Osteonecrosis of the jaws in 194 patients who have undergone intravenous bisphosphonate therapy in Spain

BACKGROUND: Osteonecrosis of the jaw (ONJ) is a destructive bone process in patients undergoing bisphosphonate therapy and it is modulated by local and systemic factors. The purpose of this article is to determine the prevalence of ONJ in patients who have undergone intravenous bisphosphonate therapy, and relate the risk factors described to establish a protocol to reduce the risk of developing ONJ.MATERIAL AND METHODS: We performed a retrospective study on 194 patients treated with IV bisphosponates, analyzing clinical and pathological variables. RESULTS: The prevalence of ONJ was 12.9 %. The most remarkable complication was pain, which was reported by 80% of patients. The average age of the patients undergoing bisphosphonate therapy was 68.91 years. Most of non-diabetic patients did not develop ONJ (92.3%) (p=0.048). During bisphosphonate therapy, 3.1% of patients underwent extractions in the same percentage in the maxilla and in the mandible; all of which, except for one patient, developed ONJ (p<0.001). In regards to the periodontal state, 94.3% of patients without periodontal problems did not develop ONJ (p=0.001). Almost 50% of the necrosis were located unifocally on the mandible (p<0.001). The number of affected patients and the aggressiveness of the disease increased significantly three years after starting treatment (p<0.001). CONCLUSIONS: Etiology still is a controversial issue and we should focus on known risk factors, such as the as the devel-opment of surgical procedures in patients undergoing bisphosphonate therapy, especially in patients who have already started their treatment, a group in which ONJ prevalence increases. Moreover, a bad periodontal state in these patients is also an important risk factor, and the control of diabetes reduces it. Due to the above, all patients should be diagnosed and educated in oral hygiene prior to treatment, performing periodical maintenance, to detect possible traumatisms and periodontal infection as soon as possible

Osteonecrosis of the jaws in 194 patients who have undergone intravenous bisphosphonate therapy in Spain.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is a destructive bone process in patients undergoing bisphosphonate therapy and it is modulated by local and systemic factors. The purpose of this article is to determine the prevalence of ONJ in patients who have undergone intravenous bisphosphonate therapy, and relate the risk factors described to establish a protocol to reduce the risk of developing ONJ. MATERIAL AND METHODS: We performed a retrospective study on 194 patients treated with IV bisphosponates, analyzing clinical and pathological variables. RESULTS: The prevalence of ONJ was 12.9 %. The most remarkable complication was pain, which was reported by 80% of patients. The average age of the patients undergoing bisphosphonate therapy was 68.91 years. Most of non-diabetic patients did not develop ONJ (92.3%) (p=0.048). During bisphosphonate therapy, 3.1% of patients underwent extractions in the same percentage in the maxilla and in the mandible; all of which, except for one patient, developed ONJ (p<0.001). In regards to the periodontal state, 94.3% of patients without periodontal problems did not develop ONJ (p=0.001). Almost 50% of the necrosis were located unifocally on the mandible (p<0.001). The number of affected patients and the aggressiveness of the disease increased significantly three years after starting treatment (p<0.001). CONCLUSIONS: Etiology still is a controversial issue and we should focus on known risk factors, such as the development of surgical procedures in patients undergoing bisphosphonate therapy, especially in patients who have already started their treatment, a group in which ONJ prevalence increases. Moreover, a bad periodontal state in these patients is also an important risk factor, and the control of diabetes reduces it. Due to the above, all patients should be diagnosed and educated in oral hygiene prior to treatment, performing periodical maintenance, to detect possible traumatisms and periodontal infection as soon as possible.

Surgical neurolysis for the treatment of neuropathic pain in 2 postmenopausal women with mandibular necrosis resulting from oral bisphosphonates.

We analyze the use of surgical neurolysis for the treatment of neuropathic pain of the inferior alveolar nerve. For that, 3 surgical neurolysis were performed on 2 postmenopausal women experiencing neuropathic pain of the inferior alveolar nerve due to mandibular necrosis resulting from treatment with oral bisphosphonates. Both patients showed sensory impairment of the inferior alveolar nerve. We obtained complete control of neuropathic pain after 6 months of the patients' evolution, preserving the function of the lingual nerve in all 3 neurolysis, without causing any impact as regards to the sensitive situation before treatment. Surgical neurolysis of the inferior alveolar nerve may be considered as the choice therapeutic technique to treat neuropathic pain of this nerve when there is a sensory impairment in patients showing mandibular necrosis resulting from bisphosphonates.

Dental implants placed on bone subjected to vertical alveolar distraction show the same performance as those placed on primitive bone

Introduction: Vertical osteogenic alveolar distraction (VOAD) allows for the augmentation of the alveolar ridge for the placement of dental implants in atrophic alveolar ridges. The goal of this paper is to assess long-term peri-implant bone resorption in implants placed on bones subjected to VOAD, comparing it with a group of patients who had implants placed directly on the alveolar bone without previous bone regeneration. Material and Methods: We conducted a follow-up study on 32 patients who were divided into two groups: The Distraction Group (14 patients), and the Distraction-Free Group (18 patients), who received a total of 100 implants. Peri-implant bone loss was measured by means of panoramic X-rays, at the time of loading and one year later, and in 35 implants of each group after 3 years of functional loading. Results: The peri-implant bone resorption (PBR) average observed in the Distraction Group at the time of prosthetic placement is higher (0.50±0.09 mm) than in the Distraction-Free Group (0.25±0.06 mm), showing statistically significant results (p=0.047). PBR levels 1 year after loading were the same for both groups (0.66 mm). At 3 years, they were higher in the Distraction Group (1.03 ± 0.22 mm vs. 0.68 ± 0.08 mm) (AU)

Dental implants placed on bone subjected to vertical alveolar distraction show the same performance as those placed on primitive bone.

INTRODUCTION: Vertical osteogenic alveolar distraction (VOAD) allows for the augmentation of the alveolar ridge for the placement of dental implants in atrophic alveolar ridges. The goal of this paper is to assess long-term peri-implant bone resorption in implants placed on bones subjected to VOAD, comparing it with a group of patients who had implants placed directly on the alveolar bone without previous bone regeneration. MATERIAL AND METHODS: We conducted a follow-up study on 32 patients who were divided into two groups: The Distraction Group (14 patients), and the Distraction-Free Group (18 patients), who received a total of 100 implants. Peri-implant bone loss was measured by means of panoramic X-rays, at the time of loading and one year later, and in 35 implants of each group after 3 years of functional loading. RESULTS: The peri-implant bone resorption (PBR) average observed in the Distraction Group at the time of prosthetic placement is higher (0.50 ± 0.09 mm) than in the Distraction-Free Group (0.25 ± 0.06 mm), showing statistically significant results (p=0.047). PBR levels 1 year after loading were the same for both groups (0.66 mm). At 3 years, they were higher in the Distraction Group (1.03 ± 0.22 mm vs. 0.68 ± 0.08 mm).

The role of p21Waf1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma (Review)

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21Waf1/CIP1, are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21Waf1/CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancerous lesions and their roles in anticancer treatments. The results of p21WAF1/CIP1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21Waf1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21Waf1/CIP1 levels, the small number of studies, have forced us to (..) (AU)

The role of p21Waf1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma (Review).

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21Waf1/CIP1, are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21Waf1/CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancerous lesions and their roles in anticancer treatments. The results of p21WAF1/CIP1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21Waf1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21Waf1/CIP1 levels, the small number of studies, have forced us to disregard the hypothesis that HPV infected lesions that present better prognosis are due to a p21Waf1/CIP1-dependent control. The role of p21WAF1/CIP1 as cell-cycle regulator has been well described; however, its relationship to OSCC, the clinical and pathological variables of tumors, HPV and different treatments are not entirely clear. Thus, it would be very interesting to pursue further study of this protein, which may have a significant value for the diagnosis, prognosis and therapy of this type of tumors.

The role of carbonic anhydrase IX in hypoxia control in OSCC.

Tumoral microenvironments play a key role in the evolution of solid tumors. Tumor hypoxia is actively involved in the promotion of genetic instability, the invasive capacity of tumor cells, metastasis, and a worsening of the clinical evolution. Endogenous hypoxia markers are controlled by hypoxia-related genes, formed by HIF-1, which is related to several target genes that involve the energy metabolism, angiogenesis, and transmembrane carbonic anhydrases (CAs), mainly CA-IX that is one of the tumor-related carbonic anhydrases. The goal of this paper is to establish the role of CA-IX as a hypoxia marker in OSCC, while analyzing its expression in this type of tumors and its relationship with several clinical and pathological parameters and prognosis, evaluating its relationship with angiogenesis, other hypoxia markers, and clarifying its role in chemotherapy and radiotherapy resistance.

Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients.

INTRODUCTION: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. MATERIAL AND METHODS: This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. RESULTS: Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484. CONCLUSIONS: Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor.

Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target?

Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet.

Applications of OralCDx ® methodology in the diagnosis of oral leukoplakia

Objective: We aim to evaluate the effectiveness of the brush biopsy technique using OralCDx ® (OralScan Laboratories Inc., Suffern, NY) as a new method for early diagnosis and control of a "potentially malignant disorder" such as oral leukoplakia. Design of the study: We performed a study in which samples were taken using OralCDx® on 24 patients who visited the Master of Oral Medicine, Oral Surgery and Implantology of the University of Santiago de Compostela between February 2009 and May 2010. These patients presented clinical and histological lesions that were consistent with oral leukoplakia. We evaluated the relationship between the keratinization degree of the lesions and cell representation; the diagnosis obtained through OralCDx ® and biopsies; and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Results: 50% of patients were men and 50% women with an average age of 62.38 years. The Kappa coefficient relating keratinization of lesions and cell representation was 0.33, the OralCDx ® - biopsy diagnostic rate reached a Kappa value of 0.66, recording 72.7%, sensitivity and 92.3% specificity, PPV was 88.8%, while NPV reached 80%. Conclusions: cytology sampling with OralCDx ® showed high sensitivity and specificity values, which make it a good tool for monitoring oral leukoplakia, but nowadays the most reliable method that allows us to confirm the exact diagnosis of the lesions and their anatomical and pathological characteristics still is conventional biopsy using a surgical scalpel (AU)

An analysis of oral biopsies extracted from 1995 to 2009, in an oral medicine and surgery unit in Galicia (Spain)

Objective: To conduct an analysis of the frequency of oral lesions in biopsies over a 14-year period in the Oral Medicine, Oral Surgery and Implantology Unit. Material and Methods: We conducted a retrospective study of biopsies removed from 1995-2009, recording data regarding age, sex, location of the lesions, biopsy types, anatomical and pathological diagnosis and definitive diagnosis. Results: Of the 562 patients studied, the average age was 51.8 years, with a standard deviation of 18.5 (range 5-96).The distribution by sex was 318 (56.6%) women and 244 (43.4%) men. The most common diagnostic category was mucosal pathologies in 37.9% of cases, followed by odontogenic cysts in 27.8%. Malignant tumors accounted for3.9% of cases, oral squamous cell carcinomas were the most frequent malignancy, appearing in 22 cases. Bisphosphonate-related osteonecrosis of the jaws was the most common injury within the bone lesions group. Conclusion: Following the performance of 647 biopsies on 562 patients, we can say that the most common injury was radicular cysts (appearing in 108 cases), having found statistical differences in relation to the patients’ sex and age (AU)

The role of the adenomatous polyposis coli (APC) in oral squamous cell carcinoma.

The main cause of death in oral squamous cell carcinomas (OSCC) is metastasis. Intercellular adhesion is mediated by a family of glycoproteins called cadherins and other molecules like catenins and APC (adenomatous polyposis coli) among other. The WNT (wingless-type) gene family is a group of genes, key signaling pathway for embryonic development and oncogenesis. The goal of this paper is to describe the role of the APC gene, and its derivatives, in the carcinogenicity pathway of WNT-1, identifying its role as a tumor suppressor gene in OSCC, while describing the genetic (loss of heterozygosity and mutations) and epigenetic alterations that modulate its expression and evaluate its relationship with the clinicopathological parameters of this type of tumors. As for APC, its activity as a tumor suppressor gene appears muted on a relatively frequent basis in these tumors, either by LOH, mutations or epigenetic control mechanisms, thus resulting in a low degree of agreement between the results of different studies.

Applications of OralCDx® methodology in the diagnosis of oral leukoplakia.

OBJECTIVE: We aim to evaluate the effectiveness of the brush biopsy technique using OralCDx ® (OralScan Laboratories Inc., Suffern, NY) as a new method for early diagnosis and control of a "potentially malignant disorder" such as oral leukoplakia. DESIGN OF THE STUDY: We performed a study in which samples were taken using OralCDx ® on 24 patients who visited the Master of Oral Medicine, Oral Surgery and Implantology of the University of Santiago de Compostela between February 2009 and May 2010. These patients presented clinical and histological lesions that were consistent with oral leukoplakia. We evaluated the relationship between the keratinization degree of the lesions and cell representation; the diagnosis obtained through OralCDx ® and biopsies; and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: 50% of patients were men and 50% women with an average age of 62.38 years. The Kappa coefficient relating keratinization of lesions and cell representation was 0.33, the OralCDx ® - biopsy diagnostic rate reached a Kappa value of 0.66, recording 72.7%, sensitivity and 92.3% specificity, PPV was 88.8%, while NPV reached 80%. CONCLUSIONS: cytology sampling with OralCDx ® showed high sensitivity and specificity values, which make it a good tool for monitoring oral leukoplakia, but nowadays the most reliable method that allows us to confirm the exact diagnosis of the lesions and their anatomical and pathological characteristics still is conventional biopsy using a surgical scalpel.

An analysis of oral biopsies extracted from 1995 to 2009, in an oral medicine and surgery unit in Galicia (Spain).

OBJECTIVE: To conduct an analysis of the frequency of oral lesions in biopsies over a 14-year period in the Oral Medicine, Oral Surgery and Implantology Unit. MATERIAL AND METHODS: We conducted a retrospective study of biopsies removed from 1995-2009, recording data regarding age, sex, location of the lesions, biopsy types, anatomical and pathological diagnosis and definitive diagnosis. RESULTS: Of the 562 patients studied, the average age was 51.8 years, with a standard deviation of 18.5 (range 5-96). The distribution by sex was 318 (56.6%) women and 244 (43.4%) men. The most common diagnostic category was mucosal pathologies in 37.9% of cases, followed by odontogenic cysts in 27.8%. Malignant tumors accounted for 3.9% of cases, oral squamous cell carcinomas were the most frequent malignancy, appearing in 22 cases. Bisphosphonate-related osteonecrosis of the jaws was the most common injury within the bone lesions group. CONCLUSION: Following the performance of 647 biopsies on 562 patients, we can say that the most common injury was radicular cysts (appearing in 108 cases), having found statistical differences in relation to the patients' sex and age.

Current trends in miRNAs and their relationship with oral squamous cell carcinoma.

A micro RNA (miRNA) is a single-stranded endogenous, non-coding RNA, with length ranging between 18 and 24 nucleotides and the ability of regulating the expression of other genes on a post-transcriptional level by means of various processes, degradation or repression of target mRNA. miRNAs play a crucial role in regulating fundamental processes such as cell cycle, differentiation and apoptosis; thus, their deregulation can affect normal cell growth and development, and even participate in carcinogenesis. The goals of this paper are: to outline the formation and functions of miRNAs; to determine their role in oral squamous cell carcinoma; to analyze the different miRNAs described and their roles as oncogenes or tumor suppressor genes, depending on their overexpression or subexpression; to describe the different polymorphisms and epigenetic alterations identified; and to determine their role in multidrug resistance.

Hypoxia-inducible factors in OSCC.

Oral squamous cell carcinoma (OSCC) is a characteristic locally aggressive tumor in which hypoxia levels are very high, causing a low response to chemotherapy and providing basic resistance to anticancer drugs. Tumoral hypoxia directly depends on hypoxia-inducible factors (HIF). The goal of this paper is to describe HIF basic biology and tumor cells (HIF-1α, mainly), analyzing the effects of its expression in OSCC, study its relation with other molecules such as nitric oxide (NO), carbonic anhydrase (CA) or VEGF and assess the possibility of its manipulation as a therapeutic target.

Histopathological findings in oral lichen planus and their correlationwith the clinical manifestations

Objectives: To highlight the most characteristic histopathological findings of oral lichen planus and their correlationwith the clinical manifestations and forms.Study design: We performed a retrospective study of 50 biopsied and diagnosed cases of oral lichen planus obtainedover a period of 11 years, spanning from May 1998 to April 2009. We analyzed the age and sex of thepatient, type of lichen planus, location and different histopathological findings, comparing them with the clinicallesions.Results: Seventy eight percent of the patients are female and 22% are male, with an average age of 56.06 years forboth sexes. The most frequent clinical form is reticular, present in 78% of the cases, and the most common locationis the buccal mucosa, present in 70% of the patients. Hydropic degeneration of the basal layer and lymphocyticinfiltration in the subepithelial layer are observed in the entire sample. Signs of atypia were identified in 4% of thecases, but without dysplasic features. Other common histological findings were the presence of necrotic keratinocytes(92%), hyperplasia (54%), hyperkeratosis (66%), acanthosis (48%), and less frequently, serrated ridges (30%)and the presence plasma cells (26%) (AU)

What real influence does the proto-oncogene c-myc have in OSCC behavior?

The influence of c-myc in the carcinogenic process has been previously described although in the specific case of oral tumors it has been poorly tested. Myc proteins are a family of proto-oncogenes involved in the cell proliferation regulation, differentiation and apoptosis. The goal of this paper is to describe the functions of c-myc and its role as oncogene, assessing its expression by immunohistochemistry and genetic amplification studies, and studying its relationship with tumoral clinical and pathological variables, and describing genetic and molecular interactions in OSCC.

p16(INK4a)/CDKN2 expression and its relationship with oral squamous cell carcinoma is our current knowledge enough?

Oral squamous cell carcinomas (OSCC) are the most common malignancy of the oral cavity and their multistep development requires the accumulation of multiple genetic and epigenetic alterations. Inactivation of p16(INK4a), encoded by the CDKN2 gene has been widely associated with this type of tumors. The purpose of this review is to elucidate the relationship between p16(INK4a) expression and the different clinical and pathological aspects of OSCC, analyze the variation in results between studies, detailing the described genetic/epigenetic alterations that result in gene silencing and the relationship between p16(INK4a) and HPV infection.