Outcomes of oral squamous cell carcinoma arising from oral epithelial dysplasia: rationale for monitoring premalignant oral lesions in a multidisciplinary clinic.

Surveillance of oral epithelial dysplasia results in a number of newly diagnosed cases of oral squamous cell carcinoma (SCC). The clinical stage of oral SCC at diagnosis influences the magnitude of treatment required and the prognosis. We aimed to document the stage, treatment, and outcome of oral SCC that arose in patients who were being monitored for oral epithelial dysplasia in a dedicated multidisciplinary clinic. Those with histologically diagnosed lesions were enrolled on an ethically approved protocol and molecular biomarker study. Details of clinical and pathological TNM, operation, radiotherapy, recurrence, second primary tumour, and prognosis, were recorded in patients whose lesions underwent malignant transformation. Of the 91 patients reviewed (median follow-up 48 months, IQR 18-96), 23 (25%) had malignant transformation. All were presented to the multidisciplinary team with stage 1 disease (cT1N0M0). Of these, 21 were initially treated by wide local excision, 2 required resection of tumour and reconstruction, and 2 required adjuvant radiotherapy. At follow-up 3 had local recurrence, one had regional recurrence, one had metachronous lung cancer, and 5 had second primary oral SCC. There were further diagnoses of oral dysplasia in 5 during follow-up, and it is estimated that 76% of patients will have one or other event in 5 years. Disease-specific survival was 100% and overall survival was 96% (22/23). Median follow-up after diagnosis of oral SCC was 24 months (IQR 11-58). Specialist monitoring of oral epithelial dysplasia by a multidisciplinary team allows oral SCC to be detected at an early stage, and enables largely curative treatment with simple and usually minor surgical intervention. The high incidence of second primary oral SCC in high-risk patients with oral epithelial dysplasia further supports intensive targeted surveillance in this group.

The clinical determinants of malignant transformation in oral epithelial dysplasia.

BACKGROUND: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED). METHODS: We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade. RESULTS: Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48 months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5 years, with significant predictors being: non-smoking status (χ(2)=15.1, p=0.001), site (χ(2)=15.3, p=0.002), non-homogeneous appearance (χ(2)=8.2, p=0.004), size of lesion >200 mm(2) (χ(2)=4.7, p=0.03) and, of borderline significance, high grade (χ(2)=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation. CONCLUSIONS: Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation.

Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Tumor stroma as a target in cancer.

Solid tumors are composed of the malignant cell itself (most commonly a carcinoma) and supporting cells that comprise the stroma. Significant stromal components include the extracellular matrix, supporting fibroblasts, vessels comprised of endothelium, pericytes and in some cases vascular smooth muscle, lymphatics and usually a major leukocyte infiltration. Indeed, macrophages may constitute up to 50% of the viable cells within the tumor. For many years, researchers have concentrated almost exclusively on the malignant carcinoma and looked for ways to either selectively kill or restrict its growth. In recent years the frustrating lack of advances in cytotoxic cancer therapy provoked a search for more novel strategies and foremost amongst these were anti-angiogenesis and vascular targeting. The purpose of this article is to illustrate how the stroma is now being pursued as an anti-cancer target. The article will briefly touch on anti-angiogenics that are now entering the clinic but concentrate on recent studies looking at vascular disrupting agents, stromal tumor fibroblasts and macrophages. Target identification is illustrated by the search for tumor endothelial markers. Finally, we draw attention to efforts to develop a cancer vaccine. The genetic instability and variation found in carcinoma cells made vaccination in the past a near impossibility. In contrast, genetically stable tumor endothelium with its unique accessibility to blood borne agents, together with recent advances in immunotherapy means that the possibility of a cancer vaccine now takes on a reality not previously recognised.

Assessing antibiotic therapy for Acinetobacter baumannii infections in an academic medical center.

In 2006, our clinical microbiology laboratory suspected that our institution was experiencing an increase in Acinetobacter baumannii infections and was concerned about resistance. A cross-sectional study was conducted to determine the A. baumannii antibiogram for 2006 and assess the appropriateness of antibiotics therapy. The study included all adult inpatients with a positive culture for A. baumannii between January 1 2006 and December 31 2006. A total of 129 isolates were identified. A. baumannii was highly susceptible to imipenem (97.7%) and meropenem (95.3%). Among the aminoglycosides, A. baumannii had reduced susceptibility to gentamicin (40.5%). Based on their susceptibility patterns, only 76 (58.9%) antibiotics regimens were susceptible against the isolates. At our institution, A. baumannii remains highly susceptible to the carbapenems and aminoglycosides. We encourage our practitioners to analyze the susceptibility pattern of each isolate when ordering antibiotics, which will help increase our rate of appropriate antibiotic selection.

Alpha-lipoic acid treatment of 31 patients with sore, burning mouth.

OBJECTIVE: To review a series of patients with sore, burning mouth treated with alpha-lipoic acid between 2000 and May 2006 and subjectively evaluate improvement in symptoms. DESIGN: Retrospective review of medical records of 195 consecutive patients who sought treatment for sore, burning mouth. Treatment of 47 patients was a prescription/recommendation for alpha-lipoic acid. Of these patients, 35 were available for follow-up. SETTING: Tertiary care academic medical center. SUBJECTS: Ambulatory patients given prescription /recommendation for alpha-lipoic acid 600 mg per day, in divided doses. MAIN OUTCOME MEASURE: Reported improvement in symptoms documented in medical records and at follow-up (visits or telephone interviews). RESULTS: Thirty-one of the 35 patients (66% of all 47) actually took alpha-lipoic acid as recommended. No patient reported a complete alleviation of symptoms. Six (19%) of these 31 patients felt mostly better, five (16%) felt somewhat better, and 14 (45%) reported no difference. Two patients (7%) reported a worsening of symptoms and four (13%) did not know whether there had been improvement. CONCLUSION: Eleven of 31 patients (35%) reported benefit from taking alpha-lipoic acid. Because we examined only a small number of patients and relied on a subjective outcome assessment, further larger studies using a prospective, randomized, controlled, and double-blind structure are warranted.

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens.

We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

Pyodermatitis-pyostomatitis vegetans complicated by methicillin-resistant Staphylococcus aureus infection.

Pyodermatitis-pyostomatitis vegetans (PPV), a rare disorder of the skin and oral mucosa, is considered a highly specific marker for inflammatory bowel disease, especially ulcerative colitis (UC). Oral lesions (pyostomatitis vegetans) are seen without skin involvement but rarely without gastrointestinal symptoms. Bowel symptoms may be minimal and precede the onset of other lesions by months or years. Dermatologically, PPV is characterized by annular, pustular lesions, which may precede or appear at the same time as the oral lesions. We report a case of PPV and UC in which presentation was confused by acneiform lesions and methicillin-resistant Staphylococcus aureus colonization. Management was complicated because of the patient's job commitments and need to travel, and the involvement of a number of different specialties at different locations.

T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia.

Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4+ responders was far lower among those with progressive disease, indicating that the CD4+ T-cell response might be important in HPV clearance. CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4+ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

Congenital heart block associated with undiagnosed maternal Primary Sjögren's Syndrome -- a case report and discussion.

Congenital heart block (CHB) has been linked with Sjögren's Syndrome. This paper reports a case of previously undiagnosed maternal Primary Sjögren's Syndrome (1 degrees SS) that was only discovered following the birth of the patient's first child with CHB. The possible pathophysiological mechanisms underlying CHB associated with 1 degrees SS are discussed.

Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam.

We tested the brain tissues of the Chamorro people of Guam who died of amyotrophic lateral sclerosis/Parkinsonism dimentia complex (ALS/PDC) for the neurotoxin beta-methylamino-l-alanine (BMAA). We used validated high-pressure liquid chromatography and liquid chromatography-mass spectrometry analyses to test well-characterized archival tissues of the superior frontal gyrus from eight Chamorros from Guam and a comparison group of 15 Canadians. BMAA was found as a free amino acid in 83% of Chamorro ALS/PDC patients (3-10 microg/g) as a protein-associated amino acid in 100% of the Chamorro individuals (149-1190 microg/g). Both forms of BMAA were also found at comparable levels in two Canadians who died of progressive neurodegenerative disease. BMAA, which is produced by cyanobacteria, may be associated with some cases of neurodegenerative disease.

Lingual striated muscle hamartoma or herniation?

Three grouped, small polypoid lesions were removed from the right lateral border of tongue of a healthy male aged 12 years. They were composed of packed, mature striated muscle fibres covered by oral epithelium and thinned lamina propria. Hamartomatous growth of striated muscle, or herniation through underdeveloped lamina propria is postulated to explain the exceedingly rare clinicopathological features.

Two novel assays for the detection of haemin-binding properties of antimalarials evaluated with compounds isolated from medicinal plants.

Forty-two compounds isolated from nine plants used within South America for the treatment of malaria were tested for haemin binding using two novel, rapid screening methods. The data obtained were analysed with respect to IC(50) values for in vitro toxicity to Plasmodium falciparum trophozoites. One method, a multiwell assay based on the inhibition of the interaction of haemin with glutathione (GSH), is sensitive in the 10 microM range, takes c. 1 h and is suitable for either a high throughput screen or rapid assay during natural product isolation. Of 19 compounds showing antiplasmodial activity (IC(50) < 40 microM), 16 (84%) showed >40% inhibition of GSH-haemin reaction. The sensitivity and specificity of the assay were 0.85 and 0.82, respectively. The positive predictive value was 0.81 and the negative predictive value 0.86. A more sensitive assay (0.1 microM range) is based on the reversal by haemin-binding compounds of the haemin inhibition of the L-dopachrome-methyl ester tautomerase activity of human macrophage migration inhibitory factor. This assay gives a better idea of the affinity of interaction and uses very small amounts of test compound. The log[RI(50)] of eight of the compounds that tested positive in the above assays together with those of quinine and chloroquine showed a positive correlation with log[antiplasmodial IC(50)] for strain T9-96 (r = 0.824) and strain K1 (r = 0.904). Several of the antimalarial compounds that bind haemin are isoquinolines, a class not shown previously to interact with haemin.

A clinical and pathological study of motor neurone disease on Guam.

Despite over 40 years of intensive study, the cause of the high incidence of motor neurone disease (MND) on Guam, and the relationship between this disease and MND seen in the rest of the world are still uncertain. We present a series of 45 cases of Guamanian MND, which reaffirm the clinical similarity between this disease and MND seen in other countries. However, the occurrence of MND among the indigenous Chamorros of Guam is distinguished by four factors: (i) high prevalence; (ii) frequent familial occurrence; (iii) co-occurrence with the parkinsonism-dementia complex (PDC); and (iv) association with an unusual and distinctive linear retinopathy termed Guam retinal pigment epitheliopathy (GRPE). These distinguishing factors were not present in four non-Chamorros who resided on Guam when their MND symptoms occurred. Pathologically, the classical features of MND were seen in Guamanian Chamorro cases including ubiquitin inclusions. Neurofibrillary tangles were frequently seen. The neurofibrillary tangles appeared in the same distribution as described in the PDC but, unlike classical PDC, they were not usually associated with cell loss and occurred less frequently. While neurofibrillary tangle formation and the clinicopathological syndrome of MND may occur in parallel, observations from this series suggest that pathologically classical MND on Guam may occur independently of neurofibrillary degeneration and the clinical features of PDC.

Rotavirus.

Rotavirus is the leading cause of nonbacterial gastroenteritis in young children and may infect neonates, older children, and adults as well. A large number of serogroups and types complicates the study, epidemiology, diagnosis, and prevention of rotaviral illness. Currently, routine diagnostic methods are satisfactory only for group A rotaviruses, and most commercially available kits in widespread use detect only this serogroup. Rehydration therapy and electrolyte management remain the primary treatment modalities. Recent vaccine developments offer the promise of a reduced burden of the viral pathogen worldwide.