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The routine procedure of estrous cycle synchronization in pigs allows for the use of gonadotropins to stimulate ovarian activity. The applied protocols of eCG and hFSH priming similarly affected development of ovarian follicles in two classes 3–6 mm and >6 mm of diameter, however, the number of small follicles (

Altrenogest with gonadotropins is commonly used to synchronize the estrous cycle, but it can also lead to follicular cyst formation, especially in prepubertal gilts. Here, we aimed to investigate how maturity and altrenogest treatment affect the development, endocrine milieu, and molecular control of ovarian follicles. Crossbred prepubertal and mature gilts were challenged or not (control) with altrenogest, and ovaries were collected in the morning on the first day of behavioral estrus. In prepubertal gilts, altrenogest decreased the percentage of primordial and atretic small follicles, but increased large antral follicles when compared with controls. In mature gilts, altrenogest reduced the percentage of primary follicles and elevated the total number of antral follicles. Maturity affected the estradiol level in the follicular fluid of preovulatory follicles, luteinizing hormone (LH)-stimulated cyclic adenosine monophosphate (cAMP) generation, and LH receptor messenger RNA (mRNA) expression in granulosa. Moreover, cytochrome P45017A1 (CYP17A1) mRNA levels in the theca layer were affected and correlated with follicular androstendione and estradiol concentration. Altrenogest negatively affected follicular fluid progesterone concentration and decreased levels of prostaglandin (PG) E2 in prepubertal gilts and PGF2alpha metabolite in mature gilts. LH-stimulated cAMP release in granulosa cells of mature gilts as well as human chorionic gonadotropin- and forskolin-induced cAMP were also affected. In addition, altrenogest downregulated CYP17A1 mRNA in the prepubertal theca layer and PGF2alpha synthase expression in the granulosa and theca layer of mature gilts. To the best of our knowledge, this is the first study to report multiple effects of maturity and altrenogest on the endocrine milieu and molecular regulations governing ovarian follicle development in gilts.

Ocular medulloepithelioma (ME) is a rare congenital tumor which occurs usually during childhood but is also reported in adults. They have seen an intraocular tumor in an 89 years-old female with a history of small cell lung carcinoma. Transscleral fine needle aspiration was performed. Aspirates were rich and composed of two distinctive populations of cells. The first consisted of epithelioid large cohesive cells with rare rosettes. Nuclei were oval and chromatin was delicate with small nucleoli. The second population consisted of smaller and dispersed cells with regular nuclei and dusty chromatin. Immunohistochemistry performed on paraffin-embedded cell block sections showed that the larger cells and rosettes were cytokeratin AE1/AE3, Synaptophysin, Chromogranin A, CD56, NSE, and EMA positive, whereas the smaller cells were always negative. Interestingly smaller cells expressed only weak nuclear positivity for TTF1, whereas larger cells were TTF1 negative. Melanocytic markers were negative in both populations. Morphological patterns and immunohistochemical staining confirmed ocular ME and allowed to exclude pulmonary metastasis or primary malignant melanoma. The patient was successfully treated by brachytherapy alone and is alive and well 10 months after treatment. Diagn. Cytopathol. 2017;45:561-564. © 2017 Wiley Periodicals, Inc.

Research was conducted to determine the effect of altrenogest and exposure to exogenous gonadotropins on ovarian function in prepubertal and mature gilts. Crossbred, presumably sexually mature gilts (n = 51), were fed with altrenogest for 18 consecutive days and the day after the last feeding with altrenogest, gilts were treated with eCG and 72 hours later challenged with hCG. Animals were slaughtered on Days 10 to 13 of their gonadotropins synchronized estrous cycle. Ovaries were examined for the number of CL, number of follicular cysts, and presence of corpora albicantia. Gilts were divided into two groups: those possessing corpora albicantia (group A-mature; n = 36) and those without corpora albicantia (Group W-prepubertal; n = 15) on their ovaries. In addition, each group was divided into two subgroups depending on the presence of follicular cysts (AC and WC) or their absence (AO and WO). There was no difference between the number of CL in group A and group W. Presence of corpora albicantia determined percentage of gilts possessing follicular cysts (13.9% group A vs. 66.7% group W). Gilts without follicular cysts (AO plus WO; n = 36) had higher number of CL (P 0.01) than gilts bearing cysts (AC plus WC; n = 15). Comparison AO-AC did not show significant difference (P = 0.075) between CL number in mature cyst-free and cysts bearing gilts. A prepubertal gilts not bearing follicular cysts (WO) had higher (P 0.02) number of CL than gilts bearing cysts. A significant negative correlation between the number of CL and number of follicular cysts was found (r = -0.664; P = 0.007). There were no differences in blood plasma progesterone and estradiol concentration between cyst-free and cyst-bearing gilts. These results indicate: (1) a higher follicular cysts appearance in prepubertal than mature gilts challenged with altrenogest and exposed to exogenous gonadotropins and (2) a negative effect of follicular cysts on the number of CL (ovulations) in prepubertal gilts.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a rare disease in the Western countries. Cases involving extranasal sites often have poorer prognosis than nasal cases. We report a patient with an extranodal NK/T[HYPHEN]cell lymphoma of nasal[HYPHEN]type, in the right ovary. She had surgical removement of the involved ovary and was treated with CEOP[HYPHEN]B based therapy followed by high[HYPHEN]dose therapy with autologous stem cell support. She remains in complete remission six years after diagnosis. Stage I ENKTL in the ovary is an unusual manifestation, and to our knowledge not described earlier.

Ocular medulloepithelioma (ME) is a rare congenital tumor which occurs usually during childhood but is also reported in adults. They have seen an intraocular tumor in an 89 years-old female with a history of small cell lung carcinoma. Transscleral fine needle aspiration was performed. Aspirates were rich and composed of two distinctive populations of cells. The first consisted of epithelioid large cohesive cells with rare rosettes. Nuclei were oval and chromatin was delicate with small nucleoli. The second population consisted of smaller and dispersed cells with regular nuclei and dusty chromatin. Immunohistochemistry performed on paraffin-embedded cell block sections showed that the larger cells and rosettes were cytokeratin AE1/AE3, Synaptophysin, Chromogranin A, CD56, NSE, and EMA positive, whereas the smaller cells were always negative. Interestingly smaller cells expressed only weak nuclear positivity for TTF1, whereas larger cells were TTF1 negative. Melanocytic markers were negative in both populations. Morphological patterns and immunohistochemical staining confirmed ocular ME and allowed to exclude pulmonary metastasis or primary malignant melanoma. The patient was successfully treated by brachytherapy alone and is alive and well 10 months after treatment. Diagn. Cytopathol. 2017;45:561-564. © 2017 Wiley Periodicals, Inc.

The proliferation factors: mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki67 have strong prognostic value in early breast cancer but their independent value to each other and other prognostic factors has not been evaluated. In 237 T₁₋₂N₀M₀ breast cancers without systemic adjuvant treatment, formalized MAI assessment and strictly standardized, fully automated quantitative immunohistochemistry (IHC) for Ki67, PPH3, estrogen (ER) and progesterone receptor (PR), HER2, cytokeratins-5/6 and -14, and automated digital image analysis (DIA) for measuring PPH3 and Ki67 were performed. Section thickness was measured to further control IHC measurements. All features were measured in the periphery of tumors. The different proliferation assessments and other well-established clinicopathological and biomarker prognostic factors were compared. DIA-Ki67 added prognostically to PPH3. None of the other biomarkers or clinicopathological variables added prognostically to this PPH3/Ki67 combination. However, when PPH3 is replaced by MAI the prognostic value is nearly the same. In early operable node negative breast cancer without adjuvant systemic treatment, Ki67 with a threshold of 6.5% assessed by digital image analysis in the periphery of the tumor is prognostically strong. The combination of either PPH3/Ki67 or MAI/Ki67 overshadowed the prognostic value of all other features including Ki67 alone.

The role of consolidative radiotherapy (RT) in advanced diffuse large B-cell lymphoma (DLBCL) is not established.In a population-based retrospective analysis of patients with DLBCL in Western Norway during 2003 to 2008, 170 consecutive patients admitted to Haukeland University Hospital (HUS) and 94 to Stavanger University Hospital (SUS) were included. The mean age was 64 years (range, 17-95 years), 147 patients (56%) were male, 80 patients (30%) had stage I/II, 126 patients (48%) stage III/IV, and 57 patients (22%) had primary extranodal disease.There were no differences between hospitals in patient characteristics, use of rituximab, number of chemotherapy courses or cumulative doses, or in distribution of response categories after chemotherapy. The use of RT was significantly different: 17 patients (23%) received RT at SUS and 92 patients (65%) at HUS (P .001). For 219 patients with International Prognostic Index (IPI) score of 0 to 3, 5-year cancer-specific survival (CSS) was 67% at SUS and 81% at HUS (P = .012). For 73 patients with complete response after chemotherapy there were no differences in survival between patients with and without RT. For 138 patients with any residual mass after chemotherapy, there were highly significant differences in favor of receiving RT (n = 81) versus no RT (n = 57): 5-year CSS 89% versus 69% (P .001), and 5-year overall survival 82% versus 59% (P = .005). The effect of RT on residual mass was evident in most subgroups, mainly in low to intermediate risk, but not in high-risk (IPI 4-5) patients.With the limitations of a retrospective study, these data suggest that consolidative RT might improve survival in DLBCL patients with a residual mass after chemotherapy, also in advanced disease.

Mantle cell lymphomas (MCLs) are associated with a characteristic t(11;14)(q13;q32) chromosomal translocation. This causes the CCND1 gene on chromosome 11 to be co-localized with the immunoglobulin heavy chain gene on chromosome 14, resulting in increased expression of cyclin D1. The cyclin D1/D3 expression ratio, as an approach to segregate MCLs from other small B-cell lymphomas, has not previously been evaluated in formalin-fixed, paraffin-embedded tissue. We found that mean cyclin D3 expression was lower in MCLs (P0.05) than in chronic lymphocytic leukemias (CLLs), follicular lymphomas (FLs), marginal zone/mucosa-associated lymphoid tissue lymphomas (MALTs), multiple myelomas (MMs), and reactive lymph nodes. As expected, mean cyclin D1 expression was increased in MCL (P0.05), but in several cases the expression of cyclin D1 did overlap with the level observed in CLLs, FLs, MALTs, MMs, and reactive lymph nodes. The cyclin D1/D3 expression ratio, however, did fully separate MCLs from FLs, CLLs, and reactive lymph nodes. The mean expression ratio was also significantly different between MCL and MALT (P0.05), but 3 MCL cases had values overlapping those of some MALTs. The expression ratio was not significantly different between MCL and MM. In conclusion, the cyclin D1/D3 expression ratio gave an improved segregation of MCLs from CLLs, FLs, MALTs, and reactive lymph nodes, as compared with determination of cyclin D1 alone in formalin-fixed, paraffin-embedded tissue.

Independent studies have shown that in node negative breast cancer patients less than 71 years, the proliferation marker mitotic activity index (MAI) is the strongest, most well reproducible prognosticator and chemotherapy success predictor. The MAI overshadows the prognostic value of tubule formation, nuclear atypia and thereby grade. An often used crude mitotic impression is much less prognostic than the MAI; strict adherence to the MAI protocol is therefore important. The prognostic value of the MAI is age dependent: although patients with a MAIor = 10 always have a poor prognosis irrespective of age, a low MAI (10) loses its favourable prognostic association in women70 years. PPH3 counts are prognostically stronger than the MAI, and markers such as Cyclin-B and E2FR are promising, but must be validated. Compared with commercial prognostic gene expression signatures, the MAI is at least as strong prognostically, has far fewer false positive results and as such should be included as an independent feature in any node negative breast cancer pathology report.

Aim To compare HER-2 scoring reproducibility by subjective and digital image analysis (DIA) scores with each other and with fluorescence in situ hybridization (FISH) assessed HER-2 amplification. Methods Herceptest-stained Tissue Micro Arrays of 219 breast carcinomas were scored (DAKO protocol) by 3 observers (both independent and as consensus), scored by DIA and both scores were compared with FISH amplification results. Results Interobserver subjective scores reproducibility was good (κ 0.82 to 0.86) but therapeutically important 3+/2+discrepancies occurred in 11% to 16% of all 3+ cases. Subjective scores and FISH results differed considerably. Consensus scores by 3 pathologists correlated better with FISH, reducing the number of both Immunohistochemical (IHC) negative/FISH positives and IHC 3+/FISH negatives. DIA scores were well reproducible and correlated better with FISH amplification than did subjective scores. Conclusions DIA scores were comparable with consensus scores between 3 expert pathologists, were very well reproducible and performed better in classifying IHC 3+/FISH+ cases than did subjective scores.

Background: HER2/neu expression and fluorescence in situ hybridisation (FISH) amplification have therapeutic significance. Aims: To compare subjective HER2/neu expression scores with digital image analysis (DIA) and conventional and modified FISH scores in breast cancer. Methods: Sixty HercepTest-immunostained breast carcinomas, prospectively scored as consensus 2+ and 3+ (DAKO protocol) by two observers, were analysed with DIA, and conventional (Vysis) and modified FISH scoring protocols. Results: With consensus scoring, 23 (38%) of the 60 cases were 2+ and 37 (62%) were 3+. Agreement with DIA scores was 100%. With conventional FISH scoring, 4 of the 3+ cases did not show amplification, but all of those negative cases had high HER2/neu copy numbers. With the modified FISH scoring protocol, all HercepTest immunohistochemical 3+ cases were amplified. Of the 2+ cases, 3 were amplified with the modified FISH protocol and 4 with the conventional FISH protocol. Conclusions: Modified FISH scores were better correlated with HercepTest 3+ consensus and DIA scores than were conventional FISH scores. HER2/neu DIA scoring is a cost-effective supplementary tool in surgical pathology.

The syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is an autoinflammatory disorder of unknown aetiology. Tonsillectomy may cause a prompt resolution of the syndrome. The aim was to study the histologic and immunological aspects of the palatine tonsils in PFAPA, to help understand the pathophysiology of the syndrome. Tonsils from children with PFAPA (n = 11) and children with tonsillar hypertrophy (n = 16) were evaluated histologically after haematoxylin and eosin staining. The number of different cell types was identified immunohistochemically by cluster of differentiation (CD) markers: CD3 (T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), CD15 (neutrophils), CD20 (B cells), CD45 (all leucocytes), CD57 (NK cells) and CD163 (monocytes and macrophages). Tonsils from children with PFAPA showed reactive lymphoid hyperplasia dominated by well-developed germinal centres with many tingible body macrophages. The histologic findings were unspecific, and a similar morphologic appearance was also found in the tonsils from controls. The number of CD8+ cells in germinal centres differed between children with PFAPA [median 9 cells (quartiles: 5, 15)] and controls [18 cells (12, 33) (P = 0.001)] and between children with PFAPA with (median 14 cells; 9, 16) and without (4 cells; 3, 8) aphthous stomatitis (P = 0.015). For the other cell types, no differences in germinal centres were found between children with PFAPA and controls. In conclusion, a lower number of CD8+ cells were found in germinal centres of tonsils in children with PFAPA compared to controls, which may be a feature linked to the aetiology of the syndrome.

In early cervical intraepithelial neoplasia (CIN), the Ki67 stratification index 90th percentile (Si90) is a strong predictor of progression. This study was designed to further investigate the mechanisms leading to elevated Ki67 levels in lesions that progress and to try to improve the prognostic accuracy of Ki67-Si90. We studied 90 CIN lesions in which consensus existed regarding the grade between two experienced gynecologic pathologists. All CINs were p16-positive and showed Ki67 cell clusters above the lower third of the epithelium (both features diagnostic for CIN). Ki67 parameters, cell cycle regulators (Rb, p53, Cyclin A, E and D, p16, p21, p27, and telomerase), and cellular differentiation products (involucrin, CK13, CK14) were compared in the basal zone as well as the deeper and upper halves of the epithelium. Fifteen CIN cases (17%) progressed to a higher CIN grade, including 2 of 25 CIN1 (8%) and 13 of 65 CIN2 (20%) (these proportions of progressing CINs are similar to those in a large meta-analysis). Ki67 quantitation effectively predicted CIN progression as 0 of 40 "Ki67 low-risk" and 15 of 50 (30%) "Ki67 high-risk" lesions progressed. CIN progressors showed decreased Rb, CK13, CK14, and involucrin, but increased p21 and p27 expression. Ki67-Si90 and Rb in the deeper half of the epithelium (RbDeep) were the strongest multivariate independent predictors of progression. Ki67-Si900.57 was unfavorable, but only if it coexisted with RbDeep45% (progression risk = 47%). All early CINs with combined Si900.57+RbDeep45% or any Ki67-Si90 value below 0.57 were nonprogressors. In the high-risk progression subgroup (Ki67-Si900.57+RbDeep45%), all cases with combined CK1450% and CK1380% (both in the basal cell layer) (4% of all lesions) progressed. We hypothesize that onco-HPV E7 expression reduces Rb, causing increased and upward proliferation (Ki67-Si900.57). Increased RbDeep can reduce proliferation, including its upward spread. Combined quantitation of Ki67, Rb, CK13, and CK14 gives accurate information about the progression risk of early CIN lesions.

The proliferation factors: mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki67 have strong prognostic value in early breast cancer but their independent value to each other and other prognostic factors has not been evaluated. In 237 T₁₋₂N₀M₀ breast cancers without systemic adjuvant treatment, formalized MAI assessment and strictly standardized, fully automated quantitative immunohistochemistry (IHC) for Ki67, PPH3, estrogen (ER) and progesterone receptor (PR), HER2, cytokeratins-5/6 and -14, and automated digital image analysis (DIA) for measuring PPH3 and Ki67 were performed. Section thickness was measured to further control IHC measurements. All features were measured in the periphery of tumors. The different proliferation assessments and other well-established clinicopathological and biomarker prognostic factors were compared. DIA-Ki67 added prognostically to PPH3. None of the other biomarkers or clinicopathological variables added prognostically to this PPH3/Ki67 combination. However, when PPH3 is replaced by MAI the prognostic value is nearly the same. In early operable node negative breast cancer without adjuvant systemic treatment, Ki67 with a threshold of 6.5% assessed by digital image analysis in the periphery of the tumor is prognostically strong. The combination of either PPH3/Ki67 or MAI/Ki67 overshadowed the prognostic value of all other features including Ki67 alone.

Immunohistochemical staining is important for diagnosis and therapeutic decision making but the results may vary when different detection systems are used. To analyze this, 5 different labeled polymer immunohistochemical detection systems, REAL EnVision, EnVision Flex, EnVision Flex+ (Dako, Glostrup, Denmark), NovoLink (Novocastra Laboratories Ltd, Newcastle Upon Tyne, UK) and UltraVision ONE (Thermo Fisher Scientific, Fremont, CA) were tested using 12 different, widely used mouse and rabbit primary antibodies, detecting nuclear, cytoplasmic, and membrane antigens. Serial sections of multitissue blocks containing 4% formaldehyde fixed paraffin embedded material were selected for their weak, moderate, and strong staining for each antibody. Specificity and sensitivity were evaluated by subjective scoring and digital image analysis. At optimal primary antibody dilution, digital image analysis showed that EnVision Flex+ was the most sensitive system (P < 0.005), with means of 8.3, 13.4, 20.2, and 41.8 gray scale values stronger staining than REAL EnVision, EnVision Flex, NovoLink, and UltraVision ONE, respectively. NovoLink was the second most sensitive system for mouse antibodies, but showed low sensitivity for rabbit antibodies. Due to low sensitivity, 2 cases with UltraVision ONE and 1 case with NovoLink stained false negatively. None of the detection systems showed any distinct false positivity, but UltraVision ONE and NovoLink consistently showed weak background staining both in negative controls and at optimal primary antibody dilution. We conclude that there are significant differences in sensitivity, specificity, costs, and total assay time in the immunohistochemical detection systems currently in use.

We validated and compared the prognostic value of the proliferation marker phosphohistone H3 (PPH3) with classical variables in 241 T(1-2)N(0)M(0) breast cancer patients less than 71 years old with long-term follow-up (median 117 months) and without adjuvant treatment. PPH3 was measured by automated digital image analysis. Thirty-seven patients (15%) developed distant metastases and 29 (12%) died. The previously established PPH3 prognostic threshold H313 (n = 157; 65% of all cases) vs.or=13 (n = 84; 35% of all cases) was the strongest prognostic threshold exceeding all other characteristics, with 10-year recurrence-free survival of distant metastases of 96 and 64%, respectively (P =0.0001, hazard ratio = 7.8, 95% confidence interval = 3.4-17.9). PPH3 is robust as it showed high inter-observer reproducibility and was prognostic over wide range of thresholds around 13 and is the strongest prognostic variable in invasive node-negative breast cancer patients less than 71 years old.

The nineteenth century is a very important period from our contemporary point of view. It is then that many socio-political ideas were born and have affected our social and individual life until now. It is in the nineteenth century that humankind sought to reflect on freedom, individualism and progress, and often paid dearly for any utopian misinterpretations in this area. Last but not least, in the nineteenth century the modern philosophical perception clashed with Christianity. The paper sought to show this intellectual turmoil by focussing on the main adherents of reconciling new ideas with religion. This reconciliation could be effected with an integral view of the human being in mind. The integral human being, advocated by Newman and Acton, can manage to abide by timehonoured traditions and assimilate whatever there is of positive value in civilization.Le 19eme siecle est une periode riche en enseignements pour notre reflexion contemporaine. C'est durant ce siecle que nombre d'idees sociopolitiques ayant influe jusqu'a present sur notre vie individuelle et sociale sont nees. C'est au 19eme siecle que l'humanite chercha a reflechir sur la liberte, l'individualisme et le progres, et elle paya au prix fort les erreurs d'interpretation utopiste commises dans ces domaines. Aussi, et non des moindres, c'est au 19eme siecle que la perception philosophique moderne entra en conflit avec le christianisme. L'article vise a depeindre cette agitation intellectuelle en mettant l'accent sur les principaux tenants de la reconciliation des nouvelles idees avec la religion. Cette reconciliation peut se faire si on a a l'esprit une vision complete de l'etre humain. Cet etre humain complet, tel que defendu par Newman et Acton, possede les qualites suffisantes pour respecter les traditions ancestrales et assimiler ce qu'il y a de valeureux dans la civilisation.

Objective To analyze the prognostic value of molecular biomarkers in curettages of endometrioid endometrial cancer pathologic FIGO stages 1 and 2. Study Design Population-based survival analysis in 258 patients of classical prognostic features and molecular biomarkers of cell cycle regulation, (anti)apoptosis, proliferation, squamous differentiation, and PTEN/Akt pathway. Results With 74 months median follow-up (range, 1-209), 24 (9.3%) patients had metastases develop. Pathologic FIGO stage 2B (6% of all cases) and age > 68 years had independent multivariate prognostic value. Many molecular biomarkers were prognostic, particularly cell-cycle regulators p16, p21, p27, p53, p63, and the antiapoptosis marker survivin (which mostly stains mitoses). The strong prognostic value of a multivariate model with survivin, p21, and p53 overshadowed all other prognosticators in pathologic FIGO 1 and 2A. Conclusion In pathologic FIGO stage 1 and 2A endometrioid endometrial cancer curettages, combined biomarkers survivin, p21, and p53 expression patterns are prognostically stronger than classical feature combinations.