Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Measures of expressions of love.

This study developed scales for Chapman's five expressions of love: quality time, receiving gifts, words of affirmation, physical touch, and acts of service (two dimensions). A total of 338 student respondents were surveyed resulting in 321 usable surveys (95%). Of this total, 177 were women and 144 men, with a median age of 24 yr.

Elemental propagation of calcium signals in response-specific patterns determined by environmental stimulus strength.

Plant cells can respond qualitatively and quantitatively to a wide range of environmental signals. Ca(2+) is used as an intracellular signal for volume regulation in response to external osmotic changes. We show here that the spatiotemporal patterns of hypo-osmotically induced Ca(2+) signals vary dramatically with stimulus strength in embryonic cells of the marine alga Fucus. Biphasic or multiphasic Ca(2+) signals reflect Ca(2+) elevations in distinct cellular domains. These propagate via elemental Ca(2+) release in nuclear or peripheral regions that are rich in endoplasmic reticulum. Cell volume regulation specifically requires Ca(2+) elevation in apical peripheral regions, whereas an altered cell division rate occurs only in response to stimuli that cause Ca(2+) elevation in nuclear regions.

Terminal core values associated with adolescent problem behaviors.

This study investigated the relationship of terminal core values to delinquency, substance use, and sexual behavior in a sample of 544 high school students. Students were classified according to their dominant value, and comparisons were made in regard to thirty-one indicators of delinquency, substance use, and sexual activity. As predicted by social control and strain theories, groups valuing fun/enjoyment and security were strongly identified with delinquency and substance use. Groups valuing self-respect, being well-respected, sense of accomplishment, warm relationships with others, and sense of belonging exhibited low frequency of delinquent behavior and substance use. Sense of belonging tended to be related to lower sexual activity, while warm relationships with others and being well-respected were associated with the most sexual activity. Gender differences in problem behaviors were also explored. The implications for theory and intervention are discussed, and values self-confrontation is proposed as a method for reducing problem behaviors.

Pulmonary giant cell carcinoma: pathological entity or morphological phenotype?

AIMS: To evaluate the morphological spectrum and clinical significance of giant cell carcinoma and to assess the frequency of tumour giant cell production in a consecutive series of primary (non-giant cell) lung tumours. METHODS AND RESULTS: Forty-six cases of giant cell carcinoma of the lung were collated from two centres over a 12-year period. Giant cell carcinoma was found to be associated with areas of clear cell carcinoma, spindle cell carcinoma and showed trophoblastic differentiation (syncytiotrophoblastic giant cells and beta-human chorionic gonadotrophin immunopositivity) in 57%, 34% and 26% cases, respectively. 'Pure' giant cell carcinoma was identified in five (11%) cases. Eleven of the tumours contained diastase-resistant periodic acid-Schiff positive material and were separately designated as giant cell adenocarcinomas. Areas of squamous cell and neuroendocrine differentiation (as determined by chromogranin A and Leu-7 immunopositivity) were not found. The median survival for giant cell carcinoma (excluding the giant cell adenocarcinomas) was 18 months. Median survival was not adversely affected by the extent of tumour giant cell formation or by the presence of trophoblastic differentiation. Of 200 consecutive non-small cell lung carcinomas, tumour giant cells constituting < 10% of the tumour were identified in 32% of adenocarcinomas and 26% of squamous cell carcinomas. CONCLUSIONS: The presence of tumour giant cells in lung carcinoma does not, in itself, indicate a more aggressive tumour type, Giant cell carcinoma of the lung does not appear to be a distinct entity but a morphological phenotype expressed by a heterogenous group of tumours. We support and advocate the use of an encompassing term such as 'pleomorphic' or 'anaplastic' carcinoma for those tumours showing no specific differentiation pattern but which express diverse morphological features such as giant cell formation, clear or spindle cell change.

Mesothelioma-binding antibodies: thrombomodulin, OV 632 and HBME-1 and their use in the diagnosis of malignant mesothelioma.

The aim of this study was to examine the expression of three putative mesothelioma-binding antibodies, thrombomodulin, OV 632 and HBME-1 in 42 malignant mesotheliomas (27 pleural and 15 peritoneal) and 32 pulmonary adenocarcinomas. Evaluation of their use in differentiating between the mesotheliomas and pulmonary adenocarcinomas was assessed. Thrombomodulin was expressed by 22 of 42 (52%) mesotheliomas but was seen in eight of 12 pure epithelial-type mesotheliomas of the pleura and in all four papillary epithelial peritoneal mesotheliomas. For pure epithelial mesotheliomas thrombomodulin was 75% sensitive. Only two of 32 pulmonary adenocarcinomas were immunoreactive yielding a 94% specificity for thrombomodulin. In comparison, OV 632 and HBME-1 showed 67% and 62% antibody sensitivity, respectively, for malignant mesothelioma but this was accompanied by low specificity (OV 632, 37%; HBME-1, 28%). Both OV 632 and HBME-1 are considered unsuitable for use in differentiating between mesotheliomas and pulmonary adenocarcinomas. We advocate the use of thrombomodulin as a mesothelioma-binding antibody in the standard panel of antibodies used in the evaluation of malignant mesothelioma.

A comparative immunohistochemical study of malignant mesothelioma and renal cell carcinoma: the diagnostic utility of Leu-M1, Ber EP4, Tamm-Horsfall protein and thrombomodulin.

Metastatic renal cell carcinoma has occasionally been reported to mimic malignant pleural mesothelioma. Morphologically, histochemically and immunohistochemically, similarities in the two tumours exist making their differentiation difficult, particularly in biopsy specimens. The aim of this study was to make a comparative immunohistochemical analysis of the two tumours by use of a panel of four antibodies (Leu M1; Ber EP4; thrombomodulin and Tamm-Horsfall protein). Their suitability in differentiating between the two tumours was assessed. We examined 20 cases of renal cell carcinoma and 20 cases of malignant pleural mesothelioma. On immunostaining with Leu M1, 14 of 20 renal cell carcinomas were positive, yielding 70% sensitivity and 95% specificity and one of 20 mesothelioma. In comparison, Ber EP4 antibody stained only seven of 20 of the renal cell carcinomas. In addition, it was noted that four tubulo-papillary pattern renal cell carcinomas stained positively with both anti-Leu M1 antibody and Ber EP4 antibody. Thrombomodulin immunostaining was present in 11 of 20 mesotheliomas (55% sensitivity and demonstrated 95% specificity) and one of 20 renal cell carcinomas. For epithelial mesotheliomas only, thrombomodulin staining was identified in 10 of 14 cases. In the differentiation of renal cell carcinoma from epithelial mesothelioma we recommend the use of Leu M1 and thrombomodulin as diagnostically useful markers. None of the antibodies used in this study was effective in distinguishing sarcomatoid renal cell carcinoma from sarcomatous mesothelioma. Tamm-Horsfall protein showed little diagnostic utility in differentiating the two tumours.

Selected values, perceived control, and reasons for choice.

The present study related terminal core values measured by the List of Values and perceived control with reasons for an exercise program. Data (N = 531) were derived from a national sample of treadmill owners. Principal components analysis confirmed Veroff, Douvan, and Kulka's five categories for the nine values; however, the hierarchy of needs previously postulated in the list was not substantiated. For this sample, self-fulfillment appears to be a type of self-gratification. These social cognitions, i.e., values, and perceived control appear to capture different domains and both are linked to reasons for choice.

p53 immunostaining suggests that uterine carcinosarcomas are monoclonal.

The histogenesis of carcinosarcomas has intrigued pathologists for a long time and remains unresolved. Two main theories have been put forward, one suggesting that they are monoclonal, another suggesting that they are biclonal. Our study examined p53 immunostaining in 17 uterine carcinosarcomas (mixed Müllerian tumours) and found positivity in five (30%). There was no disparity in immunostaining between the epithelial and the stromal components in any of the 17 tumours. This concordance in every tumour would be very unlikely if carcinosarcomas are biclonal. However, it would be expected if carcinosarcomas are monoclonal.

The diagnostic implications of variable cytokeratin expression in mesotheliomas.

Immunostaining for cytokeratin has a well-established diagnostic application in distinguishing sarcomatous mesotheliomas from sarcomas based on the premise that cytokeratin expression is common in mesotheliomas but very rare in sarcomas. However, the frequency of cytokeratin detection is highly dependent on the choice of antibody. The aim of this study was to examine the distribution of simple cytokeratins and stratified cytokeratins in 45 mesotheliomas of various types and to assess the diagnostic utility of a simple cytokeratin antibody, a stratified cytokeratin antibody, and a broad spectrum cytokeratin antibody with the aim of establishing the superiority of one for routine diagnostic use. Particular attention was paid to the potential utility of these antibodies in biopsy specimens. The broad spectrum cytokeratin antibody performed better than both the simple cytokeratin antibody (paired t-test: P < 0.01) and the stratified cytokeratin antibody (P < 0.01) as a diagnostic marker of mesothelioma and should be used in preference to the other two antibodies, particularly when considering small biopsy specimens.

The frequency of p53 immunostaining in asbestos-associated mesotheliomas and non-asbestos-associated mesotheliomas.

It has been suggested that asbestos might have an important role in the development of p53 mutations in mesotheliomas. The objective of this study was to examine asbestos-associated mesotheliomas and non-asbestos-associated mesotheliomas to establish whether the frequency of p53 immunostaining and, by implication, p53 gene mutation is related to asbestos exposure. Immunopositivity for p53 was found in seven (44%) of the 16 mesotheliomas examined. The frequency was approximately the same in both the asbestos-associated mesotheliomas and the non-asbestos-associated mesotheliomas. It is concluded that the frequency of p53 immunostaining in mesotheliomas and, by implication, the frequency of p53 gene mutation is probably not related to asbestos exposure.

p53 immunostaining in the distinction between benign and malignant mesothelial proliferations using formalin-fixed paraffin sections.

The distinction between reactive mesothelium and mesothelioma in pleural biopsy specimens is notoriously difficult, and conventional immunohistochemical markers have provided no relief. The object of this study was to examine the frequency of immunohistochemically detectable p53 overexpression in routinely processed, paraffin-embedded tissue from pleural mesotheliomas and from pleura showing reactive mesothelial hyperplasia, using a polyclonal antibody to formalin-resistant p53 epitopes, and to consider the diagnostic utility of this antibody in the distinction between mesothelioma and reactive mesothelium in pleural biopsy specimens. Immunostaining was enhanced by pepsin predigestion prior to the application of the primary antibody. Positivity occurred in 10/16 epithelial mesotheliomas, 9/19 biphasic mesotheliomas, 2/12 sarcomatous mesotheliomas but in none of 20 reactive pleura. Immunostaining was particularly intense in some of the biopsy specimens, which may be due to the rapidity with which these small pieces of tissue were fixed. In conclusion, this study suggests that p53 immunostaining can help to distinguish epithelial or biphasic mesothelioma from reactive mesothelial hyperplasia in formalin-fixed, paraffin-embedded pleural biopsy specimens.

Intermediate filament expression in mesotheliomas: leiomyoid mesotheliomas are not uncommon.

In this study we examined intermediate filament expression in 45 formalin-fixed mesotheliomas. Immunostaining for cytokeratin was found in 86%, for vimentin in 71%, and for desmin in 4%; none stained for glial fibrillary acidic protein or neurofilament. The two biphasic mesotheliomas which expressed desmin also expressed smooth muscle actin but were negative for myoglobin. This, together with the ultrastructural findings, was taken as unequivocal evidence of a leiomyoid form of mesothelioma which might easily be confused with leiomyosarcoma. Both of these tumours co-expressed cytokeratin, exemplifying the value of cytokeratin immunostaining in the distinction between mesothelioma and sarcoma. Consistent non-expression of glial fibrillary acidic protein in mesotheliomas may help to distinguish them from nerve sheath tumours.

An assessment of involucrin as a diagnostically useful immunohistochemical marker in lung tumours.

A previous report has described involucrin as a specific immunohistochemical marker of squamous differentiation in lung carcinomas. The aim of our study was to examine the expression of this antigen in a wide variety of lung tumours, with particular attention to its potential value in the typing of biopsy specimens. We found that immunostaining for involucrin was common in squamous carcinomas but was also found in adenocarcinomas, adenosquamous carcinomas, large cell carcinomas and carcinosarcomas. Small cell carcinomas, carcinoid tumours and mesotheliomas were negative. Contrary to previous claims, this marker appears to have little diagnostic utility in the typing of lung tumours.

Proportion of necrosis in transplanted murine adenocarcinomas and its relationship to tumor growth.

Percentage of necrosis has been measured in 30 murine adenocarcinoma transplants of known volume. It was found that changes in necrotic proportion during the growth of these particular tumors agree with the concept of a core of necrosis surrounded by a viable shell of constant thickness. This means that viable and necrotic fractions were proportional to the surface area of the tumor, which is consistent with the frequently observed superficial distribution of nutrient-supplying arteries. According to this model a plot of 1n tumor volume versus necrotic fraction is sigmoid and, if tumor growth is directly related to viable fraction, such a plot is not compatible with popular mathematical growth equations. However, the equation of von Bertalanffy gives a reasonable fit to the data here for total tumor growth, suggesting that growth too was proportional to surface area and in accord with a surface-related viable fraction and blood supply. An appropriate physiological explanation is given of necrosis development resulting from a superficial nutrient supply.