Multiple concomitant oral cavity cancers: Incidence, management, and outcomes.

BACKGROUND: Little is known about the appropriate treatment and long-term survival of patients with multiple concomitant oral cavity cancers (MOC). The aim of this study was to clarify the clinicopathological features of MOC, to compare the prognosis of MOC patients with that of patients with single oral cavity cancers (SOC), and to describe reconstructive options based on the concept of economy in autologous tissue transfer. METHODS: Data from 603 patients diagnosed with at least one squamous cell carcinoma of the oral cavity who underwent surgery for primary oral cavity cancers between 2006 and 2014 were reviewed retrospectively to identify MOC patients. RESULTS: Among 603 cases of surgically resected primary oral cancers, 20 cases (3.3%) with MOC were identified. Patients with MOC did not differ from patients with SOC in age, and their index lesions did not differ in pT value, pN value, pathological stage, extracapsule spread, or perineural or bone invasion. The 5-year overall and disease-free survival rates for MOC and SOC cases were 72.6% versus 68.7%, and 65.3% versus 64.8%, respectively (P = 0.785 and 0.770, respectively). The anterolateral thigh flap was widely applied. According to its origin of blood supply, the reconstructive options of MOC patients with separated defects were classified and proposed. CONCLUSIONS: MOC and SOC were similar in clinicopathological characteristics. The prognosis of patients with MOC was similar to that of patients with SOC. Resections were performed with curative intent. A multidisciplinary team management approach is essential for customized treatment in MOC patients.

Molecular progression in unusual recurrent non-pediatric intracranial clear cell meningioma.

We report a case of a recurrent clear cell meningioma (ccm) in the frontal lobe of the brain of a 67-year-old man. The patient developed three recurrences: at 3, 10, and 12 years after his initial surgery. Histopathology observations revealed a grade 2 ccm with positivity for vimentin and epithelial membrane antigen. Expression of E-cadherin was positive only in the primary tumour and in the first available recurrence. Fluorescence in situ hybridization analyses demonstrated 1p and 14q deletions within the last recurrence. Multiplex ligation-dependent probe amplification studies revealed a heterozygous partial NF2 gene deletion, which progressed to total loss in the last recurrence. The last recurrence showed homozygous deletions in CDKN2A and CDKN2B. The RASSF1 gene was hypermethylated during tumour evolution. In this report, we show the genetic alterations of a primary ccm and its recurrences to elucidate their relationships with the changes involved in the progression of this rare neoplasm.

Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies.

The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

The use of pedicled buccal fat pad combined with sequestrectomy in bisphosphonate-related osteonecrosis of the maxilla.

The use of pedicled buccal fat pad flap (BFP) has proved of value for the closure of oroantral and oronasal communications and is a well-established tool in oral and maxillofacial surgery. Otherwise, the perceived limitations of surgical therapy for bisphosphonate-related osteonecrosis of the jaws (BRONJ) have been widely discussed, and recommendations have largely been made to offer aggressive surgery only to stage 3 patients refractary to conservative management. Oroantral communication may be a common complication after sequestrectomy and bone debridement in upper maxillary BRONJ. We report a case series of stage 3 recalcitrant maxillary BRONJ surgically treated with extensive sequestrectomy and first reconstruction using pedicled BFP. All the cases presented an uneventful postoperative healing was uneventful without dehiscence, infection, necrosis or oroantral communication. We postulate that managing initially the site with BFP and primary closure may ensure a sufficient blood supply and adequate protection for an effective bone-healing response to occur. This technique may represent a mechanic protection and an abundant source of adipose-derived adult stem cells after debridement in upper maxillary BRONJ. We evaluate in this work results, advantages and indications of this technique.

Mediastinitis of odontogenic origin. A serious complication with 80 years of history.

We performed a systematic review of the literature about descending necrotising mediastinitis (DNM) of odontogenic origin. In parallel, a retrospective review of this pathology was carried out in an Oral and Maxillofacial Surgery Service of a reference hospital for a population of 1,100,000 inhabitants. The main objectives were to determine changes in mortality and prevalence of this serious complication. The systematic review included 51 articles with 89 patients and our study comprised seven patients. The period of time with the highest number of cases was between 2000-2009 (38 patients). The percentage of mortality observed was 20.2% in diffuse DNM and 4.9% in localised DNM. Thirty-one patients with DNM in our review were admitted for more than 41 days. Despite evidence of a decrease in DNM cases, publications have increased over the years, but it does not appear to be due to an increase in those of odontogenic origin. The survival of DNM has improved since 1998 and remained stable since then. Despite the low prevalence of this disease, multicentre control studies are needed to achieve better evidence about this entity.

The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes.

OBJECTIVES: Previous work has shown that the CO-releasing molecule CORM-2 protects against cartilage degradation. The aim of this study was to examine whether CORM-2 can control the production of inflammatory mediators in osteoarthritic chondrocytes and determine the mechanisms involved. METHODS: Primary cultures of chondrocytes from OA patients were stimulated with IL-1beta. The production of reactive oxygen species, nitrite, PGE(2), TNF-alpha and IL-1 receptor antagonist (IL-1Ra) were measured in the presence or absence of CORM-2. The expression of nitric oxide synthase-2 (NOS-2), cyclo-oxygenase-2 (COX-2) and microsomal PG E synthase-1 (mPGES-1) was followed by western blot and real-time PCR. Activation of nuclear factor-kappaB (NF-kappaB) and hypoxia inducible factor-1alpha (HIF-1alpha), and phosphorylation of NF-kappaB inhibitory protein alpha (IkappaBalpha) were determined by ELISA. RESULTS: CORM-2 decreased the production of oxidative stress, nitrite and PGE(2). In addition, CORM-2 inhibited IL-1beta-induced TNF-alpha but enhanced IL-1Ra production. Treatment of chondrocytes with CORM-2 strongly down-regulated NOS-2 and mPGES-1 protein expression, whereas COX-2 was reduced to a lesser extent. These changes were accompanied by a significant decrease in mRNA expression for NOS-2 and mPGES-1. CORM-2 showed a concentration-dependent inhibition of DNA-binding activity for p65 NF-kappaB and HIF-1alpha. IkappaBalpha phosphorylation was also reduced by CORM-2 treatment. CONCLUSIONS: These data have opened new mechanisms of action for CORM-2, raising the prospect that CO-releasing molecules are an interesting strategy for the development of new treatments in articular conditions.

The carbon monoxide-releasing molecule CORM-2 inhibits the inflammatory response induced by cytokines in Caco-2 cells.

BACKGROUND AND PURPOSE: Recent evidence indicates that carbon monoxide-releasing molecules (CO-RMs) exhibit potential anti-inflammatory properties. In the present study, we have investigated whether tricarbonyl dichloro ruthenium(II) dimer (CORM-2) can control the inflammatory response induced by cytokines in a human colonic epithelial cell line, Caco-2. EXPERIMENTAL APPROACH: Caco-2 cells were preincubated with CORM-2 for 30 minutes and then stimulated with interleukin (IL)-1beta, tumor necrosis factor-alpha and interferon-gamma for different times. Gene expression was analyzed by real-time PCR. Protein expression was investigated by Western blot and ELISA. Transcription factor activation was determined by the luciferase method. KEY RESULTS: We have shown that CORM-2 significantly decreased the mRNA expression of nitric oxide synthase-2 (NOS-2) and the production of nitrite, in Caco-2 cells stimulated with cytokines. IL-8, IL-6 and metalloproteinase-7 (MMP-7) mRNA and protein were also significantly reduced by CORM-2. Time-course and small interfering RNA studies suggest that inhibition of IL-6 plays a role in the regulation of MMP-7 expression by CORM-2. These effects of CORM-2 can be dependent on the modulation of nuclear factor-kappaB (NF-kappaB), activator protein-1, CCAT/enhancer binding protein and the phosphorylated forms of NF-kappaB inhibitory protein-alpha, c-Jun N-terminal protein kinase 1/2, p38 and extracellular signal-regulated kinase 1/2. CONCLUSIONS AND IMPLICATIONS: CORM-2 can regulate a number of genes relevant in intestinal inflammation and cancer progression. These findings provide new insights into the anti-inflammatory properties and potential applications of this class of compounds.

COX-2 and sPLA2 inhibitory activity of aqueous extract and polyphenols of Rhizophora mangle (red mangrove).

The aqueous extract of Rhizophora mangle bark and its polyphenolic fractions showed remarkable in vitro antiinflammatory activity in a preliminary study. The low molecular weight fraction exhibited cyclooxygenase-2 inhibitory activity while the total aqueous extract and the low molecular weight fraction showed secretory phospholipase A(2) inhibitory activity.

[Control and elimination of tuberculosis in Spain: recommendations for the twenty-first century]. / Control y eliminación de la tuberculosis en España: las estrategias para el siglo XXI.

OBJECTIVE: The objective of tuberculosis (TBC) control is to eradicate the disease by interrupting transmission of Mycobacterium tuberculosis. The WHO's strategy to achieve global control of this disease is known as directly observed treatment, short-course (DOTS). The goals are to detect 70% of cases of bacilliferous TBC and to successfully treat 85% of these cases in order to reduce the number of sources of infection. Analysis of the epidemiology of TBC in Spain has revealed an incidence of > 20 cases per 100,000 inhabitants. METHODS: The strategies that should be applied are those for disease control: to improve case detection and treatment of cases with surveillance of cure (especially in contagious cases), to identify, investigate and treat individuals exposed to contagious persons, and to control epidemic outbreaks of TBC. Treatment of infected individuals is an elimination strategy and should be reserved for groups at high risk of developing the disease.

Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches.

Flumazenil antagonizes the effect of diazepam on negative contrast in one-way avoidance learning.

The main aim of the present work was to study whether the effect of diazepam upon successive negative contrast in one-way avoidance learning-induced by shifting rats from a large reward (30s spent in the safe compartment) to a small reward (1s)-is mediated by the action of this drug on the benzodiazepine (BZ) receptor. Therefore, we studied the influence of flumazenil (FL), a BZ antagonist, on the effect of diazepam (DZ) on negative contrast. The i.p. administration of 5 and 12mg/kg, but not of 2mg/kg of FL, reliably antagonized the abolition by DZ (1mg/kg) on successive negative contrast. Moreover, FL (12mg/kg) did not affect either the avoidance response or the contrast effect. These results suggest that the GABA system is involved in the successive negative contrast effect in one-way avoidance learning, and that this experimental procedure may be useful in studies of anti-anxiety agents.

Effect of diazepam on successive negative contrast in one-way avoidance learning.

The effect of administration of diazepam on successive negative contrast in one-way avoidance learning was examined in rats. Contrast was induced by shifting rats from a large reward, 30 s spent in the safe compartment, to a small reward, 1 s spent in the safe compartment. IP administration of 2 mg/kg diazepam eliminated this negative contrast. Moreover, this effect is dose dependent, with doses of 2 and 2.5 mg/kg, but not 0.5 mg/kg, effective in reliably reducing contrast. These results suggest the existence of similar or common underlying mechanisms in both aversive and appetitive contrast effects; they are discussed in light of the current theories of frustrative nonreward and as a mean of studying the behavioral and biological mechanisms of anxiety.

Epidemiological factors on hymenoptera venom allergy in a Spanish adult population.

BACKGROUND: The prevalence and risk factors of hymenoptera venom allergy (HVA) have been studied in several countries. However, there are few studies on the general population and these have very variable results. METHODS: An observational, prospective and cross-sectional study was carried out on a sample of 1064 subjects in a total working population of 7887 subjects (Ford factory, Spain) in order to know the prevalence of HVA in this population and the influence of several risk factors in its development. RESULTS: The rate of exposure to stings was 84.1% (ci 95%: 81.8-86.3%). The prevalence of HVA was 7.6% (ci 95%: 6.1-9.4%), with local severe reactions (LSR) in 5.3% (ci 95%: 4-6.8%) and systemic reactions (SR) in 2.3% (ci 95%: 1.5-3.4%). More than 82% of individuals over 20 years had already had some exposure, a figure that did not change in the age groups of older decades. In our study, the prevalence of HVA was not dependent on either age (similar age in all groups), sex: for LSR OR 2.75 (ci 95%: 0.37-20.30), for SR OR 0.54 (ci 95%: 0.12-2.38), or atopy OR 0.96 (ci 95%: 0.50-1.83); SR being more frequent among the residents of rural habitats, with ranges approaching statistically significant levels OR 2.15 (ci 95%: 0.95-4.81). The number of stings was larger in HVA group with respect a control group. The degree of venom sensitization measure by skin test and CAP-RAST was more intensive in SR group versus LSR group. Among vespids, sensitization to Polistes was more frequent than Vespula. CONCLUSIONS: HVA in our sample has a similar prevalence to other countries located in similar geo-climatic environments. Rural habitat and the number of stings suffered along life are risk factors of HVA development.

[Pulmonary symptomatic tuberculosis' diagnostic delay study]. / Estudio del retraso diagnóstico de la tuberculosis pulmonar sintomática.

OBJECTIVE: To study symptomatic pulmonary tuberculosis (PTB) diagnostic delay. PATIENTS AND METHODS: Prospective study of new symptomatic PTB cases (aged > or = 15 years) by structured interview with the patients and their families. The main variables analyzed were patient's delay (PD), doctor's delay (DD), diagnostic process delay (DPD), health care system delay (HCSD) and total delay between the onset of symptoms and start of treatment (TD). Univariate and multivariate statistical analyses were performed for each component of delay. RESULTS: Two hundred eighty-seven patients were studied. The mean delays in days standard deviations were TD 81.8 77.3; PD 43.3 55.7; DD 28.4 59.6; DPD 10.0 17.7, and HCSD 38.5 62.5. CONCLUSIONS: Patients are responsible for 50% of excess delay in diagnosing symptomatic PTB. Patients in the health care system experienced diagnostic delays over 60 days in 18.5% of cases, doctors being responsible for 75% of the diagnostic delay attributable to the system.

[Active tuberculosis case finding among immigrants in Barcelona]. / Búsqueda activa de tuberculosis en inmigrantes en Barcelona.

OBJECTIVE: To assess the prevalence of tuberculous infection and disease in recent economic immigrants in Barcelona. SUBJECTS AND METHOD: Examination and testing of immigrants. Tuberculin tests (TTs) were given and the presence of scars from tuberculosis vaccinations were noted. Thresholds of 5 and 15 mm were established for positivity in unvaccinated and vaccinated individuals, respectively. RESULTS: A total of 3651 persons were examined, but only 3151 completed the study. Eighteen were diagnosed with tuberculosis (571.2 per 100,000) and 50.6% were classified as positive TT reactors, 34.4% because of infection and 16.3% possibly because of tuberculosis vaccination. The percentage of reactors was significantly higher in the sample of economic immigrants than in the local population. Age, male sex, place of origin, greater poverty, and higher prevalence of disease in the country of origin were associated with tuberculous infection in the sample. DISCUSSION: Active case finding proved efficient. Interference from tuberculosis vaccination greatly affects the findings, depending on the positivity threshold that is established. We recommend that chest radiographs be used in addition to TTs. Immigration will change the nature of endemic tuberculosis in Spain, and strategies should be specifically designed to deal with the new challenges that will appear.

[Results and epidemiological impact of directly observed treatment of tuberculosis]. / Resultados e impacto epidemiológico de una unidad de tratamiento directamente observado de la tuberculosis.

OBJECTIVES: To analyze the results and epidemiological impact on tuberculosis (TB) of directly observed therapy (DOT) for uncooperative patients. METHOD: Retrospective study of the case histories of patients admitted to the DOT unit in Catalonia (Spain) since its March 1993 inauguration until August 1998. RESULTS: Of a total of 470 patients, 102 were cared for during the unit's first phase, in which funding resources were insufficient. Of the 368 admitted during the second phase beginning January 1996; 176 (47.5%) were cured, 27 (7.3%) died, 72 (19.5%) were still at the unit and 93 (25.2%) left the unit before completing treatment. Of the last group, 25 were cured, 31 died 19 continued DOT and 18 (4.9% of all enrolled in the second phase) were lost to follow-up. Thus, the final outcome distribution for the patients was 201 (54.6%) cured, 58 (15.7% died, 91 (24.7%) still in DOT and 18 (4.9%) lost to follow-up. The compliance rate during the second phase was 91.8%. These results may have contributed significantly to the nearly 30% reduction in the incidence of TB in Catalonia between 1992 and 1997, a period which saw large decreases in the number of cases among 20-to-44-year-olds (33%) and consequently also among under-15-year-olds (55%). Likewise the number of cases of TB in high risk groups decreased, 55% on the average with a minimum decrease of 40.1% among AIDS patients and a maximum decrease of 85.2% among indigents. CONCLUSION: DOT has proven highly effective both for patients and for the community, although many other factors must also be considered when accounting for the current epidemiological trend.

[Tuberculosis epidemiology in Catalonia: 1982-1989]. / Epidemiología de la tuberculosis en Cataluña: 1982-1989.

The epidemiological indicators of tuberculosis in Catalonia and their trends since 1982 were evaluated. It was shown that the reported morbidity rate has increased because of an increased number of reports, but it probably is still lower than the real one. The epidemiological value of the parameters of tuberculous infection was also shown, particularly the yearly infection rate (YIR), or probability of an individual to be infected. In spite of the multiple interferences that these indexes may have undergone during the past BCG vaccination campaign, their reduction is very important, the yearly reduction of YIR being estimated in 11%.