Nanoparticles for the delivery of zoledronic acid to prostate cancer cells: A comparative analysis through time lapse video-microscopy technique

Time-lapse live cell imaging is a powerful tool for studying the responses of cells to drugs. Zoledronic acid (ZOL) is the most potent aminobiphosphonate able to induce cell growth inhibition at very low concentrations. The lack of clear evidence of ZOL-induced anti-cancer effects is likely due to its unfavorable pharmacokinetic profile. The use of nanotechnology-based formulations allows overcoming these limitations in ZOL pharmaco-distribution. Recently, stealth liposomes (LIPOs) and new self-assembly PEGylated nanoparticles (NPs) encapsulating ZOL were developed. Both the delivery systems showed promising anticancer activity in vitro and in vivo.In this work, we investigated the cytostatic effect of these novel formulations (LIPOs and NPs) compared with free ZOL on 2 different prostate cancer cell lines, PC 3 and DU 145 and on prostate epithelial primary cells EPN using time lapse video-microscopy (TLVM). In PC3 cells, free ZOL showed a significant anti-proliferative effect but this effect was lower than that induced by LIPOs and NPs encapsulating ZOL; moreover, LIPO-ZOL was more potent in inducing growth inhibition than NP-ZOL. On the other hand, LIPO-ZOL slightly enhanced the free ZOL activity on growth inhibition of DU 145, while the anti-proliferative effect of NP-ZOL was not statistically relevant. These novel formulations did not induce anti-proliferative effects on EPN cells. Finally, we evaluated cytotoxic effects on DU145 where, LIPO-ZOL induced the highest cytotoxicity compared with NP-ZOL and free ZOL. In conclusion, ZOL can be transformed in a powerful anticancer agent, if administered with nanotechnology-based formulations without damaging the healthy tissues.     

Angiostatic,tumor inflammatory and anti-tumor effects of CXCL447–70 and CXCL4L147–70 in an EGF-dependent breast cancer model

CXCL4 and CXCL4L1, platelet-derived CXC chemokines, and their carboxy-terminal peptides CXCL4^47–70 and CXCL4L1^47–70 previously displayed angiostatic and anti-tumoral activity in a melanoma model. Here, we found CXCL4^47–70 and CXCL4L1^47–70 to inhibit lymphatic endothelial cell proliferation in vitro. Furthermore, the angiostatic potential of CXCL4^47–70 and CXCL4L1^47–70 was tested against different angiogenic stimuli (FGF1, FGF2, FGF8, EGF and VEGF). Besides reducing FGF2-induced vascular endothelial cell growth, CXCL4^47–70 and CXCL4L1^47–70 efficiently counteracted EGF. Consequently, we considered their anti-tumoral potential in EGF-dependent MDA-MB-231 breast tumors. In tumor-bearing mice, CXCL4^47–70 reduced tumor growth better than CXCL4L1^47–70. In CXCL4^47–70-treated tumors significantly more intratumoral monocytes/macrophages and dendritic cells were present and higher expression levels of CCL5 and IFN-γ were detected by qPCR on tumor lysates. Because neither peptide was able to specifically bind CXCR3A or CXCR3B, differential glycosaminoglycan binding and direct interaction with cytokines (EGF and CCL5) might explain any differences in anti-tumoral effects. Notably, CCL5-induced monocyte chemotaxis in vitro was increased by addition of CXCL4^47–70 or CXCL4L1^47–70. Finally, CXCL4^47–70 and CXCL4L1^47–70 inhibited proliferation of MDA-MB-231 cells. Our results suggest a tumor type-dependent responsiveness to either CXCL4^47–70 or CXCL4L1^47–70 treatment, defined by anti-proliferative, angiostatic and inflammatory actions, and substantiate their therapeutic potential.     

High-dose continuous-infusion ifosfamide in advanced well-differentiated/dedifferentiated liposarcoma

Background

Liposarcomas represent the most common histological type of soft-tissue sarcomas (STS). Its main subgroups, WD/DD, is known to be poorly sensitive to chemotherapy, with few active agents, i.e., anthracyclines +/- ifosfamide and trabectedin. High-dose ifosfamide (HDIFX >12 g/m2) is active in STS pts pretreated with standard-dose IFX, though with greater toxicity. A prolonged continuous-infusion (ci) through a portable external pump may be an alternative way to administer HDIFX.

Methods

From March 2002 to August 2013, 28 pts (median age =60, range =37–73 yrs) with advanced disease (6 WD and 22 WD/DD) were given ciHDIFX, at the dose of 14 g/m2 as a 14-day continuous infusion every 4 weeks. Twenty-four pts (86%) were previously treated with chemotherapy (19 with anthracyclines and ifosfamide; 4 with anthracycline monotherapy; 1 with trabectedin).

Results

Seven PR (all in DDLPS), 2 minor response (MR) and 11 SD were observed. Of interest, 6 of 9 patients with PR or MR had had SD with the previous therapy with anthracycline plus ifosfamide. The median progression-free survival was 7 months. Most common side effects were mild myelosuppression (anemia G2-3 in 3 pts; G2-3 neutropenia in 3 pts and G4 in 1; G3 thrombocytopenia in 1 pt); nausea (G3 in 3 pts) and fatigue (G3 in 6 pts). One pts had transient G3 confusion.

Conclusions

These data suggest that ciHDIFX is active in WD/DDLPS, even in patients already treated with a combination of anthracyclines plus ifosfamide. In this series, ciHDIFX regimen was better tolerated than HDIFX in published studies.

     

Development of transplantable human chordoma xenograft for preclinical assessment of novel therapeutic strategies

Background

Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies.

Methods

In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor.

Results

All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and posttreatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors.

Conclusions

Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies.     

Magnetic resonance imaging with diffusion-weighted imaging in the evaluation of thyroid-associated orbitopathy: getting below the tip of the iceberg

Objectives

To compare extraocular muscles (EOMs) T2, post-contrast T1 (T1Gad) signal intensity ratios (SIRs) and normalized-apparent diffusion coefficient (n-ADC) values in patients with thyroid-associated orbitopathy (TAO) at different phases of activity and severity and correlate MRI modifications to clinical evolution during follow-up.

Methods

A total of 74 TAO patients were classified as active or inactive on the basis of the clinical activity score (CAS). Severity of EOM impairment was evaluated by assigning a functional score to each rectus. T2, T1Gad SIRs and n-ADC of EOMs were compared in patients with active inflammation, those with inactive disease and 26 healthy controls, and correlated with clinical scores. MRI parameter variation was correlated with clinical modifications during follow-up.

Results

All MRI parameters in TAO EOMs were significantly higher than in healthy subjects and correlated with muscle dysfunction and CAS. EOMs of active patients showed higher T2 and T1Gad SIRs than those with inactive disease. The T2 SIR and n-ADC of normally functioning TAO EOMs were higher than those of healthy controls. SIRs decreased in clinically improved and clinically stable EOMs after therapy.

Conclusions

T2 SIR, T1Gad SIR and n-ADC are objective measures of activity and severity of EOMs in TAO patients. MRI shows clinically silent muscle involvement and modifications.

Key Points

? MRI and DWI measures are objective, quantitative parameters of TAO activity and severity ? MRI and DWI measures significantly correlate with clinical scores in TAO patients ? MRI and DWI can identify clinically silent inflammation of deep orbital structures ? MRI and DWI can depict subclinical modifications during follow-up ? MRI and DWI may aid clinicians in choosing the most appropriate treatment     

Triage of children with headache at the ED: a guideline implementation study

We present a multicenter validation of a modified Manchester Triage System (MTS) flowchart for pediatric patients who present with headache to the emergency department.     

Surprising results regarding MASCC members' beliefs about spiritual care

Background

Through our survey of Multinational Association of Supportive Care in Cancer (MASCC) members and its analysis, we sought to gain a broader, more inclusive perspective of physicians’ understanding of patients’ spiritual care needs and improve our approach to providing spiritual care to patients.

Methods

We developed a 16-question survey to assess spiritual care practices. We sent 635 MASCC members four e-mails, each inviting them to complete the survey via an online survey service. Demographic information was collected. The results were tabulated, and summary statistics were used to describe the results.

Results

Two hundred seventy-one MASCC members (42.7 %) from 41 countries completed the survey. Of the respondents, 50.5 % were age ≤50 years, 161 (59.4 %) were women and 123 (45.4 %) had ≥20 years of cancer care experience. The two most common definitions of spiritual care the respondents specified were “offering emotional support as part of addressing psychosocial needs” (49.8 %) and “alleviating spiritual/existential pain/suffering” (42.4 %). Whether respondents considered themselves to be “spiritual” correlated with how they rated the importance of spiritual care (p?≤?0.001). One hundred six respondents (39.1 %) reported that they believe it is their role to explore the spiritual concerns of their cancer patients, and 33 respondents (12.2 %) reported that they do not feel it is their role. Ninety-one respondents (33.6 %) reported that they seldom provide adequate spiritual care, and 71 respondents (26.2 %) reported that they did not feel they could adequately provide spiritual care.

Conclusions

The majority of MASCC members who completed the survey reported that spiritual care plays an important role in the total care of cancer patients, but few respondents from this supportive care-focused organization actually provide spiritual care. In order to be able to provide a rationale for developing spiritual care guidelines, we need to understand how to emphasize the importance of spiritual care and, at minimum, train MASCC members to triage patients for spiritual crises.     

Cardiac and hepatic iron and ejection fraction in thalassemia major: Multicentre prospective comparison of combined Deferiprone and Deferoxamine therapy against Deferiprone or Deferoxamine Monotherapy

Background

Due to the limited data available in literature, the aim of this multi-centre study was to prospectively compare in thalassemia major (TM) patients the efficacy of combined deferiprone (DFP) and deferoxamine (DFO) regimen versus either DFP and DFO in monotherapy by cardiovascular magnetic resonance (CMR) over a follow up of 18 months.

Methods

Among the first 1135 TM patients in the MIOT (Myocardial Iron Overload in Thalassemia) network, we evaluated those who had received either combined regimen (DFO + DFP, N=51) or DFP (N=39) and DFO (N=74) monotherapies between the two CMR scans. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images.

Results

The percentage of patients that maintained a normal global heart T2* value was comparable between DFP+DFO versus both monotherapy groups. Among the patients with myocardial iron overload at baseline, the changes in the global heart T2* and in biventricular function were not significantly different in DFP+DFO compared with the DFP group. The improvement in the global heart T2* was significantly higher in the DFP+DFO than the DFO group, without a difference in biventricular function. Among the patients with hepatic iron at baseline, the decrease in liver iron concentration values was significantly higher with combination therapy than with either monotherapy group.

Conclusions

In TM patients at the dosages used in the real world, the combined DFP+DFO regimen was more effective in removing cardiac iron than DFO, and was superior in clearing hepatic iron than either DFO or DFP monotherapy. Combined therapy did not show an additional effect on heart function over DFP.     

Utility of ultrasound in the diagnosis of chronic worsened gout

Ultrasound (US) may be used to diagnose chronic worsened gout. US confirmed the clinical evidence of tophaceous deposits in the left elbow of a 75-year-old man; it also identified crystalline materials on the cartilage surface of the second metacarpophalangeal joint of the left hand. US may be helpful to detect signs of deposition of monosodium urate crystals in periarticular and intra-articular joints of patients with clinically suspected chronic worsened gout.