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Background The effective detection and monitoring of potentially malignant oral lesions (PMOL) are critical to identifying early‐stage cancer and improving outcomes. In the current study, the authors described cytopathology tools, including machine learning algorithms, clinical algorithms, and test reports developed to assist pathologists and clinicians with PMOL evaluation. Methods Data were acquired from a multisite clinical validation study of 999 subjects with PMOLs and oral squamous cell carcinoma (OSCC) using a cytology‐on‐a‐chip approach. A machine learning model was trained to recognize and quantify the distributions of 4 cell phenotypes. A least absolute shrinkage and selection operator (lasso) logistic regression model was trained to distinguish PMOLs and cancer across a spectrum of histopathologic diagnoses ranging from benign, to increasing grades of oral epithelial dysplasia (OED), to OSCC using demographics, lesion characteristics, and cell phenotypes. Cytopathology software was developed to assist pathologists in reviewing brush cytology test results, including high‐content cell analyses, data visualization tools, and results reporting. Results Cell phenotypes were determined accurately through an automated cytological assay and machine learning approach (99.3% accuracy). Significant differences in cell phenotype distributions across diagnostic categories were found in 3 phenotypes (type 1 [“mature squamous”], type 2 [“small round”], and type 3 [“leukocytes”]). The clinical algorithms resulted in acceptable performance characteristics (area under the curve of 0.81 for benign vs mild dysplasia and 0.95 for benign vs malignancy). Conclusions These new cytopathology tools represent a practical solution for rapid PMOL assessment, with the potential to facilitate screening and longitudinal monitoring in primary, secondary, and tertiary clinical care settings., A point‐of‐care oral cytology tool has been developed for the noninvasive detection and monitoring of potentially malignant oral lesions. The distribution of cell phenotypes identified by machine learning and a cytology‐on‐a‐chip approach provides useful information as part of the assessment of oral lesions, with improved interpretability, calibration, and generalizability compared with conventional methods.

A possible link between protein kinase C (PKC) and P-glycoprotein (P-gp)-mediated-multidrug resistance (MDR) was assumed from studies on MDR cell lines selected in vitro. The functional relevance of PKC for the MDR phenotype remains unclear, and the involvement of a particular PKC isozyme in clinically occurring drug resistance is not known. Recently, we have demonstrated significant correlations between the expression levels of the PKC eta isozyme and the MDR1 or MRP (multidrug resistance-associated protein) genes in blasts from patients with acute myelogenous leukaemia (AML) and in ascites cell aspirates from ovarian cancer patients. To extend these findings to further types of human tumours we analysed specimens from 64 patients with primary breast cancer for their individual expression levels of several MDR-associated genes (MDR1, MRP, LRP (lung cancer resistance-related protein), topoisomerase (Topo) II alpha/IIbeta, cyclin A and the PKC isozyme genes (alpha, beta1, beta2, eta, theta, and mu) by a cDNA-PCR approach. We found significantly enhanced mean values for MRP, LRP and PKC eta gene expression, but significantly decreased Topo II alpha and cyclin A gene expression levels in G2 tumours compared with G3. Remarkably, significant positive correlations between the MDR1, MRP or LRP gene expression levels and PKC eta were determined: MDR1/PKC eta (rs = +0.6451, P < 0.0001) n = 62; MRP/PKC eta (rs = +0.5454, P < 0.0001) n = 63; LRP/PKC eta (rs = +0.5436, P < 0.0001) n = 62; MRP/LRP (rs = +0.7703, P < 0.0001) and n = 62, MDR1/MRP (rs = +0.5042, P < 0.0001) n = 62. Our findings point to the occurrence of a multifactorial MDR in the clinics and to PKC eta as a possible key regulatory factor for up-regulation of a series of MDR-associated genes in different types of tumours. Images Figure 1

We report on a 60 year old patient with a 6 month history of vulval pruritus and an erosive vulval lesion which was mistaken for lichen sclerosus et atrophicus. Histologically the diagnosis of an amelanotic malignant melanoma of the vulva was established. We review the literature about this rare malignant tumor.

AEZS-115 (Aeterna Zentaris GmbH, Frankfurt/M, Germany) is an orally active peptidomimetic antagonist of gonadotropin-releasing hormone (GnRH). In various tumors, an autocrine growth-promoting loop has been described for GnRH. The current study evaluates the antitumor activity and mechanism of action of AEZS-115 in models of ovarian and endometrial cancer.Human A2780, Acis2780, OAW-42, Ovcar-3, SKOV-3, Hec1A and Ishikawa cells were analyzed for GnRH receptor expression by reverse transcription polymerase chain reaction (RT-PCR). These cell lines were incubated with AEZS-115 at 1, 10 and 100 μM for 24 h, 48 h, and 72 h and the number of viable cells was determined. Fluorescence activated cell sorting (FACS) cell cycle analyses were performed with increasing concentrations of AEZS-115. Co-treatment experiments of cancer cells with GnRH antagonist cetrorelix and peptidomimetic GnRH antagonist AESZ-115 were carried out.A2780, Acis2780, OAW-42, Ovcar-3, SKOV-3, Hec1A and Ishikawa cells expressed GnRH receptors as demonstrated by RT-PCR. GnRH antagonist AEZS-115 inhibited growth of all cell lines in a dose- and time-dependent manner. Half maximal inhibitory concentration (IC(50)) values at 48 h of incubation were between 7 and 17.5 μM and for 72 h between 4.5 and 12.5 μM. IC(50) values for ovarian and endometrial cancer cells were rather similar. These results were obtained by tetrazolium salt [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT] assay and confirmed by additional crystal violet staining. Cell cycle FACS analysis revealed that AEZS-115 dose-dependently increased the fraction of apoptotic cells. Co-treatment experiments carried out with AEZS-115 and peptidic GnRH-antagonist cetrorelix suggest that the antitumor effect of AEZS-115 is not mediated by blockade of the GnRH receptor.GnRH antagonist AEZS-115 exhibited substantial antitumor activity in ovarian as well as endometrial cancer cell lines. However, this antitumor effect was not mediated by the tumoral GnRH receptors. To identify the mechanism of action of this compound, further research is warranted. Its in vitro antitumor activity makes AEZS-115 a promising candidate for in vivo studies of ovarian and endometrial cancer.

The polycomb group (PcG) proteins form chromatin-modifying complexes that are commonly deregulated in cancer. The PcG protein BMI-I is overexpressed by various tumours and thus may contribute to malignant transformation. The current study investigated the expression of BMI-I in human specimens of breast, ovarian, endometrial and cervical cancer.Expression of BMI-I was evaluated in human ovarian cancer samples by Western blot analysis and immunohistochemistry (IHC) and compared to healthy ovarian tissue. BMI-I expression in human specimens of breast, endometrial and cervical cancer was evaluated by IHC and then compared with the respective benign tissues.BMI-I was significantly (p0.05) overexpressed in human breast, ovarian, endometrial and cervical cancer specimens as compared to benign controls. BMI-I expression was also more pronounced in the ovarian cancer samples as demonstrated by Western blot analysis. In human breast cancer samples, BMI-I expression was most pronounced in the invasion front of the tumour.The current study showed for the first time that the BMI-I protein is significantly overexpressed in ovarian, endometrial and cervical cancer and may thus be a potential target for novel antitumor therapies.

Fifteen-30% of breast cancer patients develop central nervous system (CNS) metastases. The most potent drugs for the treatment of breast cancer like taxanes, anthracyclines and trastuzumab have limited efficacy for brain metastases. No standardized therapy has yet been established for this condition. Drugs with proven efficacy in the CNS and which are commonly used for primary brain tumors were applied. We evaluated the capacity of these drugs to inhibit breast tumor cell growth in vitro.Twelve primary cell cultures of pulmonary/pleural metastases of breast cancer and 3 commercially available cell lines were used for non-radioactive cytotoxicity assays to evaluate the efficacy of 3 different concentrations of Topotecan, Cisplatin, Nimustine, Vincristine, Irinothecan, Caelyx (pegylated liposomal Doxorubicin) and Etoposide.Topotecan, Cisplatin, Caelyx and Vincristine showed significantly higher cytostatic activity in vitro than Irinotecan, Etoposide and Nimustine. With regard to the median cytotoxicity, the order of drugs in our assays was Topotecan, Cisplatin, Vincristine, Caelyx, Irinotecan, Etoposide and Nimustine. Nimustine showed almost no efficacy against breast cancer cells.Topotecan, Cisplatin, Vincristine and Caelyx seem to be suitable candidates for further clinical evaluation. The data and the "liposomal packaging" suggest that Caelyx might be effective in the CNS. Since pulmonary metastases are often associated with brain metastases, evaluatingprimary cell cultures from malignant pleural effusions could be a valuable approach for the testing of new cytostatic drugs for brain metastases.

Several studies have indicated that dendritic cells (DC) participate in anti-tumor immunity, possibly influencing the course of malignant disease. We tested whether tumor infiltration by S100+ DC could be a prognostic marker for endometrial cancer.A retrospective study analyzing 115 tissue samples from patients with endometrial carcinoma and known histological grading as well as hormone receptor, Ki-67, Her-2/neu and p53 expression. Sections of paraffin-embedded endometrial tissue were immunohistochemically-stained with anti S100 antibody. Tumor infiltrating S100+ DC were counted via microscopic examination and calculated as S100+ DC per mm2 of tissue.Samples were divided into group 1: less than 10 S100+DC/mm2 (n = 44) and group 2: 10 or more S100+ DC/mm2 (n = 71). Correlation with clinico-pathological markers was calculated by Chi-square test. Compared to group 1, the DC-rich group 2 showed a higher level of differentiation (p=0.045), a lower overexpression of p53 (p=0.021) and less proliferation (p=0.028). DC infiltration was not correlated with Her-2/neu, hormone receptor status and FIGO-stage. Although no significant correlation could be seen, the DC-poor group samples seemed to correlate with a higher FIGO-stage compared to the DC-rich group. In uni- and multivariate analysis, DC infiltration proved to be a significant prognostic marker for adjusted survival but not for overall survival.Our results indicate that the immunohistochemical determination of S100+ DC could contribute to the identification of a high-risk subgroup and, therefore, would be a favorable prognostic factor for endometrial carcinoma. Our observation that pronounced DC infiltration is associated with good prognosis points to an important role of the host's immune system response for the clinical course of endometrial cancer.

We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.

The influence of intramural intestinal innervation on the morphogenesis of the mucosa and in particular of the enteroendocrine cells (EECs) has been studied on male Wistar rats with morphometric, autoradiographic and immuno-histochemical methods in the duodenum, proximal and distal jejunum and ilium before and after myenteric ablation with benzalkonium chloride (BAC). Twenty-one days after denervation alterations were observed in the mucosal structure with thickening of the mucosa, increase in the proliferation rate and with changes in numerical and spatial distribution of D-cells, I-cells, N-cells, glucagon and glicentin i.r. L-cells and 5-HT i.r. cells which myenteric ablation caused. Analysis of the genetic constructs involved in the alterations of EECs on the EECs provide evidence for the cAMP responsive elements as the main mediator.

Endocrine evaluation as a prerequisite for every patient undergoing routine in-vitro fertilization (IVF) and embryo transfer for tubal or male factor infertility is still a matter of debate. The aim of this study was to determine if a full endocrine work-up, including the measurement of androgens, gonadotropins, prolactin and TSH, is conclusive for the subsequent success in IVF/ET. 71 infertile women without known endocrinopathies (e.g., polycystic ovarian disease), who were scheduled to enter the IVF/ET program were studied under strictly standardized conditions during the follicular phase of a natural cycle. Fasting serum concentrations of follicle stimulating hormone, luteinizing hormone, oestradiol, progesterone, prolactin, testosterone (T), dehydroepiandrosterone, 17-OH-progesterone, androstenedione and thyroid stimulating hormone (TSH) were measured using commercially available radioimmunoassays. Ovarian stimulation was performed by a long gonadotrophin-releasing hormone agonist/human menopausal gonadotrophin protocol. The overall clinical pregnancy rate was 15.5% in the first started IVF cycle. While patients who conceived in the first treatment cycle had significantly lower T levels (368 +/- 49 pg/ml) than those who did not (518 +/- 27 pg/ml, p=0.042, KruskalWallis H-test), but the percentage of women with elevated T concentrations was not different. Similarly, TSH concentrations were significantly higher in women with a clinical pregnancy (1.9 +/- 0.2 mU/ml) than in non-pregnant women (1.4 +/- 0.3 mU/ml, p=0.046), but levels were still within the normal range. There were no further significant differences in hormone levels between pregnant and non-pregnant patients. These results do not suggest the measurement of a full hormonal profile in all infertile women before IVF/ET in non-endocrine infertility, taking into account the low likelihood to identify endocrinological disturbances, the considerable cost of endocrine testing and the paucity of therapeutic consequences.

Human ovarian papillary cystadenocarcinoma cells were injected intraperitoneally into severe combined immunodeficient (SCID) mice. After intraperitoneal application the cells, designated SoTü, grew well in vivo, lodged on to the peritoneum, formed local metastatic deposits, led to the development of ascites in the mice and formed distant metastases in the lungs. If lodged in the ovary, the morphology of the SoTu¨ tumour remarkably resembled that of the primary tumour in the patient. In contrast, several attempts failed to maintain the SoTü cells in vitro. If SCID mouse ascites derived SoTü were transplanted subcutaneously in SCID mice, they formed cystic tumours which also metastasized into the lungs. Immunophenotypical analysis of cell adhesion molecule expression, cell proliferation markers, various oncoproteins, keratin, vimentin, and lectin binding site expression all showed striking similarity between the primary tumour and the SCID mouse explants. In particular, expression of binding sites for the lectin Helix pomatia agglutinin (HPA), which has been shown to be an index of metastatic potential in several human carcinomas, was found on the primary tumour as well as on tumour cells grown in SCID mice, indicating that HPA might be a prognostic indicator in ovarian carcinoma as well. Our results demonstrate that the human/SCID mouse system can mimic growth and distant metastasis formation of human ovarian carcinoma. Although the formation of distant metastases is a relatively rare event in patients, this model system might help to elucidate mechanisms of metastasis formation in ovarian cancer.

Background Triplenegative breast cancer (TNBC) is associated with a dismal prognosis, although these tumors are chemosensitive. This phenomenon could be at least in part due to tumor immune escape. The current study investigates the host's immune response to TNBC cells and explores the presence of immunesuppressive factors, such as pAKT-expression and infiltration with FoxP3 positive regulatory T-cells (Tregs), in human TNBC samples. Material and Methods: NK-cell induced lysis of tumor cells was evaluated in human breast cancer cell lines MCF-7 (ER/PR pos.), HCC 1937 (triplenegative, BRCA 1 mutated) and HCC 1806 (triplenegative). Expression of pAKT and infiltration with Tregs was determined by immunehistochemistry and evaluated semiquantatitavely (0 no expression- 3 strong expression). Control groups consisted of: Fibroadenoma (N=6), prohpyhlactic mastectomy (BRCA 1 mutated, N=3), ER/PR + breast cancer (N=13). They were compared with triplenegative breast cancers: N = 9 BRCA wildtype and N = 6 BRCA 1 mutated. Results: At an effector target/target-ratio of 10/1 NK-cell induced lysis in HCC 1937 and HCC 1806 was 2.27 and 4.45 increased, respectively, as compared to MCF 7 cells. No infiltration with Tregs was detected in fibroadenoma and prophylactic mastectomy samples. Infiltration with FoxP3-positive Tregs was 0.92 +/− 0.75 in ER/PR+ breast cancers and 2.66 +/−0.5 (p Discussion: TNBC cells stimulated the NK-cell response to a stronger extent than did ER-positive MCF 7 cells mirrored by a more pronounced NK-cell- induced lysis. Thus, the observed stronger infiltration with FoxP3-positive Tregs in TNBC tumor samples could reflect a compensatory mechanism to suppress the host's immune response. In other tumor entities, such as ovarian cancer infiltration with Tregs is associated with a worse overall survival (1). Thus, the significantly increased infiltration with Tregs, could suggest that the worse prognosis of TNBC is due to tumor immune escape and further investigation of immunemodulatory therapeutic strategies in TNBC could prove fruitful. (1) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. Nat Med. 2004 Sep;10(9):942–9. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-06.

It has been a long tradition to quote from Joseph Dietl's 'manifesto' of therapeutic nihilism from 1845 to illustrate the perils of medical extremism. But Dietl's claim for medicine as a natural science cannot fully be understood without considering the social and political circumstances the developing New Vienna School had to face. The professionalization of Viennese academic medicine was opposed by the forces of restaurative absolutism and, in particular, the traditional preponderance of medical practitioners who played a major role in the medical faculty.

Worldwide, the incidence of nonruptured tubal pregnancy has increased, and so has the feasibility of conservative management of this condition. Following conservative surgery the rate of intrauterine pregnancy is significantly higher than after salpingectomy. The rate of ectopic pregnancy has not (or hardly) increased. For a surgeon skilled in this technique, the laparoscopic approach has advantages because it avoids laparotomy. For the time being, medical treatment of ectopic pregnancy with methotrexate, prostaglandins, and antiprogesterone should be confined to clinical studies. For nonviable, nonruptured tubal pregnancy with decreasing HCG titers expectant management seems possible; following conservative treatment, monitoring of HCG until it becomes undetectable is mandatory.

PROFESSOR Michael Scriven has recently suggested that the relation between syphilis and paresis offers material for a counter-example to the thesis that there exists a logical symmetry between explanation and prediction?. Professors Carl G. Hempel and Adolf Griinbaum have given independent arguments against the efficacy of the example. I wish to suggest in this note that the example does not show what it is intended to show but that the reasons Hempel and Grfinbaum have given show a misunderstanding of the example rather than its impotence.

cannot infer 'x cannot perish.' That is, from the claim that somethin cannot be both a person and not alive, we cannot infer that persons are immortal. Plto, however, uses 'immortal' in an equivocal sense. In (6) it means simply 'cannot die,' whereas in (7), it means what is usually meant, i.e., 'cannot perish.' And as he has pointed out, something which cannot admit death may perish. 5 Philosophical Studies, 18:46. l bid.

A new solid-phase antigen immunoassay was developed for the detection of anti-zona pellucida-antibodies. The assay was validated in a double blind study with clinically defined sera. The new assay is easy to perform and large numbers of sera can be processed in one day. The antigen can be prepared in advance and stored until use. This represents an advantage over other methods, such as immunofluorescence and RIA, which require fresh antigen preparation for each set of assays. With this new test ca. 7% of females and ca. 20% of males with unexplained infertility have shown elevated antibody concentrations compared with fertile controls. The estimated intra-assay and inter-assay CV were 8.5% and less than 10% respectively.

Worldwide, the incidence of nonruptured tubal pregnancy has increased, and so has the feasibility of conservative management of this condition. Following conservative surgery the rate of intrauterine pregnancy is significantly higher than after salpingectomy. The rate of ectopic pregnancy has not (or hardly) increased. For a surgeon skilled in this technique, the laparoscopic approach has advantages because it avoids laparotomy. For the time being, medical treatment of ectopic pregnancy with methotrexate, prostaglandins, and antiprogesterone should be confined to clinical studies. For nonviable, nonruptured tubal pregnancy with decreasing HCG titers expectant management seems possible; following conservative treatment, monitoring of HCG until it becomes undetectable is mandatory.

Contact between gametes takes place on a molecular basis via receptors on the surface of the egg coat. The functional part of this receptor glycoprotein is limited to the O-glycosidic-linked carbohydrate side chains, and a polypeptide chain of it may induce an acrosomal reaction on the sperm head, thereby inducing penetration of the sperm into the egg cell. Another function of sperm receptors is to block polyspermy, probably due to modification by limited proteolysis of the receptor glycoprotein. Fertilization is likely to be inhibited by steric hindrance of the receptor due to antibodies specific for glycoproteins of the egg coat. The study of gamete interactions on a molecular basis may serve as a model for intercellular recognition in general.

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New Zealand white rabbits were immunized with low doses of pig zona pellucida material with the aim of reducing nonspecific antibodies in the antiserum. The antibody levels were assayed by the standard precipitation and immunofluorescence methods. The titers produced were comparable with those obtained using large amounts of zona material.

Recently Professor William Dray counted it as an advantage of one account of historical explanation over another that on the former the explanation "focused precisely on what was to be explained" while the latter, which rested on statistical information, allowed the individual event to be explained room to "rattle around" in the sense that the statistical law given as an explanation is compatible with both the occurrence and non-occurrence of what is thus explained.' The authors of the two theories are Professors Scriven and Hempel.2 The irony of Dray's congratulating Scriven on being more faithful than Hempel to this aim of the hypothetico-deductive model has probably struck many. The situation is remarkable partly because Dray has become known as one of the best critics of that model; and more especially, I think, because Dray has been the most concerned to argue that explanations of human actions in terms of the reasons for which they are done are essential to history, and to try to give an adequate account of them. One who insists on the importance of reasons as opposed to causes in historical explanations might be expected to find sources of intelligibility other than that which accrues when what is to be explained is deducible from the explanation. But there does not seem to be any non-deductive way to stop the rattling. Another aspect of the irony of Hempel's giving up deduction as necessary while Dray and Scriven try to save it is only apparent. Hempel still believes in the logical symmetry between explanation and prediction and takes it as a necessary condition of any "rationally acceptable" answer to "Why?" that it "provide information which constitutes good grounds for the belief that X