Zoledronic Acid as an adjuvant therapy in patients with breast cancer: a systematic review and meta-analysis

Background

Zoledronic acid is widely used as adjuvant chemotherapy for the treatment of breast cancer. However, previous trials reported inconsistent findings regarding their clinical efficacy and safety. We carried out a comprehensive systematic review and meta-analysis to evaluate the effects of zoledronic acid on disease-free survival (DFS), overall survival (OS), and drug-related toxicities.

Methodology and Principal Findings

We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures with a time limit of Dec. 1, 2011. Randomized controlled trials evaluated the effects of zoledronic acid on OS, DFS, and RFS compared with control were eligible for inclusion in our research. Of 175 identified studies, we collected data from 7 randomized controlled trials of zoledronic acid that had OS, DFS, and RFS reported as one of the endpoint. Overall, we noted that patients receiving zoledronic acid therapy had significant longer OS than the group with non-zoledronic acid therapy (HR, 0.85, 95%CI, 0.73 to 1.00, P = 0.047). Furthermore, zoledronic acid therapy also had a clear effect on frature events (RR, 0.66, 95%CI, 0.52 to 0.84, P<0.001). Subgroup analysis indicated that zoledronic acid therapy showed a great beneficial effect on disease recurrence in patients with early-stage breast cancer, however, it also significantly increased the harm of disease recurrence in patients with advanced breast cancer. Bone pain, neutropenic fever, pyrexia, rash were more frequent in the zoledronic acid therapy group.

Conclusion/Significance

Treatment with zoledronic acid had a clear effect on fracture events, and it might contribute an important role for overall survival.     

Maintenance Therapy with Immunomodulatory Drugs after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

Background

Although high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has been confirmed to result in longer remission time than conventional chemotherapy, multiple myeloma (MM) remains incurable. Post-ASCT maintenance is considered as a strategy for obtaining durable remissions and preventing tumor progression. Randomized controlled trials (RCTs) studying maintenance therapy with immunomodulatory drugs (IMiDs) after ASCT have shown some valuable survival improvements. This meta-analysis of RCTs therefore assesses the effect of post-ASCT IMiDs maintenance on MM patients.

Methods

We performed a meta-analysis to evaluate the impact of IMiDs (thalidomide or lenalidomide) as post-ASCT maintenance therapy on the survival of newly diagnosed MM patients. The outcomes for this meta-analysis were progression-free survival (PFS) and overall survival (OS).

Results

Eight RCTs enrolling 3514 patients were included for analysis. An obvious improvement in Os (hazard ratio [HR] 0.75) and a significant PFS advantage (HR 0.58) with post-ASCT IMiDs maintenance was revealed. Thalidomide maintenance after ASCT can result in significant benefit in Os (HR 0.72), particularly combined with corticosteroids (HR 0.66).

Conclusions

MM patients after ASCT have a significant overall survival benefit with IMiDs maintenance. IMiDs maintenance was justified for MM patients who received HDT with ASCT.     

Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis

Background

Zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption and has been widely used in bone metastasis malignancies and postmenopausal osteoporosis as a preventive therapy against skeletal-related events. The purpose of this study was to evaluate the clinical outcome of zoledronic acid as an adjuvant therapy for patients with early stage breast cancer.

Patients and methods

Entries in the PubMed and EMBASE databases up to 12 July 2013 were systematically reviewed. Online abstracts from the proceedings of the Annual Meetings of the American Society of Clinical Oncology (ASCO) (1992–2013) and the San Antonio Breast Cancer Symposium (SABCS) (2004–2013) were also reviewed. Primary endpoints included overall survival (OS) and disease-free survival (DFS), while secondary endpoints included bone metastasis-free survival (BMFS), distant metastasis-free survival (DMFS), and fracture-free rate (FFR).

Results

A total of eight studies including 3,866 subjects and 3,864 controls met our search criteria and were evaluated. The use of zoledronic acid was found to improve OS (relative risk (RR), 0.88; 95% confidence interval (CI), 0.77–1.01; p- value?=?0.06) and DMFS (RR, 0.77; 95% CI, 0.60–1.00; p- value?=?0.05). Furthermore, statistically significant benefits were associated with BMFS (RR, 0.81; 95% CI, 0.66–0.99; p- value?=?0.04) and FFRs (RR, 0.75; 95% CI, 0.61–0.92; p- value?=?0.007). In contrast, there was no significant difference in DFS with the application of zoledronic acid (RR, 0.88; 95% CI, 0.72–1.09; p- value?=?0.24). Sensitivity analysis further identified the improvement of 5-year OS for the adjuvant zoledronic acid therapy in early stage breast cancer patients (RR, 0.86; 95% CI, 0.75–0.99; p- value?=?0.03), while a borderline statistically significant benefit was observed for 5-year DFS (RR, 0.90; 95% CI, 0.81–1.00; p- value?=?0.06).

Conclusion

Zoledronic acid as an adjuvant therapy appears to improve the 5-year OS rate for early stage breast cancer patients, and was associated with a protective effect for the bone metastases and fractures evaluated in more than 7,000 patients. However, further research is needed to confirm our findings, and sub-group analyses according to menopause status or hormone status may provide further insight.

     

FGF signaling inhibits the proliferation of human myeloma cells and reduces c-<Emphasis Type="Italic">myc</Emphasis> expression

Background  

Multiple myeloma is a cancer of antibody producing plasma cells whose etiology is unknown. FGF signaling has been implicated in myeloma pathogenesis but its precise role remains unclear.     

The Use of Novel Drugs Can Effectively Improve Response,Delay Relapse and Enhance Overall Survival in Multiple Myeloma Patients with Renal Impairment

Background

Renal impairment is a common feature in multiple myeloma and is considered a poor prognostic factor.

Aim

To determine the impact of novel drugs (i.e. bortezomib, lenalidomide and thalidomide) in the treatment of myeloma patients with renal impairment. The primary endpoint was overall survival and secondary endpoints were time to next treatment and response.

Methods

The study population included all patients diagnosed with treatment-demanding multiple myeloma January 2000 to June 2011 at 15 Swedish hospitals. Renal impairment was defined as an estimated glomerular filtration rate under 60 mL/min/1.73 m².

Result

The study population consisted of 1538 patients, of which 680 had renal impairment at diagnosis. The median overall survival in patients with renal impairment was 33 months, which was significantly shorter than 52 months in patients with normal renal function (P<0.001). Novel agents in first line improved overall survival (median 60 months) in non-high-dose treated patients with renal impairment (n = 143) as compared to those treated with conventional cytotoxic drugs (n = 411) (median 27 months) (P<0.001). In the multivariate analysis up front treatment with bortezomib was an independent factor for better overall survival in non-high-dose treated renally impaired patients. High-dose treated renally impaired patients had significantly better median overall survival than non-high-dose ones (74 versus 26 months) and novel drugs did not significantly improve survival further in these patients. Patients with renal impairment had both a shorter median time to next treatment and a lower response rate than those with normal renal function. However, novel drugs and high dose treatment lead to a significantly longer time to next treatment and the use of novel agents significantly improved the response rate of these patients.

Conclusion

High dose treatment and novel drugs, especially bortezomib, can effectively overcome the negative impact of renal impairment in patients with multiple myeloma.     

A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

Introduction  

Osteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss.     

Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells

Background  

Thalidomide is an immunomodulatory agent, which arrests angiogenesis. The mechanism of anti-angiogenic activity of thalidomide is not fully understood. As nitric oxide is involved in angiogenesis, we speculate a cross-talk between thalidomide and nitric oxide signaling pathway to define angiogenesis. The aim of present study is to understand the mechanistic aspects of thalidomide-mediated attenuation of angiogenesis induced by nitric oxide at the cellular level.     

Integrated safety in tocilizumab clinical trials

Introduction  

The efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program. Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials. Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported.     

Zoledronic Acid Treatment of Osteoporosis: Effects in Men

ObjectiveTo study changes in bone mineral density (BMD) and a bone resorption marker in elderly men who received off-label zoledronic acid for osteoporosis treatment.MethodsWe conducted a retrospective review of medical records of 50 male veterans who had received at least one 4-mg intravenous infusion of zoledronic acid and had BMD measurements at 2 of 3 skeletal sites both before the infusion and at a mean of 2.2 years after the infusion. Patients were classified into those who had never received bisphosphonate therapy versus those who had previously received such treatment.ResultsIn our study population, 66% of patients had been prescribed orally administered bisphosphonates or intravenously administered pamidronate before receiving zoledronic acid. Larger increases in spine BMD (6.7% versus 3.4% [P < .05]; per year: 2.8% versus 1.2% [P < .01]) and total hip BMD (3.2% versus 0.1% [P < .03]; per year: 1.3% versus 0.02% [P < .02]) occurred after infusion of zoledronic acid in bisphosphonate-naïve patients in comparison with those who had previous bisphosphonate exposure. In addition, 26 of 50 patients (52%) had suppressed urinary N-terminal telopeptide of cross-linked collagen type I (NTx) (a bone turnover marker) at 12 months, and 5 men had NTx suppression for 24 months after infusion.ConclusionOur data suggest that 4 mg of intravenously administered zoledronic acid is an effective treatment for increasing BMD in a “real-world” population of men with osteoporosis. The prolonged suppression of urinary NTx after zoledronic acid infusion raises the question of whether this treatment could be given less frequently than every year. The changes seen in BMD during a mean period of 2 years were similar to those reported in clinical studies with alendronate therapy in men and zoledronic acid treatment in women. (Endocr Pract. 2010;16:960-967)     

唑来膦酸注射液联合经皮椎体成形术治疗脊柱多发性骨髓瘤的临床疗效

目的:观察脊柱多发性骨髓瘤行唑来膦酸注射液与经皮椎体成形术联合治疗的临床疗效。方法:2010年8月至2017年3月,16例行多发性骨髓瘤患者接受经皮椎体成形术与唑来膦酸注射液联合治疗,评定疗效、疼痛缓解及治疗前后血碱性磷酸酶、血清钙、生活质量,记录不良反应。结果:(1)疗效:完全缓解1例,部分缓解12例,微小缓解1例,疾病进展1例,无变化1例,总有效率为87.5%(14/16)。(2)疼痛缓解:显效9例,有效6例,无效1例。总有效率93.75%(15/16)。(3)血碱性磷酸酶、血清钙、生活质量:治疗后优于治疗前(P0.05)。(4)研究期间不良反应轻微。结论:脊柱多发性骨髓瘤行唑来膦酸注射液与经皮椎体成形术联合治疗有助于缓解疼痛和改善生活质量。     

Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth

Purpose

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA).

Experimental design

Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15⁺CD11b⁺) by flow cytometry and compared to cancer-free controls. The suppressive capacity of MDSC (CD11b⁺Gr-1⁺) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1⁺CD11b⁺), effector T cells, and tumor cytokine levels.

Results

Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8⁺ T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10.

Conclusions

MDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer.     

Is elevated SUA associated with a worse outcome in young Chinese patients with acute cerebral ischemic stroke?

Background  

Elevated serum uric acid (SUA) levels can enhance its antioxidant prosperities and reduce the occurrence of cerebral infarction. Significantly elevated SUA levels have been associated with a better prognosis in patients with cerebral infarction; however, the results from some studies on the relationship between SUA and the prognosis of patients with cerebral infarction remain controversial.     

74-week follow-up of safety of infliximab in patients with refractory rheumatoid arthritis

Introduction  

The objective was to describe the prevalence, types, and predictors of adverse events (AEs) in rheumatoid arthritis (RA) patients treated with infliximab and methotrexate in a daily clinical setting.     

A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease

Background  

Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.     

Thalidomide Inhibits Alternative Activation of Macrophages In Vivo and In Vitro: A Potential Mechanism of Anti-Asthmatic Effect of Thalidomide

Background

Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood.

Objective

This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma.

Methods

Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro.

Results

The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro.

Conclusion

These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.     

Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma

Background

Regulatory T (Treg) cells play an important role in the maintenance of immune system homeostasis. Multiple myeloma (MM) is a plasma cell disorder frequently associated with impaired immune cell numbers and functions.

Methods

We analyzed Treg cells in peripheral blood (n = 207) and bone marrow (n = 202) of pre-malignant and malignant MM patients using flow cytometry. Treg cells and their subsets from MM patients and healthy volunteers were functionally evaluated for their suppressive property. A cohort of 25 patients was analyzed for lymphocytes, CD4 T cells and Treg cells before and after treatment with cyclophosphamide, thalidomide plus dexamethasone (CTD).

Results

We found elevated frequencies of Treg cells in newly diagnosed (P<0.01) and relapsed MM patients (P<0.0001) compared to healthy volunteers. Also, Treg subsets including naïve (P = 0.015) and activated (P = 0.036) Treg cells were significantly increased in MM patients compared to healthy volunteers. Functional studies showed that Treg cells and their subsets from both MM and healthy volunteers were similar in their inhibitory function. Significantly increased frequencies of Treg cells were found in MM patients with adverse clinical features such as hypercalcemia (>10 mg/dL), decreased normal plasma cell (≤5%) count and IgA myeloma subtype. We also showed that MM patients with ≥5% of Treg cells had inferior time to progression (TTP) (13 months vs. median not reached; P = 0.013). Furthermore, we demonstrated the prognostic value of Treg cells in prediction of TTP by Cox regression analysis (P = 0.045). CTD treatment significantly reduced frequencies of CD4 T cells (P = 0.001) and Treg cells (P = 0.018) but not Treg cells/CD4 T cells ratio compared to pre-treatment.

Conclusions

Our study showed immune deregulation in MM patients which is evidenced by elevated level of functionally active Treg cells and patients with increased Treg cells have higher risk of progression.     

Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus

Introduction

Cutaneous lupus erythematosus (CLE) is a chronic disease characterized by disfigurement and a relapsing course. Thalidomide has proven its efficacy in refractory cutaneous lupus disease, although it is not exempt from significant side effects and frequent relapses after withdrawal. New thalidomide analogues have been developed but lack clinical experience. The aim of this preliminary phase II study was to evaluate the efficacy and safety of lenalidomide in patients with refractory CLE.

Methods

Fifteen patients with refractory cutaneous lupus disease were enrolled in this single-center, open-label, non-comparative pilot trial between January 2009 and December 2010. Oral lenalidomide (5 to 10 mg/day) was administered and tapered according to clinical response. Patients were followed up for a mean of 15 months (range: 7 to 30). Primary efficacy endpoint was the proportion of patients achieving complete response, defined by a Cutaneous Lupus Erythematosus Disease Area and Severity index (CLASI) activity score of 0. Other secondary endpoints included development of side effects, evaluation of cutaneous and systemic flares, and impact on the immunological parameters.

Results

One patient discontinued treatment due to side effects. All remaining patients saw clinical improvement and this was already noticeable after 2 weeks of treatment. Twelve of those patients (86%) achieved complete response but clinical relapse was frequent (75%), usually occurring 2 to 8 weeks after lenalidomide''s withdrawal. No influence on systemic disease, immunological parameters or CLASI damage score was observed. Side effects including insomnia, grade 2 neutropenia and gastrointestinal symptoms, were minor (13%). These resolved after withdrawing medication. Neither polyneuropathy nor thrombosis was observed.

Conclusion

Lenalidomide appears to be efficacious and safe in patients with refractory CLE, but clinical relapse is frequent after its withdrawal.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01408199","term_id":"NCT01408199"}}NCT01408199.     

Ku86 exists as both a full-length and a protease-sensitive natural variant in multiple myeloma cells

Background  

Truncated variants of Ku86 protein have previously been detected in 86% to 100% of freshly isolated patient multiple myeloma (MM) cells. Since, the Ku70/Ku86 heterodimer functions as the regulatory subunit of the DNA repair enzyme, DNA-dependent protein kinase, we have been interested in the altered expression and function of Ku86 variant (Ku86v) proteins in genome maintenance of MM.