Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation.
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The symptomatic phases of many inflammatory diseases are characterized by migration of large numbers of neutrophils (PMN) across a polarized epithelium and accumulation within a lumen. For example, acute PMN influx is common in diseases of the gastrointestinal system (ulcerative colitis, Crohn's disease, bacterial enterocolitis, gastritis), hepatobiliary system (cholangitis, acute cholecystitis), respiratory tract (bronchial pneumonia, bronchitis, cystic fibrosis, bronchiectasis), and urinary tract (pyelonephritis, cystitis). Despite these observations, the molecular basis of leukocyte interactions with epithelial cells is incompletely understood. In vitro models of PMN transepithelial migration typically use N-formylated bacterial peptides such as fMLP in isolation to drive human PMNs across epithelial monolayers. However, other microbial products such as lipopolysaccharide (LPS) are major constituents of the intestinal lumen and have potent effects on the immune system. In the absence of LPS, we have shown that transepithelial migration requires sequential adhesive interactions between the PMN beta2 integrin CD11b/CD18 and JAM protein family members. Other epithelial ligands appear to be abundantly represented as fucosylated proteoglycans. Further studies indicate that the rate of PMN migration across mucosal surfaces can be regulated by the ubiquitously expressed transmembrane protein CD47 and microbial-derived factors, although many of the details remain unclear. Current data suggests that Toll-like receptors (TLR), which recognize specific pathogen-associated molecular patterns (PAMPs), are differentially expressed on both leukocytes and mucosal epithelial cells while serving to modulate leukocyte-epithelial interactions. Exposure of epithelial TLRs to microbial ligands has been shown to result in transcriptional upregulation of inflammatory mediators whereas ligation of leukocyte TLRs modulate specific antimicrobial responses. A better understanding of these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies aimed at inhibiting the deleterious consequences of mucosal inflammation. (+info)
Denture hyperplasia with areas simulating oral inverted ductal papilloma.
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Denture hyperplasia is a reactive lesion of the oral mucosa, usually associated to an ill-fitting denture. This lesion is easily diagnosed and in some cases distinct microscopic variations such as osseous, oncocytic and squamous metaplasia may be found. These metaplastic alterations probably are associated with the lymphocytic infiltrate usually present in denture hyperplasia. We present a case of denture hyperplasia containing salivary gland tissue with ductal alterations mimicking an oral inverted ductal papilloma. (+info)
Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects.
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Interleukin-6 (IL-6) is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. In all, 24 consecutive patients with MM in first-line therapy received DEX for 4 days, followed by melphalan (HDM: 140 mg/m2) and autologous stem cell transplantation (ASCT). The anti-IL-6 monoclonal antibody (mAb) (B-E8) was given till haematological recovery, starting 1 day before DEX. Results were historically compared to MM patients treated with HDM 140 and 200 mg/m2. Our results show (1) that B-E8 was able to fully neutralize IL-6 activity in vivo before and after HDM as shown by inhibition of C reactive protein (CRP) production; (2) no haematological toxicity; (3) a significant reduction of mucositis and fever; (4) a median event-free survival of 35 months and an overall survival of 68.2% at 5 years with a median follow-up of 72 months; and (5) the overall daily IL-6 production progressively increased on and after 7 days post-HDM, with the increased serum CRP levels. In the 5/24 patients with uncontrolled CRP production, a large IL-6 production was detected (320 microg/day) that could not possibly be neutralized by B-E8. These data show the feasibility to neutralize IL-6 in vivo with anti-IL-6 mAb in the context of HDM. (+info)
Measurement of secondary mucositis to oncohematologic treatment by means of different scale. Review.
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Oral mucositis is the inflammation that takes place in the oral epithelium, as a result of antineoplastic treatments such as radiotherapy, chemotherapy or bone marrow transplant, being very frequent in these treatments for oncohematologic disease. The consequences of this inflammation, not only affect the quality of life of the patient, but can also suppose a limitation in the application of the treatment, as well as an increase in the hospital stay and therapeutic costs. A main obstacle for the study of the mucositis, has been the lack of a system adapted for its valuation by means of the oral examination. Methods developed to measure and quantify the changes produced in oral epithelium as a result of treatment of cancer can be very varied from more simple methods, such as general scales with four or five degrees of severity that link the mucositis to the state of oral health, to specific scales of treatment. In this last type of scale the type of antineoplastic treatment that gave rise to the mucositis is identified giving a global severity score for the mucositis. The establishment of a common scale for the evaluation of mucositis is important, not only for clinical purposes but also for the investigation of the degree of toxicity of the different therapeutic regimes that give rise to the mucositis. (+info)
Epidemiology of the most common oral mucosal diseases in children.
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Dentists who treat children must be alert to the possibility of finding diseases of the oral mucosa, especially in younger children. The present study aimed to review the most updated information and the experience of our group in order to yield epidemiological data that assist diagnosis of the most common diseases of the oral mucosa in children. Recent epidemiologic studies have shown a wide variability in the prevalence of oral mucosal lesions in different regions of the world and have led researchers to draw disparate conclusions. Moreover, studies have not been designed using standard criteria, further explaining the wide variability in the percentage of different groups of children with oral lesions, which ranges from 4.1 to 52.6%. The lesions most frequently considered by authors and that most often appear in the different studies are: recurrent aphthous stomatitis (0.9-10.8%), labial herpes (0.78-5.2%), fissured tongue (1.49-23%), geographic tongue (0.60-9.8%), oral candidiasis (0.01-37%) and traumatic injury (0.09%-22.15%). Dentists must be able to detect any of the numerous possible disorders and perform the correct differential diagnosis, key to the treatment plan. The aim of this paper, based on a review of the different national and international studies, is to contribute data on the most important oral mucosal diseases in the paediatric population in terms of prevalence and differential diagnosis. (+info)
A non-randomized comparative study using different doses of acyclovir to prevent herpes simplex reactivation in patients submitted to autologous stem cell transplantation.
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The reactivation of Herpes Simplex virus (HSV) occurs in 70% to 80% of patients submitted to autologous stem cell transplantation (ASCT); it increases the severity of chemotherapy-induced mucositis. Therefore, the use of acyclovir in ASCT patients is considered standard practice. However, the minimum dose needed to prevent reactivation is a matter of debate. We compared two doses of acyclovir in a non-randomized fashion in 59 patients submitted to ASCT: 32 patients received a dose of 125 mg/m(2) IV every six hours and the subsequent 27 patients received a dose of 60 mg/m(2) IV every six hours. Viral excretion was evaluated through weekly viral culture of oral swabs. Grade 4 mucositis was more frequent in Group 1 (p= 0.03). The reactivation rates in Groups 1 and 2 were 9% and 4%, respectively (p= 0.62, 95% confidence interval -7 - 18). Prophylaxis with reduced doses of intravenous acyclovir seems to be as effective as a higher dose in inhibiting HSV reactivation, with a significant reduction in cost. Prospective randomized studies are needed to confirm our conclusions. (+info)
Acute toxicity and preliminary clinical outcomes of concurrent radiation therapy and weekly docetaxel and daily cisplatin for head and neck cancer.
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OBJECTIVE: To examine the feasibility and efficacy of concurrent weekly docetaxel and radiation therapy as a definitive treatment for head and neck cancer (HNC). METHODS: Thirty-two patients with primary HNC, who were treated with concurrent weekly docetaxel and radiation therapy, were analysed. The distribution of the disease stage was as follows: Stage II, 18 patients; Stage III, 3 patients; Stage IVA, 7 patients; Stage IVB, 3 patients; the patient of cervical lymph node metastasis with unknown primary tumor was not assessable. The average total dose of radiotherapy was 67.5 Gy. Docetaxel (10 mg/m(2), intravenously, once a week) was given to all patients up to four cycles, and cisplatin (6 mg/m(2), intravenously, five times a week) was also administered to all patients for up to 3 weeks from the beginning of the radiation therapy. RESULTS: Only in two patients did the radiotherapy need to be temporarily interrupted due to the development of acute mucositis. Grade 3 toxicity was observed in six patients. Grade 4 acute mucositis was seen in one patient. The response rate was 100%, and complete response (CR) was observed in 30 patients (94%). At the time of the analysis, the 2 year local control and relapse-free rates in the 30 patients showing CR were 90 and 76%, respectively. CONCLUSIONS: Concurrent weekly docetaxel and radiation therapy did not affect the compliance of the patients for the radiation therapy, indicating that the acute toxicities were within acceptable limits. (+info)
Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer.
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PURPOSE: To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel, cisplatin, and fluorouracil (FU; PCF) versus standard cisplatin and FU (CF), both followed by chemoradiotherapy (CRT), in locally advanced head and neck cancer (HNC). PATIENTS AND METHODS: Eligibility criteria included biopsy-proven, previously untreated, stage III or IV locally advanced HNC. Patients received either CF (cisplatin 100 mg/m2 on day 1 plus FU 1000 [corrected] mg/m2 continuous infusion on days 1 through 5) or PCF (paclitaxel 175 mg/m2 on day 1, cisplatin 100 mg/m2 on day 2, and FU 500 mg/m2 continuous infusion on days 2 through 6); both regimens were administered for three cycles every 21 days. Patients with complete response (CR) or partial response of greater than 80% in primary tumor received additional CRT (cisplatin 100 mg/m2 on days 1, 22, and 43 plus 70 Gy). RESULTS: A total of 382 eligible patients were randomly assigned to CF (n = 193) or PCF (n = 189). The CR rate was 14% in the CF arm v 33% in the PCF arm (P < .001). Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm (log-rank test, P = .006; Tarone-Ware, P = .003). PCF patients had a trend to longer overall survival (OS; 37 months in CF arm v 43 months in PCF arm; log-rank test, P = .06; Tarone-Ware, P = .03). This difference was more evident in patients with unresectable disease (OS: 26 months in CF arm v 36 months in PCF arm; log-rank test, P = .04; Tarone-Ware, P = .03). CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients (53% v 16%, respectively; P < .001). CONCLUSION: Induction chemotherapy with PCF was better tolerated and resulted in a higher CR rate than CF. However, new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment. (+info)