Impact of p16 status on pro- and anti-angiogenesis factors in head and neck cancers.

BACKGROUND: Head and neck cancers (HNC) are aggressive tumours. Overexpression of p16 in HNC correlates with human papilloma virus (HPV)-associated HNC that carry a better prognosis than HPV-negative tumours. Angiogenesis is an important factor in tumour progression. Our aim was to dissect the impact of p16 expression on angiogenesis factors in HNC. METHODS: Eighteen newly diagnosed HNC patients and controls were analysed. Eleven pro- and anti-angiogenesis factors were quantified using multiplex ELISA in HNC patients and controls. Angiogenesis factors were analysed in tumour tissue using immunohistochemistry. RESULTS: Circulating levels of endostatin (anti-angiogenesis factor) were higher in the HNC group compared with healthy donors. Interestingly, the pro-angiogenesis factors angiopoietin-1 and vascular endothelial growth factor (VEGF) were significantly higher in patients with p16-negative compared with p16-positive HNC. Moreover, the major source of VEGF in p16-positive HNC tissue was tumour stromal cells. In contrast, both tumour cells and stromal cells expressed VEGF in p16-negative tissue. CONCLUSIONS: We show that p16-negative tumours associate with increased circulating levels of pro-angiogenic VEGF and angiopoietin-1. Tissue expression of VEGF differs between p16-positive and p16-negative tumours. These findings may explain differences in the biological behaviour of p16-positive and p16-negative HNC. Better understanding of mechanisms by which the p16 status influences tumour angiogenesis may guide the development of targeted therapies.

Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival.

The aim of this study was to evaluate the expression of CC chemokine receptor 7 (CCR7) in squamous cell cancer of the tonsil with respect to patterns of spread, relapse-free, overall and disease-specific survival. Eighty-four patients with squamous cell cancer of the tonsil were identified. There was a male predominance of 3 : 1 and the median age at diagnosis was 53 (range 35-86) years. The median duration of follow-up was 33 (range 2-124) months. There was a significant association between CCR7 immunopositivity and synchronous cervical nodal metastasis in patients with tonsillar cancer (Spearman's correlation coefficient 0.564; P<0.001). Relapse-free (P=0.0175), overall (P=0.0136) and disease-specific (P=0.0062) survival rates were significantly lower in patients whose tumours expressed high levels of CCR7. On multivariate analysis, high-level CCR7 staining predicted relapse-free (hazard ratio 3.0, 95% confidence intervals 1.1-8.0, P=0.026) and disease-specific (hazard ratio 10.2, 95% confidence intervals 2.1-48.6, P=0.004) survival. Fifteen percent of patients with the highest level of tumour CCR7 immunopositivity relapsed with systemic metastases. These data demonstrated that CCR7 expression was associated with cervical nodal and systemic metastases from tonsillar cancers. High levels of CCR7 expression predicted a poor prognosis.

Pulmonary infection with Scedosporium prolificans in an immunocompetent individual.

We report a case of histologically confirmed Scedosporium prolificans pulmonary infection secondary to long-standing bronchiectasis that necessitated excision lung surgery. This case emphasizes the difficulties with the medical management of deep-seated fungal infections.

Completeness of excision and follow up cytology in patients treated with loop excision biopsy.

AIMS: To assess the relation between the grade and the status of follow up cytology, the completeness of loop excision biopsies with cervical intraepithelial neoplasia (CIN), and the findings at follow up cytology, as well as the differences between complete and incomplete exclusion, using the odds ratio. Treatment failure was assessed. METHODS: 1600 women with CIN (290 CIN1, 304 CIN2, 1006 CIN3) were followed for a minimum of six months and a maximum of 10 years. A database was created and comparisons performed. The mean age of the patients was 37 years. RESULTS: Excision was complete in over 84% of loops. Residual disease and recurrence of high grade dyskaryosis was more common in women with CIN 3 than CIN 2 or 1. No high grade dyskaryosis was seen in the fifth follow up smear in patients with CIN 1 and CIN 2. Residual, recurrent, and persistent disease was most common in patients with incompletely excised CIN at ectocervical and endocervical margins and deep margins of resection than in patients with completely excised CIN. The odds ratios were significantly higher in the women who had incomplete excision of CIN at ectocervical, endocervical, both ecto- and endocervical, and deep margins of resection compared with those with apparent complete excision of CIN lesions. One patient developed invasive squamous cell carcinoma 44 months after loop excision which showed CIN 3 invading endocervical crypts and extending to both ectocervical and endocervical margins of resection. CONCLUSIONS: At long term follow up, patients with CIN who have residual disease are at increased risk of persistent disease and should therefore be followed up regularly with cytology and colposcopy. The findings support national policy of returning women with treated CIN of any grade to normal recall after five years except for cases of CIN3 where excision was incomplete or equivocal. In these cases follow up with annual smear for 10 years is recommended.

Long term effects of tibolone on the genital tract in postmenopausal women.

OBJECTIVES: To assess the effects of six years tibolone therapy on the genital tract in postmenopausal women against matched voluntary controls. DESIGN: Prospective, non-randomised, open label study of the efficacy of tibolone. METHODS: Symptoms were assessed by questionnaires every six months. Assessment of genital tract cellular activity comprised annual vaginal smear and endometrial biopsy/smear in the tibolone group (n = 58) and vaginal smear alone in the control group (n = 55). As a recent protocol addition, transvaginal ultrasound assessment of endometrial thickness was performed in all women who gave consent. Endometrial biopsy was performed in control women if the endometrial thickness was > 5 mm. Karyopyknotic index and maturation index were calculated from the vaginal smears. RESULTS: The rate of amenorrhoea between six months and six years treatment was 90% in the tibolone group compared with 91% in the controls (P was not significant). There was improvement in reported vaginal symptomatology in the treatment group but not in the controls. Median endometrial thickness increased slightly in the tibolone treated group (3.2 mm tibolone vs 2.5 mm control; P < 0.05). There were no cases of cytologically proven endometrial stimulation in asymptomatic women in either group. Both vaginal karyopyknotic index and maturation index increased significantly in the tibolone treated group over six years, but not in the control group. CONCLUSIONS: Tibolone is effective at maintaining an inactive endometrium while providing oestrogenisation of the lower genital tract over a six year period.

Amiodarone pneumonitis: no safe dose.

Pneumonitis is a serious adverse effect of amiodarone therapy, which is related to the average daily dose. A case of pneumonitis is described which developed after exposure to a low dose of amiodarone. This challenges the concept that low dose amiodarone therapy is safe.

Clinical utility of the immunocytochemical detection of p53 protein in cytological specimens.

In the important cytopathological distinction between benign and malignant lesions, there is always a residue of suspicious cases which cannot be satisfactorily diagnosed. Overexpression of the p53 tumor suppressor gene product has been consistently correlated with p53 missense gene mutation and is associated with malignancy. Therefore, assessment of p53 expression may assist in the cytopathological diagnosis of malignancy. Immunohistological assessment of p53 expression has been performed on a prospective series of 1333 nongynecological cytological specimens in the setting of a teaching hospital group. Evaluation of p53 staining was performed without knowledge of cytological diagnosis. Resultant p53 expression data were correlated with cytological diagnosis and clinical information. Of the 999 assessable cases, 956 had a clear cytological diagnosis. In these, p53 overexpression occurred in 108 cases of which 86 were malignant lesions. Of the 848 p53-negative cases, 119 were in fact neoplasms. The false positives were predominantly (19 of 22) reactive mesothelial proliferations, and overexpression occurred in only a small proportion of cells. While the sensitivity of p53 overexpression is low (p53 overexpression only occurring in 41.9% of tumors), the overall specificity is 97%. In the 43 cytopathologically suspicious cases, 7 were p53 positive, all of which proved to be malignant. In this prospective unselected series, we have conclusively demonstrated a close correlation between overexpression of p53 protein and neoplasia. Furthermore, we have shown the possible utility of p53 immunostaining in cytopathology. While there are important technical caveats and some cytological specimens are suboptimal for immunostaining, the data indicate that assessment of p53 is a valuable adjunct to morphological assessment in the analysis of cytopathologically suspicious cases.

A study of the effect of tibolone on the vagina in postmenopausal women.

Tibolone is a synthetic compound with weak oestrogenic, progestagenic and androgenic properties. It does not appear to stimulate the endometrium, and therefore has appeal to the postmenopausal woman as a 'bleedfree' form of hormone replacement therapy (HRT). In the present study the vaginal cytological findings and symptoms were evaluated in 100 recently postmenopausal women, 50 of whom were started on tibolone 2.5 mg daily and 50 of whom received no medication. After 2 years in the tibolone group, cytological assessment showed a significant increase in the karyopyknotic index (P < 0.001) and maturation value (P < 0.01) whereas there was no change in the control group. Significant symptomatic improvement occurred in vaginal dryness (P < 0.001), dyspareunia (P < 0.001), sexual enjoyment (P < 0.001) and libido (P < 0.05). It is therefore concluded that tibolone has a significant oestrogenic effect on the vagina as demonstrated by vaginal cytology. In addition, improvement in the symptoms of vaginal dryness, dyspareunia, sexual enjoyment and libido occurs.

Relapse and recovery: five to ten year follow-up study of chemically dependent physicians--the Georgia experience.

Of 100 physicians who entered into a continuing care contract during a five-year period with the Impaired Physicians Program of the Medical Association of Georgia, seventy-seven have maintained documentable abstinence from all mood-altering substances. One physician was lost to follow-up. Twenty-two relapsed, eighteen of whom have undergone another treatment for chemical dependence. Only one physician in the relapse group has been involved in a pattern of chronic relapsing behavior.

The immunolocalization of protein gene product 9.5 using rabbit polyclonal and mouse monoclonal antibodies.

In order to assess the potential of protein gene product (PGP) 9.5 as a marker of the nervous and neuroendocrine systems, we examined its immunolocation in human, rat and guinea-pig tissues, using a rabbit polyclonal antiserum and two new mouse monoclonal antisera, I3C4 and 3IA3. Our results demonstrate immunoreactive PGP 9.5 in neurons and nerve fibres at all levels of the central and peripheral nervous system, in many neuroendocrine cells, in part of the renal tubule, in spermatogonia and Leydig cells of the testis, and in ova and in some cells of the pregnant and non-pregnant corpus luteum. In routinely processed tissues, standard immunohistochemical techniques using the polyclonal antibody demonstrated peripheral nerve fibres of all sizes with striking clarity.

The Medical Association of Georgia's Impaired Physicians Program. Review of the first 1000 physicians: analysis of specialty.

Risk factors for the disease of chemical dependence, or addiction to alcohol and/or drugs, for physicians have not been clearly defined. Yet chemical dependence is believed to be a leading occupational hazard for physicians. This study compares the specialties of a population of physicians assessed for the presence of impairment (study group, N = 1000) with the distribution of specialties for all US physicians. Only 21 of the total were found to be free of impairment from chemical dependence or psychiatric disease, while 920 physicians (92.0%) had a primary diagnosis of chemical dependence, and 59 (5.9%) had a major psychiatric illness. Anesthesia and family and general practice were found to be overrepresented in the population under study, as compared with all US physicians. There were significant differences between the study group and all US physicians with respect to age, sex, and practice activity status. The authors urge these apparent high-risk specialties, as well as the medical profession itself, to develop control or prevention strategies that will reduce risk for chemical dependence through education, early identification, intervention, and treatment of those individuals with the disease.