone marrow in patients with skeletal metastases. J BUON. 2013 Jul-Sep; 18(3):788-94 [PubMed] Related Publications
PURPOSE: To evaluate the post-radiation lesions of the bone marrow with magnetic resonance imaging (MRI) and image analysis in patients with bone metastases undergoing radiation therapy (RT). METHODS: Thirty-five patients with bone metastases were studied from June 2008 to December 2010. All patients had osseous metastases from various primary malignancies and underwent palliative RT. MRI was performed in a Philips Gyroscan Intera 1T scanner at the beginning of RT and 12-18 days later. T1-TSE, T2-TSE and short tau inversion recovery (STIR) sequences were used. All images obtained were evaluated for early post-radiation lesions. Additionally, 1st and 2nd order textural features were extracted from these images and were introduced into a probabilistic neural network (PNN) classifier in order to create an automated classification system for those lesions. RESULTS: Changes of signal intensity in T1-TSE, T2-TSE and STIR sequences were evaluated for the presence of edema, fatty conversion of the bone marrow or areas of hemorrhage within the limits of the irradiated area. The automated classification system showed positive results in correctly discriminating the post-radiation lesions that MRI revealed. The overall classification accuracy for discriminating between pre-radiation and post-radiation lesions was 93.2%. Furthermore, the overall classification accuracy for discriminating between post-radiation lesions was 86.67%. CONCLUSION: It seems that MRI can evaluate the degree of early therapy-induced bone marrow lesions observed during the first 18 days from the beginning of RT. The proposed neural network-based classification system might be used as an assisting tool for the characterization of these lesions.
Obuchowska I, Pawluczuk B, Mariak Z Exophthalmos as a first manifestation of the systemic spread of small cell lung cancer. Klin Oczna. 2013; 115(2):135-40 [PubMed] Related Publications
Small cell lung cancer is characterized by rapid growth and early metastases. The most frequent locations of the secondary lesions include adrenal glands, brain, liver, and skeleton. On initial diagnosis, up to 70% of patients with small cell lung cancer have metastases. Metastases to the eye or orbit developed approximately 0.7-12% of patients with lung cancer. Clinical signs and symptoms of orbital metastases may include exophthalmos, diplopia, pain, limited ocular motility, blurred vision, swollen eyelid, conjunctival hyperemia and edema, increased ocular pressure and papilledema. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic tumor of orbit due to small cell lung cancer.
Rief H, Muley T, Bruckner T, et al. Survival and prognostic factors in non-small cell lung cancer patients with spinal bone metastases: a retrospective analysis of 303 patients. Strahlenther Onkol. 2014; 190(1):59-63 [PubMed] Related Publications
BACKGROUND AND PURPOSE: For palliative care of spinal bone metastases, stability assessment is of crucial importance. Pathological fractures, instability-related patient immobility and the extent of bone metastasis have been reported to affect patient outcome and these parameters have therefore been used for treatment stratification. We report on stability-dependent fracture and survival rates in over 300 non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Data from 303 patients with 868 osteolytic metastases treated with radiotherapy (RT) between 2000 and 2012 were evaluated retrospectively. RESULTS: In NSCLC patients with bone metastases only, the retrospective 6- and 12-month overall survival (OS) rates were 76.7 and 47.2%, respectively. In patients with additional non-bone distant metastases, these values were 60.0 and 34.0%, respectively. Survival rates were significantly lower in patients with multiple bone metastases and in those suffering pathological fractures (p=0.017). No significant impact of histological type, location of spinal lesions or treatment regime was detected. Furthermore, stability assessment revealed no influence of vertebral column stability on patient outcome (p=0.739). CONCLUSION: Our analysis demonstrated a correlation between the pathological fractures of bone lesions, the number of bone metastases, additional distant metastases and survival. The results offer a rationale for future prospective investigations.