Oral mucosa produces cytokines and factors influencing osteoclast activity and endothelial cell proliferation, in patients with osteonecrosis of jaw after treatment with zoledronic acid

Objectives

The intravenous injection of bisphosphonates, currently used as treatment for osteoporosis, bone Paget’s disease, multiple myeloma, or bone metastases, can cause jaw bone necrosis especially in consequence of trauma. The present research aimed to clarify the mechanisms underlying bone necrosis, exploring involvement of the oral mucosa “in vivo.”

Patients and methods

Specimens of oral mucosa were removed from bisphosphonate-treated patients with or without jaw bone necrosis. In mucosa specimens, expression was evaluated of: cytokines involved in the inflammatory process, factors involved in osteoclast activity, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin, a factor involved in cell proliferation, namely hydroxymethylglutaryl coenzyme A reductase, and a factor involved in angiogenesis, namely vascular endothelial growth factor (VEGF).

Results

Interleukin (IL)-6 and the RANK/osteoprotegerin ratio were significantly elevated in mucosa from patients with versus without jaw necrosis, whereas hydroxymethylglutaryl coenzyme A reductase and VEGF were significantly decreased.

Conclusions

Our results suggest that mucosa, stimulated by bisphosphonate released from the bone, can contribute to the development of jaw necrosis, reducing VEGF, and producing IL-6 in consequence of hydroxymethylglutaryl coenzyme A reductase reduction. In turn, IL-6 stimulates osteoclast activity, as shown by the increased RANKL/osteoprotegerin ratio.

Clinical relevance

The results of this study suggest the importance of evaluating during bisphosphonate treatment the production of IL-6, RANKL, osteoprotegerin, and VEGF, in order to monitor the jaw osteonecrosis onset. To avoid repeated mucosa excisions, the determination of these factors could be carried out in crevicular fluid.     

Tyrosine kinase inhibitors for elderly chronic myeloid leukemia patients: A systematic review of efficacy and safety data

The impact of age as a poor prognostic factor in chronic myeloid leukemia (CML) has been well described. In the interferon era, elderly patients diagnosed as having chronic phase chronic myeloid leukemia (CP-CML) had shorter survival compared to younger patients. With the advent of target therapy with imatinib, several reports described improved responses in elderly late CP-CML patients treated with imatinib after IFN failure, with similar overall survival compared to younger population. Imatinib in newly diagnosed older patients showed similar rate of cytogenetic and molecular responses compared to younger patients. Few data are available relating elderly CML patients subset treated with second-generation TKIs after resistance/intolerance to imatinib: both nilotinib and dasatinib have demonstrated efficacy and limited toxicity profile as in younger patients. The aim of this review is, through the revision of published data, to highlight the fact that elderly CML patients can benefit from target therapy with limited adverse events.     

On a heavy path – determining cold plasma-derived short-lived species chemistry using isotopic labelling

Cold atmospheric plasmas (CAPs) are promising medical tools and are currently applied in dermatology and epithelial cancers. While understanding of the biomedical effects is already substantial, knowledge on the contribution of individual ROS and RNS and the mode of activation of biochemical pathways is insufficient. Especially the formation and transport of short-lived reactive species in liquids remain elusive, a situation shared with other approaches involving redox processes such as photodynamic therapy. Here, the contribution of plasma-generated reactive oxygen species (ROS) in plasma liquid chemistry was determined by labeling these via admixing heavy oxygen ¹⁸O₂ to the feed gas or by using heavy water H₂¹⁸O as a solvent for the bait molecule. The inclusion of heavy or light oxygen atoms by the labeled ROS into the different cysteine products was determined by mass spectrometry. While products like cysteine sulfonic acid incorporated nearly exclusively gas phase-derived oxygen species (atomic oxygen and/or singlet oxygen), a significant contribution of liquid phase-derived species (OH radicals) was observed for cysteine-S-sulfonate. The role, origin, and reaction mechanisms of short-lived species, namely hydroxyl radicals, singlet oxygen, and atomic oxygen, are discussed. Interactions of these species both with the target cysteine molecule as well as the interphase and the liquid bulk are taken into consideration to shed light onto several reaction pathways resulting in observed isotopic oxygen incorporation. These studies give valuable insight into underlying plasma–liquid interaction processes and are a first step to understand these interaction processes between the gas and liquid phase on a molecular level.

Cold atmospheric plasmas (CAPs) are promising medical tools producing short-lived reactive species.     

Is essential tremor a Purkinjopathy? The role of the cerebellar cortex in its pathogenesis

Essential tremor (ET) encompasses a group of progressive neurological diseases in which the primary clinical feature is kinetic tremor of the arms. There is accumulating evidence to suggest that the cerebellum is involved in the pathogenesis of ET; the clinical presentation, neurophysiological data, and functional and metabolic abnormalities revealed by neuroimaging studies all point toward the dysregulation of cerebellar circuits. Recent neuropathological findings at postmortem demonstrate that Purkinje neurons, and some brainstem neurons, play an integral role in the pathogenesis of this common neurological disorder. The assessment of Purkinje cell linear density shows that Purkinje density is abnormal in ET brains. Specific efforts need be devoted to understanding the molecular and cellular events occurring in the Purkinje neurons of the cerebellar cortex, which are emerging as being of particular importance in the pathogenesis of ET in a subgroup of patients. © 2013 International Parkinson and Movement Disorder Society.     

Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.     

Community water fluoridation and caries prevention: a critical review

The aim of this paper was to critically review the current role of community water fluoridation in preventing dental caries. Original articles and reviews published in English language from January 2001 to June 2006 were selected through MEDLINE database. Other sources were taken from the references of the selected papers. For the past 50 years community water fluoridation has been considered the milestone of caries prevention and as one of the major public health measures of the 20th century. However, it is now accepted that the primary cariostatic action of fluoride occurs after tooth eruption. Moreover, the caries reduction directly attributable to water fluoridation have declined in the last decades as the use of topical fluoride had become more widespread, whereas enamel fluorosis has been reported as an emerging problem in fluoridated areas. Several studies conducted in fluoridated and nonfluoridated communities suggested that this method of delivering fluoride may be unnecessary for caries prevention, particularly in the industrialized countries where the caries level has became low. Although water fluoridation may still be a relevant public health measure in poor and disadvantaged populations, the use of topical fluoride offers an optimal opportunity to prevent caries among people living in both industrialized and developing countries.     

Influence of Surgical Margins on the Outcome of Breast Cancer Patients: A Retrospective Analysis

Objective

Breast-conserving surgery has become the preferred treatment for early breast cancer. Yet the question of what constitutes a ‘safe margin’, in terms of impact on patient outcome, remains unanswered. Our aim was to address this knowledge gap by determining the prevalence of positive and narrow margins after breast-conserving surgery, and evaluating how margin status impacted local recurrence and overall survival.

Materials and Methods

We collected data about all women who underwent breast-conserving cancer surgery in our department between 2002 and 2011, focusing on patient and tumor characteristics, the distance from the tumor to the surgical margin, therapies administered, and outcome (measured in terms of local recurrence and overall survival). Data were analyzed by R (version 3.0.1), considering p < 0.05 as significant. Multivariate analyses were also performed.

Results

Of 1,192 women who received breast-conserving surgery, 264 were considered for widening; 111 of these patients had positive margins and 153 narrow (where narrow was defined as less than 5 mm). Widening was performed for 38 % of these patients (99/264) and mastectomy for 27 % (70/264), while 36 % (95/264) had no further surgery and were simply followed-up. Our multivariate analysis confirmed that local tumor recurrence and overall survival were not significantly influenced by margin status, either at initial surgery, or (for those patients with initially positive margins) at secondary margin-widening surgery. However, the following were found to be significantly correlated with local recurrence: tumor multifocality, high expression of Ki-67/Mib-1, comedo-like necrosis, and non-axillary lymph node positivity (p < 0.05).

Conclusions

We found the status of resection margins and the management of infiltrated or narrow margins to have no significant influence on local tumor recurrence rates or on overall patient survival. Instead, biological factors connected with tumor aggressiveness seem to play the most important role in breast cancer prognosis, independent of surgical radicality.