Bistable Perception Is Biased by Search Items but Not by Search Priming.

During visual search, selecting a target facilitates search for similar targets in the future, known as search priming. During bistable perception, in turn, perceiving one interpretation facilitates perception of the same interpretation in the future, a form of sensory memory. Previously, we investigated the relation between these history effects by asking: can visual search influence perception of a subsequent ambiguous display and can perception of an ambiguous display influence subsequent visual search? We found no evidence for such influences, however. Here, we investigated one potential factor that might have prevented such influences from arising: lack of retinal overlap between the ambiguous stimulus and the search array items. In the present work, we therefore interleaved presentations of an ambiguous stimulus with search trials in which the target or distractor occupied the same retinal location as the ambiguous stimulus. Nevertheless, we again found no evidence for influences of visual search on bistable perception, thus demonstrating no close relation between search priming and sensory memory. We did, however, find that visual search items primed perception of a subsequent ambiguous stimulus at the same retinal location, regardless of whether they were a target or a distractor item: a form of perceptual priming. Interestingly, the strengths of search priming and this perceptual priming were correlated on a trial-to-trial basis, suggesting that a common underlying factor influences both.

Evidence for distinct mechanisms underlying attentional priming and sensory memory for bistable perception.

Attentional selection in visual search paradigms and perceptual selection in bistable perception paradigms show functional similarities. For example, both are sensitive to trial history: They are biased toward previously selected targets or interpretations. We investigated whether priming by target selection in visual search and sensory memory for bistable perception are related. We did this by presenting two trial types to observers. We presented either ambiguous spheres that rotated over a central axis and could be perceived as rotating in one of two directions, or search displays in which the unambiguously rotating target and distractor spheres closely resembled the two possible interpretations of the ambiguous stimulus. We interleaved both trial types within experiments, to see whether priming by target selection during search trials would affect the perceptual outcome of bistable perception and, conversely, whether sensory memory during bistable perception would affect target selection times during search. Whereas we found intertrial repetition effects among consecutive search trials and among consecutive bistable trials, we did not find cross-paradigm effects. Thus, even though we could ascertain that our experiments robustly elicited processes of both search priming and sensory memory for bistable perception, these same experiments revealed no interaction between the two.

Photoacoustic image patterns of breast carcinoma and comparisons with Magnetic Resonance Imaging and vascular stained histopathology.

Photoacoustic (optoacoustic) imaging can visualize vasculature deep in tissue using the high contrast of hemoglobin to light, with the high-resolution possible with ultrasound detection. Since angiogenesis, one of the hallmarks of cancer, leads to increased vascularity, photoacoustics holds promise in imaging breast cancer as shown in proof-of-principle studies. Here for the first time, we investigate if there are specific photoacoustic appearances of breast malignancies which can be related to the tumor vascularity, using an upgraded research imaging system, the Twente Photoacoustic Mammoscope. In addition to comparisons with x-ray and ultrasound images, in subsets of cases the photoacoustic images were compared with MR images, and with vascular staining in histopathology. We were able to identify lesions in suspect breasts at the expected locations in 28 of 29 cases. We discovered generally three types of photoacoustic appearances reminiscent of contrast enhancement types reported in MR imaging of breast malignancies, and first insights were gained into the relationship with tumor vascularity.

Timing of radiotherapy in breast-conserving therapy: a large prospective cohort study of node-negative breast cancer patients without adjuvant systemic therapy.

BACKGROUND: To investigate the issue of timing of radiation therapy (RT) after lumpectomy in relation to recurrences and outcome. METHODS: Analysis was done on 1107 breast-conserving therapies (BCT) with 1070 women, all without lymph node metastasis and without any adjuvant systemic therapy. Timing was defined as time from lumpectomy till RT. Patients were categorised into tertiles: <45 days, 45-56 days, and 57-112 days. RESULTS: Local control did not show a difference between the tertiles. The distant metastasis-free survival as well as the disease-specific survival showed a decreased outcome starting the RT to early after the lumpectomy. CONCLUSION: The results of this cohort study further refines the hypothesis that timing of RT in BCT might have an impact on outcome. It suggests that a randomised trial in timing of RT in BCT seems necessary to give a definite answer.

Papillary carcinoma in struma ovarii: an unusual presentation.

Struma ovarii is the presence of thyroid tissue as the major cellular component in an ovarian tumour. Papillary carcinoma in struma ovarii is exceptionally rare. We report a case of papillary carcinoma in struma ovarii in a postmenopausal 51-year-old female who initially presented clinically with hyperthyroidism. Serology, however, did not confirm hyperthyroidism. During a re-admission to our hospital later that year she appeared to have had periods of postmenopausal vaginal haemorrhage. An abdominal mass was located by radiography and pathological investigation revealed a papillary carcinoma in struma ovarii. Some striking features of this unusual presentation of importance to the internal medicine physician are discussed.

Effects of fulvestrant alone or combined with different steroids in human breast cancer cells in vitro.

OBJECTIVES: Fulvestrant is an estrogen receptor (ER) antagonist that binds, blocks and degrades the estrogen receptor and is currently used in adjuvant treatment in postmenopausal women with ER-positive breast cancer as an alternative for tamoxifen. As an antagonist, it may induce or aggravate climacteric symptoms. In order to alleviate these symptoms, one could consider hormone therapy. The objective of this study was to analyze the effect of fulvestrant alone or in combination with different steroids in human breast cancer cells in vitro, and to demonstrate whether these steroids will compromise the efficacy of fulvestrant in ER-positive breast cancer cells. METHODS: We performed experiments in vitro with various hormone therapy preparations (estradiol (E2), dihydrodydrogesterone (DHD) and tibolone) at a concentration of 10(-6) mol/l alone or combined with fulvestrant in different breast cancer cell lines, ER-positive and ER-negative. After an incubation of 144 h, proliferation and apoptosis were measured. The first was measured by quantification of the expression of cyclin D1 mRNA, the latter by the Nicoletti fragmentation assay. RESULTS: This in vitro study revealed clear differences in results when various hormone therapy preparations, alone or combined with fulvestrant, are added to ER-positive and ER-negative breast cancer cell lines. CONCLUSIONS: Our study demonstrated that fulvestrant, an ER antagonist used in the treatment of ER-positive breast cancer, combined with E2 and DHD or in combination with tibolone, is not compromised in its efficacy in inducing apoptosis in ER-positive breast cancer cell lines in vitro.

Rapid and reliable assessment of volume percentage of epithelium in borderline and invasive ovarian tumors.

OBJECTIVE: To analyze factors determining intraobserver and interobserver reproducibility of stereology in borderline and invasive ovarian tumors. STUDY DESIGN: Fast and simple assessment of VPE was possible by using a highly automated interactive video overlay system suitable for application in a routine pathology laboratory. The point distance of a Weibel grid and the number of fields of vision per area of interest required to obtain good reproducibility were investigated. In addition, intraobserver and interobserver reproducibility was assessed, and the results of the improved technique were compared to those of the classical method. RESULTS: The experiments showed that intraobserver and interobserver variations in volume percentage of epithelium (VPE) assessments in a given case were caused mainly by high field-to-field variation and not so much by differences in the precision of assessment in a single field of vision. Therefore, many fields but only few points per field need to be measured to obtain, in a short time, a precise estimate of VPE in the measurement area of a tumor. From these results, an optimized protocol for VPE assessment was constructed. Using this protocol, nine observers independently assessed VPE in seven cases. Counting only one point in each of 100 systematically randomly sampled fields of vision (corresponding to a point distance of +/- 560 microns) yielded high intraobserver reproducibility (coefficient of variation [CV], 4%; R, .99; range, 0.98-1.00) and interobserver reproducibility (CV, 6%; R, .98; range, 0.97-1.00) in a short time. Assessment of one case took approximately three minutes, and the observers experienced the work as pleasant. CONCLUSION: VPE assessed with systematic random sampling, using a grid with one point per field of vision and counting 100 hits, yields an inexpensive, fast and highly reproducible measure of an important prognostic variable in ovarian tumors. This assessment can be performed easily in a routine pathology laboratory.

Quantitative prognostic features in FIGO I ovarian cancer patients without postoperative treatment.

To identify FIGO I ovarian cancer patients at high risk, prognostic values of quantitative pathological features (volume percentage of epithelium, mitotic activity index, mean (MNA) and standard deviation of nuclear profile area, and volume-weighted mean nuclear volume (MNV) have been investigated in comparison with clinical features, histological grade, and type in 102 adequately staged patients with FIGO Ia, Ib, and Ic ovarian cancer of the common epithelial types. None of these patients received any postoperative treatment. Overall survival of patients alive and well was 78%, and 90% were alive. Of the clinical features, FIGO substage was the strongest prognosticator (Mantel-Cox = 7.2, p = 0.03, hazard ratio (HR) = 4.6). Histologic grade had significant prognostic value as well (Mantel-Cox = 9.7, p = 0.008, HR = 5.9), but histologic type did not. MNA and MNV were the strongest single prognostic factors for overall survival (Mantel-Cox = 12.3 for both; p = 0.0004 and 0. 0005). If MNA 55.6 micron2, 6-year overall survival was 69%. For MNV 460 micron2, 6-year overall survival was 70%. A multivariate combination of MNA and FIGO (early cancer of the ovary prognostic score, ECOPS) had the strongest prognostic value (p < 0.0001 and Mantel-Cox value = 22.8, HR = 29.2). If ECOPS 5.4 (n = 36), 6-year overall survival was 54%. The results from this and earlier studies emphasize the strong prognostic value of easy to assess and highly reproducible morphometric nuclear features in ovarian tumors and offer a useful instrument for the definition of patient groups for future clinical trials.

Intratumor heterogeneity of morphometric and stereologic variables in primary ovarian tumors and their omental metastatic deposits.

OBJECTIVE: To compare quantitative pathologic variables assessed in primary ovarian tumors and metastatic tumor deposits in the omentum and compare their prognostic value. STUDY DESIGN: In 29 cases of advanced ovarian cancer the mean nuclear area (MNA), volume-weighted mean nuclear volume (vv), volume percentage epithelium (VPE) and mitotic activity index (MAI) were assessed in both the primary ovarian tumor and its metastatic deposits in the omentum. Differences were evaluated using the Wilcoxon rank sum test for paired observations, and coefficients of variation were calculated in each case over the values obtained from the tumor in the ovary and omentum. RESULTS: Intraobserver and interobserver reproducibility of MNA, VPE and MAI were all good to very good except for the interobserver reproducibility for vv, which was moderate. MNA and vv, correlated well, both in the primary ovarian tumor (r = .88) and omental metastasis (r = .87). No significant differences were found between the assessments of MNA, vv, and MAI in the primary ovarian tumor and its omental metastasis, whereas significant differences were found for VPE. However, in some patients the nuclei tended to be larger and the VPE lower in the omental metastasis than in the primary ovarian tumor. No important impact of the origin of tumor tissue was reflected in the prognostic value of the nuclear features. Patients were grouped prognostically differently for the assessment of MAI and VPE in the primary ovarian tumor and its omental metastasis. CONCLUSION: Quantitative pathologic variables for prognostic purposes are best assessed in the primary ovarian tumor. Measurements in the metastatic deposits may be helpful in understanding processes of metastasis in advanced ovarian cancer.

Minimum spanning tree analysis in advanced ovarian carcinoma. An investigation of sampling methods, reproducibility and correlation with histologic grade.

OBJECTIVE: To investigate sampling methods and reproducibility of minimum spanning tree (MST) variables in advanced ovarian cancer and their discriminative power for histologic grade. STUDY DESIGN: For the methodologic investigation, 30 cases of advanced ovarian cancer of the common epithelial types were used. These cases were equally distributed over the three histologic grades according to independent, "blind" assessments by three observers: well (n = 10), moderately (n = 10) and poorly (n = 10) differentiated. Additionally, the discriminative power of the MST variables for histologic grade was assessed in 64 cases (double-blind agreement upon grade by two observers). Measurements were performed on hematoxylin-eosin-stained tumor sections. In each field of vision the centers of gravity of tumor cell nuclei were interactively marked using a digitizing video overlay system, and an MST was computed. From each MST the number of points, total line length, average line length, minimum line length, maximum line length and percentage of points with one, two three and four neighbors were obtained. Optimal performance (coefficient of error < 5%) of the method was established when the MST was constructed in 12 systematically randomly selected fields of vision at a final magnification of 1,900x. RESULTS: Intraobserver and interobserver reproducibility showed good correlation coefficients for most MST variables. Univariate analysis revealed that total, average and minimum line length were significantly different between the three histologic grades. With a jacknifed stepwise discriminant analysis an overall correct classification of 75% for the three histologic grades was achieved in 64 cases, using the average line length, standard deviation of the line length and total line length. CONCLUSION: MST syntactic structure analysis offers an easy, fast and very reproducible technique that may be of help in objective grading of advanced ovarian cancers. Further studies are under way to investigate the prognostic value of MST analysis in advanced ovarian cancer.

Influence of boundary effects on minimum spanning tree features. A computer simulation.

OBJECTIVE: To assess the influence of boundary effects on quantitative data derived from the minimum spanning tree (MST). STUDY DESIGN: In a computer simulation, 10 patterns of points (resembling populations of nuclei in tumor tissue) were generated, ranging from completely regular to very irregular. This allowed for assessing the influence of boundary effects in populations with different degrees of disorder. A stepwise reduction of the size of the sampling window enabled the analysis of the influence of boundary effects at different sample sizes (from 1,024 down to 9 points). RESULTS: Both the mean and coefficient of variation of all features remained rather constant with decreasing sample size down to a sample size of 64 points per MST. CONCLUSION: Based on this model, it is concluded that boundary effects have only a minor influence on the outcome of MST features when the sample size is larger than 64 points.

Treatment of childhood Hodgkin's disease with ABVD without radiotherapy.

Seventeen previously untreated children with Hodgkin's disease were treated with six courses of the combination adriamycin, bleomycin, vinblastine, and DTIC (ABVD), without radiotherapy, from 1984-1987. In all patients, complete remission was attained. After a median follow-up period of 73.5 months (range 59-98 months) five patients had a relapse after 4, 5, 11, 21, and 34 months, respectively, from attainment of complete remission. In 12 patients with stages I and II, two relapses occurred. Three out of five patients with stage III and stage IV developed a relapse. Based upon these results, we conclude that ABVD might be an appropriate treatment for newly diagnosed children with Hodgkin's disease stages I and II. However, for children with stages III and IV more intensive treatment is needed. Radio-therapy should be withheld for children with refractory disease, residual disease, or relapse.

Value of quantitative pathological variables as prognostic factors in advanced ovarian carcinoma.

AIMS: To evaluate correlations among clinical, pathological, morphometric, stereological, and DNA flow cytometric variables and their prognostic value in advanced ovarian cancer. METHODS: Tissue was collected from 180 patients with advanced ovarian cancer. All 180 had undergone debulking surgery and were being treated with cisplatin. Long term follow up was available for all patients. The mitotic activity index (MAI), volume % of epithelium (VPE), mean nuclear area (MNA), standard deviation of the nuclear area (SDNA), estimates of volume weighted mean nuclear volume (nu v), and variables obtained from minimum spanning tree (MST) analysis were assessed in the least differentiated tumour section in each case. DNA flow cytometry was also performed. RESULTS: Quantitative pathological features differed significantly with respect to histological grade. The MAI, MNA, SDNA, and the number of points connected to three neighbours differed significantly among the different DNA ploidy groups. The VPE and number of points connected to two or three neighbours differed significantly between FIGO stages III and IV. Fifty two (29%) patients survived. FIGO stage, residual disease and SDNA had prognostic significance on both univariate and multivariate survival analysis. In patients with FIGO III stage disease and residual tumour nodes < or = 2 cm in diameter (67 patients, 29 (43%) survivors) a prognostic index was established based on SDNA and of the line length of the MST. The median survival time was not reached in a subgroup of patients with favourable prognosis (overall survival 57%). Median survival was 32 months for patients with an unfavourable index score (overall survival 28%). CONCLUSION: Morphometric variables have important additional value in predicting prognosis in patients with advanced ovarian cancer.

An evaluation of prognostic factors in advanced ovarian cancer.

A summary is presented of currently available prognostic factors in advanced ovarian cancer of the common epithelial types. The emphasis is on the most promising clinical, classical pathological, biochemical, immunohistochemical, molecular biological and quantitative pathological factors.

The significance of differences in prognostic value of quantitative pathologic features in FIGO stage III and IV serous adenocarcinoma of the ovary between a group of Danish patients and other groups.

Previous studies have shown DNA cytometric, morphometric and stereologic features to be strong prognosticators in advanced ovarian cancer. However, in one Danish study a new stereologic parameter, the volume-weighted mean nuclear volume ( nuv), was not of prognostic significance. In that study, sampling was performed in the whole tumor section, contrary to that in other studies where measurements were performed in the worst differentiated area (the measurement area). The aim of the present investigation was, therefore, to confirm or reject the hypothesis that random estimates of nuclear {ovbar|nu}v over the whole tumor, rather than in the measurement area, are the cause for the lack of prognostic value in the Danish patients. Additionally, the mitotic activity index (MAI), volume percentage of epithelium (VPE), mean nuclear area (MNA) and standard deviation of the nuclear area (SDNA), which have proved to be of strong prognostic significance in advanced ovarian cancer, were assessed in the measurement area. The MAI, VPE, MNA, SDNA and nuclear {ovbar|nu}v were well reproducible, but prognostically not significant. This study thus excludes differences in microscopic sampling as an explanation for the contrasting findings in the Danish study and other ones. Possible remaining explanations are: (i) differences in sampling at the macroscopic level; (ii) fixation differences; (iii) patient selection bias; and (iv) geographic differences in the degree of malignancy of advanced ovarian cancer in Denmark and the Netherlands. As to the latter, in comparison with two Dutch studies the Danish ovarian cancers in this series had residual disease <2 cm (33% vs 50%) less often, were less often well differentiated (4% vs 19%), and less often had favorable morphometric characteristics (6% vs 15%). Further studies are required to analyze whether other Danish patient groups with advanced ovarian cancers differ from the Dutch.

Volume-weighted mean nuclear volume and nuclear area in advanced ovarian carcinoma. An investigation of sampling methods, sample size and reproducibility.

The influence of sampling issues on the reproducibility of volume-weighted mean nuclear volume (mean v) and mean nuclear area (MNA) assessments in patients with International Federation of Gynecology and Obstetrics stage III and IV ovarian carcinoma was evaluated. Ten cases representing the whole range of MNA values were selected from a population of 131 cases. The MNA and mean v of the same tumor cell nuclei were determined in one session by switching between the stereologic module and the morphometric module of the video overlay program used. For both MNA and mean v in one series of measurements, tumor nuclei were sampled from the whole tumor area and in a second series from the most poorly differentiated part (the measurement area) in each section, thus giving four series of measurements per case. For all four series, 500 nuclei were point sampled from approximately 100 systematically randomly selected fields of vision, using the automated scanning stage controlled by the morphometry program. These large samples, containing 500 nuclei for each case, were regarded as representative in each case. To investigate the susceptibility of MNA and mean v to variance at lower sampling levels (fields, nuclei), a nested analysis of variance was performed. Then the influence of sample size and sampling method was evaluated by drawing subsets from these 500 nuclei in each case in three different ways (cluster, systematic or random) with four different sample sizes (50, 100, 125, 250). It was shown that for MNA assessed in the measurement area, the variance between patients contributed the most to the total variance.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor uptake of intravenously administered radiolabeled antibodies in ovarian carcinoma patients in relation to antigen expression and other tumor characteristics.

To study factors that possibly influence the heterogeneous tumor uptake of radiolabeled antibodies, tissues from 34 ovarian-carcinoma patients were obtained 2 to 8 days after i.v. injection with radiolabeled murine OV-TL3 or chimeric MOv18 (cMOv18). The tumor uptake and the ratio of tumor to normal tissue (T/NT) were studied in relation to the histopathological classification, prior treatment, site of tumor, time interval, antigen expression, volume percentage of (malignant) epithelium in the tumor tissue, and the size of the tumor. The results of immunoscintigraphy were also included. In addition, autoradiography using storage phosphor technology was performed on tissue sections from patients injected with iodine-labeled cMOv18. Tumor uptake varied largely, not only between patients, but also between tumor deposits within the same patient. Uptake of OV-TL3 F(ab')2 was higher than of cMOv18 F(ab')2, but the T/NT ratios were similar. The antibody uptake was positively correlated with the pattern of antigen expression and inversely correlated with the time interval between injection and surgery. No correlation was observed with any of the other factors studied. The visibility with immunoscintigraphy was related to the size of the detected lesion, but not to the other factors studied. Autoradiography showed that antibodies preferentially localized in areas with cancer cells, which were immunohistochemically positive for MOv18. In areas with weak antigen expression, autoradiography revealed less activity. The antigen expression by the tumor is an important factor for estimation of the tumor uptake of radiolabeled antibodies.

Peripheral primitive neuroectodermal tumour and extra-osseous Ewing's sarcoma; a histological, immunohistochemical and DNA flow cytometric study.

Although peripheral primitive neuroectodermal tumour (pPNET) and extra-osseous Ewing's sarcoma (EES) are thought to be closely related neoplasms, their clinical behaviour differs considerably. To determine the clinical relevance of the Schmidt classification scheme for differentiating pPNET and EES, 20 tumour specimens of poorly differentiated round cell tumours were evaluated. In addition, the diagnostic value of several neural markers and the prognostic value of quantitative morphological variables (DNA ploidy, S-phase fraction, and the mitotic activity) were assessed. Homer-Wright rosettes were present in 9 tumours. Neuron specific enolase (NSE) was expressed in 11 tumours, 8 of which expressed a second neural marker (CD57, S100, or neurofilament). According to the Schmidt classification, 11 pPNET and 5 EES were distinguished. HBA-71 was exclusively expressed in pPNET and EES. The remaining tumours were classified as sarcoma not otherwise specified (n = 2), rhabdomyosarcoma (n = 1), and desmoplastic tumour with divergent differentiation (n = 1). EES611 patients fared significantly better than the pPNET patients (100% versus 42% 5-year survival). Neither DNA ploidy nor S-phase fraction assessed in 12 evaluative histograms (9 pPNET and 3 EES), nor mitotic activity yielded information of additional prognostic value. On the basis of this study and the Schmidt classification scheme, it can be concluded that if the diagnosis of EES and pPNET is based on light microscopy (Homer-Wright rosettes) and/or immunohistochemistry (at least two neural markers, i.e. NSE, S-100, CD57, and neurofilament), the classification provides important clinical information. Furthermore, positivity for HBA-71 is helpful in differentiating pPNET and EES from all other small round cell tumours.