Maxillary tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO) is a rare paraneoplastic form of renal phosphate wasting that results in severe hypophosphatemia, defective vitamin D metabolism, and osteomalacia. In the case reported here, maxillary TIO was not diagnosed for 6years, although initial complaints were reported when the patient was 12years old. Meanwhile she suffered from profound growth limitation, pain, weakness, and spontaneous multiple bone fractures, culminating in complete loss of ambulatory ability and severe limitation in daily activities. At age 18years, she finally received an accurate diagnosis and definitive treatment was administered. She underwent a partial maxillectomy with complete removal of the tumour, resulting in a full cure. Shortly afterwards the patient regained the ability to walk, no longer needing the wheelchair to which she had been confined. This definitive diagnosis was based on three modalities: (1) fibroblast growth factor 23 analysis (high levels of the secreted hormone were found on the left side of the maxilla in the facial vein and pterygoid plexus, pinpointing the tumour location), (2) octreotide scan, and (3) 68Ga-DOTA-NOC-PET/CT. TIO removal via partial maxillectomy led to a complete reversal of this patient's health condition, restoring her ability to walk and function. The importance of prompt employment of these diagnostic modalities and the high level of clinical suspicion required in such cases are clear.

Sporadic versus syndromic keratocysts-Can we predict treatment outcome? A review of 102 cysts.

OBJECTIVES: Keratocystic odontogenic tumor (KCOT) demonstrates variable growth mechanisms and biologic behavior, partly due to origin and histology. We looked for the most contributing factors in predicting outcome of treatment. SUBJECTS AND METHODS: We retrospectively reviewed 118 medical files of patients diagnosed with KCOT (by tissue biopsy before surgical treatment) with/without nevoid basal cell carcinoma syndrome (NBCCS) from 1995 to 2015. Data were recorded and analyzed statistically to determine the treatment-outcome correlation. KCOTs in NBCCS patients were termed "syndromic" and random KCOTs termed "sporadic." RESULTS: Of 102 cysts, 32 were diagnosed with NBCCS. Sporadic KCOTs were significantly larger upon diagnosis (p < .017). Factors most indicative of postsurgical complications are older age (p < .011), upper jaw location, and size of lesion ≥9.5 cm². Sporadic KCOTs significantly increased the chances of complications approximately threefold (p < .043). Higher recurrence rate was significant in syndromic cysts (47%) compared to sporadic cysts (20%) (p < .009). Recurrence time was 3 years on average. CONCLUSIONS: Postsurgical complications may be expected in: older patients, upper jaw location, extensive lesions, and sporadic KCOT. Most KCOT recurrence is diagnosed 3 years from treatment.

Pleural fluid analysis of lung cancer vs benign inflammatory disease patients.

BACKGROUND: Correct diagnosis of pleural effusion (PE) as either benign or malignant is crucial, although conventional cytological evaluation is of limited diagnostic accuracy, with relatively low sensitivity rates. METHODS: We identified biological markers accurately detected in a simple PE examination. We analysed data from 19 patients diagnosed with lung cancer (nine adeno-Ca, five non-small-cell Ca (not specified), four squamous-cell Ca, one large-cell Ca) and 22 patients with benign inflammatory pathologies: secondary to trauma, pneumonia or TB. RESULTS: Pleural effusion concentrations of seven analysed biological markers were significantly lower in lung cancer patients than in benign inflammatory patients, especially in matrix metalloproteinase (MMP)-9, MMP-3 and CycD1 (lower by 65% (P<0.000003), 40% (P<0.0007) and 34% (P<0.0001), respectively), and in Ki67, ImAnOx, carbonyls and p27. High rates of sensitivity and specificity values were found for MMP-9, MMP-3 and CycD1: 80 and 100%; 87 and 73%; and 87 and 82%, respectively. CONCLUSION: Although our results are of significant merit in both the clinical and pathogenetic aspects of lung cancer, further research aimed at defining the best combination for marker analysis is warranted. The relative simplicity in analysing these markers in any routine hospital laboratory may result in its acceptance as a new diagnostic tool.

Salivary profile and oxidative stress in children and adolescents with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by altered exocrine secretions; however, no comprehensive compositional profile of CF serous and mucous saliva secretions has been published. DESIGN: We analyzed salivary flow rate and composition, and oxidative stress-related parameters, comparing CF patients with non-CF bronchiectasis patients and the healthy controls. RESULTS: Median salivary magnesium concentration and lactate dehydrogenase activity were significantly lower in CF patients than in the healthy controls. Salivary total protein concentration was 45% higher in CF patients than in non-CF bronchiectasis patients. CF patients showed 8% lower levels of peroxidase compared with non-CF bronchiectasis. Salivary total antioxidant status, superoxide dismutase and uric acid values in the CF group were higher by 15%, 35% and 31%, respectively, than in both control groups. CONCLUSIONS: Cystic fibrosis patients demonstrated altered salivary profile, especially in antioxidant enzymatic and molecular activity, possibly resulting from the oral cavity's ongoing inflammatory and oxidative process. Free radical mechanisms may be involved in CF pathogenesis.

Salivary analysis of oral cancer biomarkers.

BACKGROUND: Oral cancer is a common and lethal malignancy. Direct contact between saliva and the oral cancer lesion makes measurement of tumour markers in saliva an attractive alternative to serum testing. METHODS: We tested 19 tongue cancer patients, measuring the levels of 8 salivary markers related to oxidative stress, DNA repair, carcinogenesis, metastasis and cellular proliferation and death. RESULTS: Five markers increased in cancer patients by 39-246%: carbonyls, lactate dehydrogenase, metalloproteinase-9 (MMP-9), Ki67 and Cyclin D1 (CycD1) (P< or =0.01). Three markers decreased by 16-29%: 8-oxoguanine DNA glycosylase, phosphorylated-Src and mammary serine protease inhibitor (Maspin) (P< or =0.01). Increase in salivary carbonyls was profound (by 246%, P=0.012); alterations in CycD1 (87% increase, P=0.000006) and Maspin (29% decrease, P=0.007) were especially significant. Sensitivity values of these eight analysed markers ranged from 58% to 100%; specificity values ranged from 42% to 100%. Both values were especially high for the CycD1 and Maspin markers, 100% for each value of each marker. These were also high for carbonyls, 90% and 80%, respectively, and for MMP-9, 100% and 79%, respectively. CONCLUSION: The significance of each salivary alteration is discussed. As all alterations correlated with each other, they may belong to a single carcinogenetic network. Cancer-related changes in salivary tumour markers may be used as a diagnostic tool for diagnosis, prognosis and post-operative monitoring.

Oral integrity and salivary profile in myeloma patients undergoing high-dose therapy followed by autologous SCT.

The underlying mechanism of high-dose therapy (HDT)-related oral mucositis (OM) may be partly mediated by alterations in the normal salivary composition. This study evaluated salivary antioxidant and immunological capacities observed in myeloma patients suffering from HDT-related OM, and assessed potential contribution of these factors to OM development. Twenty-five consecutive myeloma patients treated with melphalan 200 mg/m(2) followed by autologous SCT were enrolled. Patients underwent a daily assessment for OM, and salivary samples were collected on days -3 and +7 of transplantation and analyzed for secretory IgA and antioxidant capacity. The degree of mucosal damage was assessed by measuring the salivary carbonyl and albumin (Alb) levels. OM, reported in 96% of patients, appeared to be most severe on 8 day after transplantation (range: +2 to +14). Clinical mucositis was associated with significant reduction in salivary secretory IgA (54%; P=0.05), and antioxidant activity, measured by total antioxidant status (40%; P=0.0004), antioxidant capacity (ImAnOx) (23%; P=0.002) and uric acid level (51%; P=0.006). The increase found in salivary Alb (119%; P=0.024) and carbonyl (28%; P=0.047) levels, indicates mucosal and oxidative damage, respectively. These salivary changes might enhance mucositis development and symptoms. Therapeutic interventions, enhancing antioxidative and immunological activities need to be investigated.

Salivary and gustatory alterations among bulimia nervosa patients.

OBJECTIVE AND DESIGN: This study systematically examined salivary composition and taste perception and monitored related subjective complaints in a group of bulimia nervosa (BN) patients. SUBJECTS: Fifty-two consenting female individuals participated in the current cross-sectional study, 26 patients diagnosed with BN according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria (mean age: 24+/-7 years) and 26 healthy controls matching in age and body mass index (BMI). METHODS: All participants were given diagnostic BN-related questionnaires, had taste and salivary-composition analyses and were monitored for oral sensorial complaints. The patients were also subjected to psychological and psychiatric examinations focusing on established criteria known to be pathognomonic of the disease (including binge eating episodes, depression, impulsive traits, enhanced awareness of body image, typical compensatory behavior, and so on). RESULTS: The self-answered questionnaires of Bulimic Investigatory Test Edinburgh (BITE), Beck Depression Inventory (BDI), brief symptom inventory (BSI) and impulsivity scale (IS) revealed highly significant differences between the two groups with respect to the various BN diagnostic symptoms of the patients (P=0.0001). Subjective and objective examinations showed an overall disturbed salivary and taste profile in BN patients, who complained of xerostomia (dry mouth) and taste aberration or oral burning sensation. CONCLUSIONS: Regardless of the specific mechanism responsible for the disturbed salivary and taste profile in BN patients, these observed changes are associated with active illness. Accordingly, administration of therapeutic agents, including antioxidants, anti-inflammatory drugs and saliva substitutes, to the oral cavity (and maybe even systemically) of BN patients should be considered.

Altered salivary profile in heavy smokers and its possible connection to oral cancer.

Saliva is the first biological fluid to encounter inhaled cigarette smoke, whose numerous carcinogens and oxidants are responsible for the oral cancer so prevalent among smokers. Whole saliva, collected from 25 consenting heavy smokers and from a control group of 25 age- and gender-matched non-smokers, was subjected to sialochemical, biochemical, immunological and oxidative analyses. The mean flow rate was significantly higher in smokers than in non-smokers, as were the median activity value of superoxide dismutase (SOD) and the total salivary antioxidant capacity (ImAnOx) (by 32% and 12%, respectively, p=0.05). The salivary carbonyl concentration (an oxidative stress indicator) was significantly higher by 126% (p=0.0006) among smokers, while lactate dehydrogenase, albumin, total immunoglobulin G, and the metalloproteinases MMP-2 and MMP-9 concentrations were significantly lower in the smokers, by 86% (p=0.003), 65% (p=0.003), 61% (p=0.048), 35% (p=0.005) and 55% (p=0.035), respectively. Apparently, the oral cavity''s salivary antioxidant system fails to cope with the severe attack of reactive oxygen species originating in cigarette smoke. Moreover, various other salivary functional and protective parameters also decreased among the smokers. Hence, further research aimed at examining the possibility of administration of agents as antioxidants or saliva substitutes to the oral cavity of smokers should be considered.

Age- and flow-dependency of salivary viscoelasticity.

Measuring salivary viscoelasticity (by relaxation times) is of paramount importance, since salivary rheology behavior has been associated with the development of oral disease conditions (such as dental caries) in animal and human model studies. In addition, novel and improved methods to evaluate salivary distribution and lubrication are of clinical interest. We used a novel method for measuring the viscoelasticity of saliva secreted from the different glands, at rest or under stimulation and at different ages, all conditions where different viscoelastic properties might be clinically important. Submandibular/sublingual salivary viscoelasticity was significantly higher than that of parotid saliva, especially under stimulation. In addition, an age-related reduction in flow rate (by 62%) was demonstrated, accompanied by an increase in both relaxation time (by 54%) and protein (by 48%). Increased salivary viscoelasticity results in compromised salivary rheology and lubrication properties, which may render the oral cavities of the elderly and other xerostomic persons more vulnerable.

TUNEL - an efficient prognosis predictor of salivary malignancies.

Biological markers are necessary for predicting prognosis of salivary malignancies and better understanding the pathogenesis of salivary cancer. We analysed terminal deoxynucleotidyl transferase (TdT)-mediated biotinylated deoxyuridine-triphosphate (dUTP)-biotin nick-end labelling (TUNEL), p53 and Ki67 expression in 66 patients with malignant salivary tumours by immonohistochemistry, and correlated the data with survival, disease-free survival, tumour grade, stage, and local and distant metastasis. TUNEL efficiently predicted poor prognosis in salivary malignancies. The 5-year (5Y) survival probability dropped significantly with the level of TUNEL staining (from 83% in negatively stained tumours to 57 and 24% in TUNEL positively stained levels 1 and 2, respectively), (P=0.042). Extensive Ki67 staining (in addition to TUNEL) reduced the 5Y-survival rate even further and addition of positively stained p53 dropped the 5Y-survival rate to 0. The correlation rates between TUNEL and Ki67 was 58% (P=0.0001), and between TUNEL and p53 it was 50% (P=0.035). Concurrently, TUNEL correlated with metastasis, extracapsular spread, grade and stage. The correlation between TUNEL, p53 and Ki67 staining and survival probabilities, and the pathological grade, stage and metastasis spread of salivary malignancies makes this a highly effective tool in patient follow-up and prognosis.

Salivary glands and the aging process: mechanistic aspects, health-status and medicinal-efficacy monitoring.

Xerostomia is a major complaint of many elderly individuals, and although they seek medical help, it usually provides no adequate relief. This complaint is considered a major clinical problem, since not less than 25% to 50%-60% of the population over the age of 65 complain of xerostomia. By definition, Xerostomia is a subjective feeling and in up to one-third of the cases does not reflect a real reduction in salivary flow rate but rather the subjective feeling of a dry mouth. Moreover, only a minute portion of the patients suffer from xerostomia with a known aetiology such as radiotherapy or Sjögren's syndrome, while in the majority of the cases, the aetiology is assumed to be related to age, disease, various medications and drugs or is simply idiopathic. The current review focuses on age-related histological, sialometrical and sialochemical changes and on the possible mechanisms which underlie these changes. Finally, directions for further exploring the subject are suggested.

Saliva--a pivotal player in the pathogenesis of oropharyngeal cancer.

Oropharyngeal (OP) cancer, which is usually squamous cell carcinoma, is the most common head and neck malignancy and accounts for 2-4% of all new cancers. It is primarily induced by exposure to tobacco. The paradigm of cigarette smoke (CS)-induced OP cancer's pathogenesis is based on the assumption that a constant direct attack of various CS carcinogens causes widespread accumulating cellular and DNA aberrations in the OP mucosal cells, in turn eventually resulting in malignant transformation. However, there is never a direct contact between CS and the OP mucosa. Saliva, bathing the mucosa from the oral cavity to the larynx, always intervenes, and CS must first interact with saliva before it reaches the mucosa. The current study investigated the role of saliva in the pathogenesis of OP cancer. A synergistic effect of CS and saliva on oral cancer cells was demonstrated. This synergism is based on the reaction between redox active metals in saliva and low reactive free radicals in CS, which results in the production of highly active hydroxyl free radicals. Thus, when exposed to CS, salivary behavior is reversed and the saliva loses its antioxidant capacity and becomes a potent pro-oxidant milieu. The devastating role of CS-borne aldehydes was demonstrated as well. Based on these results and on our recent reports demonstrating that CS destroys various salivary components, including protective ones such as peroxidase, the most important salivary antioxidant enzyme, a comprehensive view of the pivotal role of saliva in the pathogenesis of CS-induced OP cancer is suggested.

The molecular basis of salivary gland involvement in graft--vs.--host disease.

During the past two decades, the involvement of salivary glands in graft vs. host disease (GVHD) had been intensively researched and published. GVHD occurs in 40-70% of patients treated with bone marrow and peripheral blood stem cell transplantation (PBSCT), and improved survival rates have led to a continuously increasing number of GVHD patients suffering from induced salivary insult. Limited studies suggest that a large percentage of GVHD patients is affected and that the induced salivary dysfunction occurs rapidly following the transplantation. It affects both major and minor salivary glands and reflects the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. An additional reason for this vast research is that GVHD, as an autoimmune-like disease, seemed to be an appropriate model for studying a much more prevalent and well-known and well-studied autoimmune disease involving salivary glands: Sjögren's syndrome. The purpose of the current review-which is, to the best of our knowledge, the first of its kind-is to describe the GVHD-related sialometric and sialochemical data published in the past two decades for both major and minor salivary glands and to discuss the pathogenesis and molecular basis of the disease.

Effects of head and neck radiotherapy on major salivary glands--animal studies and human implications.

OBJECTIVE: The purpose of this review is to suggest an updated description of early and late irradiation effects on salivary glands in rodents. Based on this description, the mechanism of the underlying xerostomia will be discussed. STUDY DESIGN: To examine the assumption that the so-called "irradiation" effects on the parotid gland of the rat during the first two weeks are actually mucositic effects and, thus, are transient, both function and partitution-coefficient parameters of the salivary glands were examined in both irradiated and pair-fed but not irradiated rats. MATERIALS AND METHODS: Various studies were performed in which irradiated and non-irradiated rats were examined at varying intervals up to one year post-irradiation. Head and neck irradiation resulted not only in dysfunction and tissue loss of the salivary glands but also in a systemic effect expressed as profound body weight loss. RESULTS: Based on the literature available and on our own studies, we believe that one can suggest an overall mechanism for the damage induced by irradiation to the salivary glands. Our results have shown a mutual delayed expression of irradiation-induced damage in both parotid and submandibular, more evident in the parotid gland. CONCLUSION: We have suggested the following mechanism for the parotid irradiation-induced specific damage: The injurious agents resulting in delayed serous cell death leading to the specific parotid radiosensitivity are transition, highly redox-active metal ions, such as Fe and Cu, associated with secretion granules.

Salivary gland involvement in rheumatoid arthritis and its relationship to induced oxidative stress.

OBJECTIVES: The objective of the present study was to analyse salivary gland and free radical involvement in rheumatoid arthritis (RA). METHODS: Thirty-four consenting RA patients (rheumatoid factor-positive) and 18 healthy controls, matched in age and gender, participated in the study. Plasma and saliva samples were harvested and subjected to compositional analysis and various free radical-related tests. RESULTS: The mean salivary flow rate was lower in the RA patients than in the control group, whereas all plasma and salivary antioxidants were increased. Mean values of plasma malondialdehyde and ceruloplasmin were higher in the RA patients. CONCLUSIONS: The effects of RA on salivary gland flow rates and antioxidant compositional parameters may be of great importance for the further elucidation of the role of free radicals in RA pathogenesis and for its general diagnosis and evaluation. The demonstrated correlation between the altered salivary parameters and the severity of the disease may indicate that evaluation of the salivary status of RA patients is warranted.

Sialometrical and sialochemical analysis of patients with chronic graft-versus-host disease--a prolonged study.

Patients with graft-versus-host disease (cGVHD) suffer from oral dryness and increased levels of oral infections and mucosal pathologies. The purpose of the current study was dual: 1) to investigate the salivary functional (sialometry) and compositional (sialochemistry) alterations induced by the disease during a 12-month period following the onset of the disease; and 2) to evaluate the effect of Salagen 30 mg/d on the salivary biochemical and immunological composition in cGVHD patients. Significant higher concentrations of salivary sodium (Na), magnesium (Mg), total protein (TP), albumin (Alb), epidermal growth factor (EGF), and total IgG accompanied by a concomitant increase in total IgA that did not reach significant value was observed in cGVHD patients in comparison with controls at both resting and stimulated conditions (p < 0.05) while salivary levels of potassium (K), calcium (Ca), and phosphate (P) were not altered. Two weeks of oral Salagen 30 mg/d resulted in normalization of the salivary biochemical and immunological compositional alterations in the cGVHD patients. Oral pilocarpine was able to reduce and normalize the elevated levels of Na, Mg, TP, Alb, EGF, IgG, and IgA salivary concentrations at both resting and stimulated conditions. The ability of oral pilocarpine to normalize and reverse salivary biochemical and immunological alterations induced by cGVHD is parallel to its stimulatory effect on salivary flow rates, as we previously showed. As the biochemical and immunological composition of the saliva results in its antimicrobial protective characteristics, the ability of oral pilocarpine (Salagen) to abrogate cGVHD salivary gland abnormalities may be of clinical importance.

Genioglossal advancement--a simple surgical procedure for sleep apnea. Case report and literature review.

Although the use of a standard nasal continuous positive airway pressure device to combat obstructive sleep apnea is often effective, it is neither curative nor universally well tolerated. Thus, surgical intervention is often inevitable. We describe a simple, conservative surgical procedure performed on a patient with profound mandibular retrognathia (dolichofacial type), accompanied by sleep apnea. The procedure resulted in a significant pharyngeal airway enlargement of 53 and 87% at the mandible angle and hyoid bone levels, respectively, increased oxygen saturation, reduction in the respiratory disturbance index by 50%, and improved sleep quality. We present a procedure for patients whose sleep apnea is due to extensive mandibular retrognathism with concomitant retrolingual narrowing and collapse.

The enigmatic mechanism of irradiation-induced damage to the major salivary glands.

Irradiation is a central treatment modality administered for head and neck malignancies. Its major and most devastating side-effect is an induced damage to the major salivary glands. This article aims at suggesting a comprehensive explanation for the underlying mechanism of this damage, which has been considered as enigmatic throughout the 90 years since it was first described in 1911. The mechanism suggested is based on the considerable literature concerning this enigma in rat salivary glands. According to this proposed mechanism, the irradiation results in a sublethal DNA damage, which manifests and becomes lethal at a delayed phase. Thus, when the acinar progenitor cells are going through a reproductive phase when parenchymal replenishment is required, they die. The injurious agents, which result in this delayed reproductive cell death, appear to be highly redox-active transition metal ions, such as iron and copper. These metal ions, which seem to be associated with secretion granules, are not necessarily contained within the granules as previously suggested, but rather are probably located at sites more proximal to the DNA.

Extended-term effects of head and neck irradiation in a rodent.

Radiotherapy to the head and neck is a common treatment for malignancies of the region. Unfortunately, exposure to irradiation often results in a variety of complications, most of which are localised and expressed in the short term following irradiation. However, prolonged and systemic effects may have greater clinical importance as the survival rate of head and neck irradiated patients is increasing yearly. Six groups of 18-20 rats were evaluated during a 1 year study. The non-irradiated control group was compared with 2.5 Gy, 5, 7.5, 10 and 15 Gy irradiated groups. We found a dose-dependent reduction in both survival and body weight in our rat models following a delayed, prolonged and chronic process. Dying animals were emaciated, dehydrated and starved, and many were blind and immunocompromised. While the exact underlying mechanism of this delayed, but devastating, phenomenon has not yet been determined, the delayed xerostomia inflicted on these animals may, at least partially, explain it. The clinical implications for head and neck patients require further evaluation, but our data should be considered, in the context of the available evidence for the long-term effects of head and neck irradiation in humans.

[The interaction between saliva and cigarette smoke and its devastating biological effects as related to oral cancer].

UNLABELLED: Saliva is the first body fluid to confront inhaled cigarette smoke (CS) which is injurious to the oral cavity and is associated with several oral diseases and cancer. We have recently demonstrated in an In vitro model that an exposure of saliva to nine 'puffs' of CS induced a distinct increase in protein carbonyls. This elevation of protein carbonyls caused by CS may be the result of aldehydes presented in the CS reacting with sulphydryl (-SH) groups of the proteins. Moreover, following the exposure to CS, the activities of several salivary enzymes amylase, lactate dehydrogenase (LDH) and acid phosphatase (ACP) were found to be significantly reduced by 83%, 57% and 77%, respectively. However, CS had no effect on the activities of aspartate aminotransferase and alkaline phosphatase. In the current study we found that CS also reduced salivary peroxidase activity by no less than 80% which may be of a great importance to the clinical set up as peroxidase is considered a pivotal enzyme of the the salivary protecting system. Furthermore, in contrast to LDH findings in saliva, the LDH activity in plasma was not reduced following its exposure to CS. CONCLUSION: Hence, we concluded that the loss of salivary enzyme activities may be due to various agents in the CS that affect the enzyme via different mechanisms.