Severe Bone Pain Research Articles

Papular Cutaneous Amyloidosis Associated with Multiple Myeloma

We report a case of papular cutaneous amyloidosis associated with multiple myeloma in a 52 years old man who presented papular xanthoma like lesions in periorbital areas and scrotum with severe bone pain in thoracic and lumbar spinal column and lower limbs. Cutaneous histopathology revealed the presence of amorphous deposits in papillary dermis surrounded with small lymphoid infiltrates with erythrocyte containing slots. Congo red staining was positive and bone marrow aspiration showed dysplastic plasma cells. Lytic lesions were observed in long bones and skull radiography. 24 hours Proteinuria was 3.69 g / l. A combination of Melphalan and prednisone as treatment could restore renal function without any change in skin lesions after 14 months.

Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis.

Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic options of future cases.

Drug Resistant Myeloma Cells Cause More Severe Bone Destruction in Myeloma

Background: Multiple myeloma (MM) is the second most common hematologic malignancy in the US and is characterized by osteolytic disease. More than 80% of MM patients have osteolysis, leading to in fractures, severe bone pain, spinal cord compression, and hypercalcemia, greatly compromising patient quality of life and resulting in mortality. While bone exists in a dynamic state between resorption and deposition, the molecular mechanisms underlying bone destruction in MM remain elusive. One contributing factor is heparanase (HPSE). In our work, we have previously shown that the expression of NEK2 and HPSE are closely correlated. We have also shown that high expression of chromosomal instability-related genes (e.g. NEK2) induces drug resistance and poor prognosis in MM. Though tumor burden is dramatically decreased in remission, bone destruction is poorly repaired, suggesting drug resistant MM cells may play a critical role in inducing bone destruction or in preventing the repair of bone disease in remission.Materials and Methods: Gene expression profiling (GEP) data and bone lytic lesions detected by MRI were collected from 333 newly diagnosed MM patients from the Total Therapy 2 (TT2) clinical trial. MM cell lines with stable overexpression or knockdown of NEK2 and/or HPSE were created using lentiviral delivery. Protein and mRNA expression was assessed by immunoblotting and real-time PCR, respectively. TRAP staining was used to assess osteoclast differentiation. In vivo studies were performed in the KaLwRij 5TGM1 MM mouse model in 3 different groups: empty vector (EV), NEK2 overexpression (NEK2 OE), or NEK2 OE with HPSE shRNA. Bone density and imaging assessment was performed via X-ray and microCT scanning. HPSE, NFκB, and USP7 contributions were examined using the specific small molecule inhibitors SST0001, BSM-345541, and P5091, respectively.Results: In correlating NEK2 expression with osteolytic lesion from 333 newly diagnosed MMs, we found the expression of NEK2 was significantly higher in MM patients with bone lytic lesion than those without lesions. NEK2 expression was also higher in patients with severe bone disease (7 or more lesions) than those fewer bone lytic lesions (< 7).To determine if NEK2 causes bone lytic lesions in MM, we performed in vivo studies injecting NEK2 OE 5TGM1 cells into KaLwRij mice. MicroCT showed clearly that bone volume and thickness of trabecular bone were decreased significantly in mice injected with NEK2 OE cells compared to EV cells. Strikingly, treatment with the HPSE inhibitor SST0001 dramatically rescued bone mass loss induced by NEK2 overexpression. Histological TRAP staining of decalcified bone sections revealed a significant increase in the number of osteoclasts in the bone surface area in mice injected with NEK2 OE cells compared to EV-treated mice, while addition of the SST0001 significantly reduced the number of osteoclast.Because osteoclast causes bone resorption, we examined the effect of applying conditioned media from MM cells with or without NEK2 overexpression to pre-osteoclast cells derived from MM patients, C57BL6 mice, and the pre-osteoclast RAW264.7 cell line. We found significantly increased mature osteoclasts (>3 nuclei) after culture with media collected from NEK2 MM cells compared to conditioned media collected from EV cells. Consistently, osteoclast differentiation-associated genes (i.e. CTSK, NFATc1, RANK, and TRAP) were upregulated in pre-osteoclasts cultured with NEK2 OE conditioned media. SST0001 suppressed osteoclast differentiation induced by NEK2, strongly suggesting that HPSE mediates NEK2 induced osteoclastogensis and bone destruction in MM. Mechanistic studies revealed that NEK2 directly binds to and activates USP7 resulting in deubiquitination of NFκB. Inhibition of NFκB decreased NEK2-induced HPSE expression induced by NEK2 at both the mRNA and protein level.Conclusions: Our findings suggest that high NEK2 expression may be a biomarker for bone disease in MM. We demonstrate that a subpopulation of drug-resistant, NEK2-overexpressing MM cells leads to increased production and activity of HPSE, and increased osteoclast differentiation contributing to severe bone disease. Mechanistically, we show that NEK2 interacts with USP7, stabilizing NFκB and upregulating HPSE. Our results demonstrate drug resistant MM cells may not only promote tumor cell survival but also contribute to bone destruction in MM. DisclosuresNo relevant conflicts of interest to declare.

Ibandronate: The loading dose concept in the treatment of metastatic bone pain

Background/AimSevere bone pain is experienced by 60–80% of patients with metastatic bone disease, and has a profound impact on quality of life. Therefore, effective pain relief is an important goal in managing metastatic bone disease. Orthopedic surgeons are often challenged with patients presenting with newly diagnosed bone metastases and severe and disabling bone pain. It is important to provide fast and sufficient analgesia. Clinical trials have demonstrated that bisphosphonates reduce effectively and sustained bone pain by approved standard dosage over time. Open label prospective trials have shown that short time high dose i.v. Ibandronate is effective in rapid pain relief in different primary tumors. Patients and methodsIn 33 patients with metastatic bone pain from newly diagnosed skeletal metastases we utilized the loading-dose concept for intravenous ibandronate (6mg infused over 1h on 3 consecutive days). ResultsIn 33 patients loading-dose ibandronate therapy significantly reduced bone pain within the first 5–7 days (VAS day 0: 6–8 vs. day 7: 3–4). Only 3 patients showed no response concerning a distinct pain reduction within the first days of therapy. There was no increase in pain medication. ConclusionThis clinical observational study in selected patients with severe metastatic bone pain undergoing an intensive high dosed ibandronate-therapy for a short period demonstrated that loading-dose ibandronate (6mg i.v., 3 consecutive days) resulted in a reduction of pain within days.

N19 - Efficacy and tolerability of oxycodone-naloxone prolonged release tablets (o/n –prt) for moderate to severe bone pain in cancer patients (pts) bone metastases (bm): data from a single-centre experience

Background: Bone pain still represents a major issue in cancer pts with bone metastases. Mild to moderate bone pain can be efficiently controlled using NSAIDs +/- weak opioids +/- adjuvant drugs whereas strong opioids are needed to control moderate to severe pain. Due to its unique mechanism of action, O/N-PRT can achieve a satisfactory control of pain with less side effects in terms of constipation. In our center we have evaluated efficacy and safety of O/N-PRT in cancer pts with symptomatic BM. Patients And methods: From March 2013 to November 2014, we evaluated efficacy and tolerability of O/N-PRT in 203 consecutive cancer pts with painful BM. Median age was 62.4 years ( range: 37-86 yrs); all pts had moderate to severe bone pain despite analgesic treatment with NSAIDs +/- weak opioids +/- adjuvant drugs. Median pain intensity (assessed on a 10-point NRS) at baseline was 6.9 (range: 6-9). After discontinuation of weak opioids, O/N-PRT was administered at dose 20/10 mg bid; after baseline, pain intensity was evaluated at day 1, 3, 5 and 7 whereas adverse events and QoL scores were daily assessed for 7 consecutive days. Results: Efficacy and safety of O/N-PRT were assessed in all recruited pts. Median pain intensity progressively decreased as follows: at day 1 a median NRS of 4.8 (range 3-6)was detected; at day 3, 5 and 7 median NRS values were 3.6 (range 3-5), 3.1 (range 2-5) and 2,2 (range 1-4), respectively. During the entire period of evaluation no modifications of QoL scores were reported; adverse events were modest: only 43 pts experienced mild constipation easily treated with common laxatives. Conclusions: In our experience, O/N-PRT confirmed its satisfactory efficacy and tolerability in cancer pts with moderate to severe pain due to BM: it represents an effective therapeutic option in cancer pts with symptomatic BM.

Bone impairment in oxalosis: An ultrastructural bone analysis

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of systemic oxalosis. Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains and specific oxalate osteopathy on plain X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction due to an invasion of bone surface by macrophages. We present data obtained in 10 samples from 8 patients with oxalosis (16–68years) who underwent iliac crest bone biopsy and bone quality analysis using modern methods (microradiography, microindentation, Fourier Transform InfraRed Microspectroscopy, transmission electron microscopy) in addition to histomorphometry. Disseminated calcium oxalate deposits (whewellite) were found in the bone marrow space (with a granulomatous reaction) but not in the bone matrix. Calcium oxalate deposits were totally surrounded by macrophages and multinucleated giant cells, and a phagocytosis activity was sometimes observed. Very few calcium oxalate crystals were directly in close contact with the mineral substance of the bone. Bone mineralization was not modified by the presence of calcium oxalate even in close vicinity. Bone quality analysis also revealed a harder bone than normal, perhaps in relationship with decreased carbonate content in the mineral. This increase in bone hardness could explain a more “brittle” bone. In patients with oxalosis, the formation and growth of calcium oxalate crystals in the bone appeared independent of apatite. The mechanisms leading to nucleation and growth of oxalate deposits are still unclear and deserve further studies.

A Rare Osteoarticular Brucellosis in Gonabad City, Iran; A Case Report

Introduction: Species of bacteria brucellosis, which can infect humans, are Brucella abortus, B melitensis, B. suis and rarely B. canis. Case Presentation: A 71-year-old woman with severe pain in the limbs, especially the left pelvic pain was admitted to 22-Bahman hospital in Gonabad, Iran. The patient’s Erythrocyte Sedimentation Rate (ESR) was 100 and C-reactive protein (CRP) had positive finding. Urea- creatinine, liver enzymes, U/A and U/C had normal results. A signal change in the soft tissue adjacent to the posterior surface of the vertebral body L4-L5 was observed. According to Wright and 2 Mercaptoethanol (ME) negative results, patient was re-introduced to neurosurgeon. Due to severe bone pain, radiotherapy was stopped and she was referred for treatment with bone tuberculosis diagnosis to a health center in Gonabad city, Iran. Daily streptomycin was started for patient and after 10 days, she referred to health center with a good general health status and without pelvic pain. Conclusions: Prominent musculoskeletal complaints (especially back pain) accompanied by constitutional symptoms such as fever, malaise and weight loss may be consistent with brucellosis.

Bone impairment in primary hyperoxaluria: a review.

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of primary hyperoxaluria (PH). Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains, and specific oxalate osteopathy on X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction corresponding to an invasion of bone surface by macrophages. The objective of this manuscript is therefore to provide an overview of bone impairment in PH, by reviewing the current literature on bone and dental symptoms as well as imaging techniques used for assessing bone disease.

Efficacy of vinorelbine plus G-CSF for CD34+ hematopoietic progenitor cell mobilization in patients with multiple myeloma

We aimed to assess the efficacy of vinorelbine plus G-CSF for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 μg per kg body weight (BW) was given twice daily subcutaneously from day 4 on until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and performed for a maximum of three consecutive days until at least 4x10(6) CD34+ cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization due to neutropenic fever and renal failure (n=1), severe bone pain (n=1), and abdominal pain with constipation (n=1). In 211 (95%) patients the leukaphereses were started as planned at day 8, while in 8 (3%) patients the procedure had to be postponed to day 9 and in two (1%) patients to day 10. In the great majority of patients (77%) the predefined amount of HPC could be collected with one leukapheresis. Fourty-four (20%) patients needed a second leukapheresis, while only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34+ cells collected was 6.56x10(6) (range, 0.18-25.9x10(6)) per kg BW at the first day of leukapheresis and 7.65x10(6) (range, 0.18-25.9x10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of three leukaphereses. Patient age (p=0.02) and prior exposition to lenalidomide (p<0.001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.

Severe Hypophosphatemic Osteomalacia Secondary to Fanconi Syndrome Due to Adefovir: A Case Report

Generalized proximal, type 2, renal tubular acidosis, also known as Fanconi syndrome, is a generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption and increased urinary loss of phosphate and other solutes, such as uric acid, glucose, amino acids, and bicarbonate. Chronic hypophosphatemia is the second most common cause of osteomalacia after vitamin D deficiency in adult patients and can have a heterogeneous presentation, ranging from mild symptoms such as muscle weakness and skeletal pain to more severe presentation, such as disabling myopathy, severe bone and joint pain, difficulty walking, and even bone fractures. This report describes a case of severe hypophosphatemic osteomalacia with multiple fragility fractures induced by adefovir, which was worsened and confounded by a previous treatment with zoledronic acid and required prolonged intravenous potassium phosphate administration. We highlight the limited diagnostic value of dual X-ray absorptiometry and bone scintigraphy in this challenging diagnosis. Bone metabolism should always be assessed in patients treated with adefovir for early detection of osteomalacia due to Fanconi syndrome. Although rare, this condition may be life-threatening and mimic other bone metabolic disorders that are treated with drugs that may further impair phosphate balance.

Abstract A43: Novel prostate cancer patient-derived xenograft models of bone metastatic castrate-resistant prostate cancer

Abstract Prostate cancer metastasis to bone occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with disease progression, therapy resistance, poor prognosis, and rapid decline. Androgen ablation therapy is standard of care for advanced prostate cancer, however, the role of androgens in bone metastatic prostate cancer is not understood. The effects of anti-androgens as seen on bone scans can also be inconsistent with the biochemical PSA response. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. It is essential to understand the unique interaction of prostate cancer with the bone environment and to develop novel therapies that target these pathways. Here we report the development of novel patient-derived intra-femoral xenograft models of prostate bone metastatic cancer. METHODS: Surgical prostate cancer bone metastasis specimens were transplanted by direct injection into the femurs of Rag2-/-γc-/- mice or sub-cutaneously into the right flank. Patient-derived xenograft (PDX) tumors that grew out were analyzed for prostate cancer biomarker expression using quantitative RT-PCR and immunohistochemistry. Bone lesion formation was measured using micro-computed tomography (μCT). RESULTS: Prostate cancer surgical bone metastasis specimens have been collected from which we have established new serially transplantable, prostate cancer bone metastasis xenograft models – PCSD1, PCSD4 and PCSD5. PCSD1 (Prostate Cancer San Diego 1) was molecularly characterized as advanced, luminal epithelial-type prostate cancer. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely mimicked those of the patient. Treatment with the anti-androgen, bicalutamide, did not inhibit intra-femoral PCSD1 xenograft growth although there was a decrease in PSA as seen in some patients treated with anti-androgen who had discordant PSA and bone scan tests. CONCLUSION: PCSD1, PCSD4 and PCSD5 are new patient-derived prostate cancer bone metastasis-derived xenograft models. PCSD1 xenograft model closely recapitulates the mixed osteolytic/osteoblastic bone metastatic lesions seen in patients, and we are using it to develop novel therapies for inhibiting prostate cancer growth in the bone-niche. Citation Format: Christina Jamieson, Christina Wu, Amy Strasner, Jason R. Woo, Michelle Muldong, Young B. Jeong, Michael A. Liss, Omer Raheem, Tomonori Yamaguchi, Heather Leu, Deborah Marshall, Sheldon Morris, Nicholas A. Cacalano, Koichi Masuda, Catriona H.M. Jamieson, Anna A. Kulidjian, Christopher J. Kane. Novel prostate cancer patient-derived xenograft models of bone metastatic castrate-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A43.

PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche.

IntroductionProstate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide.MethodsPCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2−/−;γc−/− mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR.ResultsPCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < =0.008) and increased AR (p < =0.032) relative to control.ConclusionsPCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.

Burden of skeletal-related events in prostate cancer: unmet need in pain improvement.

Up to 75% of patients with prostate cancer experience metastatic bone disease, which leads to an increased risk for skeletal-related events (SREs) including pathological bone fracture, spinal cord compression, and hypercalcemia of malignancy. Our objective was to systematically review the literature on the impact of SREs on quality of life (QOL), morbidity, and survival with a primary focus on the impact of SREs on pain in prostate cancer patients. We searched PubMed, limiting to peer-reviewed English-language human studies published in 2000-2010. The search was based on the US Food and Drug Administration and European Medicines Agency definition of an SRE, which includes pathologic fracture, spinal cord compression (SCC), hypercalcemia of malignancy, and radiotherapy or surgery to bone resulting from severe bone pain. A total of 209 articles were screened, of which 173 were excluded, and 36 were included in this review. Patients with SREs had more pain and worse survival compared with no SREs. Pathologic bone fractures worsened QOL and were associated with shorter survival. Radiation therapy of SCC alleviated pain and improved morbidity. SCC was associated with decreases in patient survival. Radiation therapy and surgery to bone improved pain. Specific SREs are associated with worse outcomes, including increased pain, poorer QOL, morbidity, and survival. Treatment of SREs is associated with improved pain, although there remains a need for more effective treatment of SREs in prostate cancer patients.

Efficacy of Vinorelbine Plus Granulocyte Colony–Stimulation Factor for CD34+ Hematopoietic Progenitor Cell Mobilization in Patients with Multiple Myeloma

We aimed to assess the efficacy of vinorelbine plus granulocyte colony–stimulating factor (G-CSF) for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m2 was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 μg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 106 CD34+ cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34+ cells collected was 6.56 × 106 (range, .18 to 25.9 × 106) per kg BW at the first day of leukapheresis and 7.65 × 106 (range, .18 to 25.9 × 106) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.

MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption.

Breast cancer cells frequently metastasize to bone and induce osteolytic bone destruction in patients. These metastases cause severe bone pain, high risk of fractures and hypercalcemia, and are essentially incurable and fatal. Recent studies show that breast cancer cells in bone activate osteoclastogenesis and bone resorption. However the underlying mechanism is poorly understood. This study shows that the p38 MAPK (p38) isoform MAPK11 (p38β) is expressed in breast cancer cells. By using specific small hairpin RNAs for MAPK11, we demonstrated that p38β-mediated p38 activity in breast cancer cells is responsible for breast cancer-induced osteolytic bone destruction. The addition of conditioned media from breast cancer cell lines MDA-MB-231 and MDA-MB-468, which have high expression of p38β, induced osteoclast differentiation and bone resorption. In contrast, knockdown of p38β in breast cancer cells reduced osteoclast differentiation in vitro and reduced bone destruction in severe combined immunodeficiency (SCID) mouse models. The knockdown of p38β did not affect tumor growth or survival or the ability of cancer cells to home to bone. Furthermore, our results showed that p38β upregulated the expression and secretion of monocyte chemotactic protein-1 (MCP-1) in breast cancer cells, and upregulated MCP-1 activates osteoclast differentiation and activity. This study elucidates a novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction. This study also indicates that targeting breast cancer cell p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer.

153Sm-EDTMP for Pain Relief of Bone Metastases from Prostate and Breast Cancer and Other Malignancies

Approximately 85% of patients with cancer suffer severe metastatic bone pain for which radionuclide therapy has been employed for pain palliation. We undertook this study to evaluate the pain relief effect of (153)Sm-EDTMP in Mexican patients with severe and painful bone metastases from mainly prostate, breast, and renal cancer and other malignancies. Patients (277) with intense sustained pain caused by bone metastases were referred to the Nuclear Medicine Department of the Oncology Hospital of the Mexican Social Security Institute. The patients had to have acceptable physical conditions, a previous positive (99m)Tc-MDP scan and blood values within normal range. (153)Sm-EDTMP was prepared at the Instituto Nacional de Investigaciones Nucleares (ININ) and 37 MBq/kg of body weight was injected intravenously. Pain palliation was evaluated with a visual analogue scale (VAS) and a verbal rating scale (VRS) before treatment and 3 and 12 weeks after treatment was started. The age interval of the patients was 24-92 years with a mean age of 64 ± 12 years. Mean values for hemoglobin, leukocyte and platelet counts did not statistically differ at zero time, 3 and 12 weeks after treatment. Pain intensity and relief assessment were statistically different: 9.1 ± 0.61 units initially; 4.2 ± 1.3 units 3 weeks later (54%) and after 12 weeks the pain diminished to 2.4 ± 1.4 units (74%) in the pain relief score scales. (153)Sm-EDTMP was readily available, safe and well tolerated. We conclude that (153)Sm-EDTMP was an adequate palliative agent and was the best option for our Mexican patients to relieve their severe metastatic bone pain.

Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: A case report

Febrile neutropenia is an oncologic emergency that can result in serious consequences. Granulocyte colony stimulating factors (G-CSFs) are often used as prophylaxis for febrile neutropenia. Bone pain is the most notorious adverse effect caused by G-CSFs. Specifically, with pegfilgrastim (Neulasta(®)), the incidence of bone pain is higher in practice than was observed during clinical trials. Traditional analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, can be ineffective in severe pegfilgrastim-induced bone pain. With the high frequency of this adverse effect, it is clear that health practitioners need additional treatment options for patients who experience severe pegfilgrastim-induced bone pain. The mechanisms of bone pain secondary to G-CSFs are not fully known, but research has shown that histamine release is involved in the inflammatory process. There is scant previous clinical data on antihistamine use in the management of G-CSF-induced pain. We present the first case report in which loratadine prophylaxis completely alleviated NSAID-resistant severe pain secondary to pegfilgrastim. The result showed that loratadine may be a promising option for severe, resistant pegfilgrastim-induced bone pain. Further clinical studies are warranted and ongoing.

Bisphosphonates for osteoporosis in people with cystic fibrosis.

Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014. Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Reversible bone lesions induced by tenofovir disoproxil fumarate

Metabolic bone disease is increasingly common in HIV-infected patients on antiretroviral therapy (ART) [1]. Manifestations of ART-induced bone disease include low bone mineral density, increased bone turnover, osteopenia, osteoporosis, and increased fracture risk [2–4]. To our knowledge, reversible tenofovir disoproxil fumarate (TDF)-induced bone lesions have not been described. We describe a patient who developed diffuse foci of increased bone turnover on a TDF-containing regimen and which resolved upon discontinuation of TDF. A 33-year-old Caucasian woman with HIV had multiple risk factors for metabolic bone disease including low BMI, Caucasian race, and tobacco use. A protease inhibitor-containing regimen was initiated and eventually included TDF, which continued unabated for 74 months. Severe lower-extremity pain began approximately 36 months after TDF was added, occurred with movement, and limited activities of daily living (ADL). Eventually, generalized pain extended to the wrists, upper arms, and thorax, and fluctuated in intensity for several months. At 74 months, pain was reported to be excruciating with significant overall impairment of ADL. Chemistries and serum markers for bone disease including vitamin D, parathyroid hormone, and calcium were within normal limits, with the exception of alkaline phosphatase and liver transaminases, each of which was greater than two and three times the upper limit of normal, respectively. Serum creatinine and blood urea nitrogen were normal. All antiretrovirals were discontinued due to severe bone pain. A technetium bone scan revealed multiple foci of increased activity in distal tibiae, bilateral calcaneus bones, multiple costovertebral junctions and ribs, sternum, sacroiliac joints, and right iliac and superior pubic ramus (Fig. 1). Shortly after these findings, the same protease inhibitor-containing regimen, without TDF, was resumed. The patient reported significant improvement in pain and function 3 months later, and a bone scan 11 months after stopping TDF was normal. Additionally, alkaline phosphatase declined shortly after TDF was discontinued and normalized 12 months later.Fig. 1: Technetium bone scan.In conclusion, reversible bone lesions detected by technetium bone scan present a unique finding and a likely manifestation of TDF-induced metabolic bone disease. In our patient, imaging abnormalities occurred after greater than 6 years of continued TDF use, and resolved after 11 months of TDF-sparing ART, whereas other risk factors for bone disease, including protease inhibitor use, remained constant. A bone scan may be useful for discriminating pain caused by metabolic bone disease on long-term TDF from other types of chronic pain. Acknowledgements Conflicts of interest Financial support: No financial support was received for the manuscript. Disclaimers: There are no conflicts of interest for Staci M. Lockhart or Douglas A. Drevets.

Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer

Background:The primary aim of this prospective non-randomized study was to evaluate the effect of hemi-body irradiation (HBI) on pain and quality of life in cancer patients with extensive bone metastases. The secondary aim was to evaluate side-effects and cost-effectiveness of the treatment.Materials and Methods:Between March 2008 and December 2010, a total of 23 (male = 14, female = 9, median age = 60 years) diagnosed cases of metastatic cancer patients (prostate = 11, breast = 6, and lung = 6) received HBI, which was delivered as lower (n = 7) (dose = 8 Gy), upper (n = 8) (dose = 6 Gy), or sequential HBI (n = 8) with a Telecobalt unit (Theratron 780C). Among them, one lung cancer patient died at 2 months and one prostate cancer patient defaulted after the second follow-up. Thus, 21 patients (male = 13, female = 8, median age = 65 years) (prostatic cancer = 10, breast cancer = 6, and lung cancer = 5) were followed up for a minimum of 6 months. Evaluations were performed before and at 2, 4, 8, 16, and 24 weeks after treatment. Pain evaluation was done by Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), Percentage of Pain Relief (PRR), and Global Pain Score (GPS). Toxicity was assessed by CTC v-3 toxicity scores in the medical record. Assessment of oral morphine consumption was done before and after radiation using paired t-test, and correlation analysis was also done with decrease of morphine consumption and reduction of pain score using statistical analysis.Results:Response (control of pain) was partial (PR) in 67% and complete (CR) in 22% of patients. For most patients, the pain control lasted throughout the follow-up period (6 months). From 66.66% patients requiring 13 or more Morphine (10 mg) tablets per day prior to HBI, none of the patients required to consume 13 or more Morphine (10 mg) tablets per day following HBI, which was correlated with significant reduction in various pain scores (P < 0.05). One way ANOVA with Dunnett's Multiple Comparison Test (P < 0.05) was significant in VAS score changes, VRS score changes, PPR score changes, and GPS score changes. Along with the decrease in morphine tablets, the Linear Correlation of various scales for pain reduction like VAS, VRS, PPR, and GPS were significant. As such, the quality of life was better due to decreased pain and also, a decrease in the dose of analgesics. Grade 1 and 2 hematological toxicity and grade 1 diarrhea were observed as common side-effects. The average total cost of treatment including hospital stay, medicines, and radiation charges was around INR 400.00.Conclusion:This study shows that hemibody irradiation is not only an effective modality for palliation of severe bone pain in advanced cancer cases but also economical, involves short hospital stay, with acceptable side-effects, utilizes the simple Telecobalt machine, and is less cumbersome in comparison to other currently available pain palliation methods like oral morphine and radiopharmaceuticals.