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Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Background: Chemokines, cytokines in the immune microenvironment of tumors, may be associated with patient outcome. We assessed the impact of CXCL13 and CXCL9 on disease-free (DFS) and overall survival (OS), in an attempt to retrospectively evaluate both T and B cell function in the microenvironment of primary tumors from patients with breast cancer. Materials and Methods: Formalin-fixed paraffin-embedded tissue blocks from patients with intermediate/high-risk, early breast cancer, treated with sequential adjuvant epirubicin, paclitaxel, and cyclophosphamide methotrexate fluorouracil within a randomized trial, were tested for CXCL13 and CXCL9 messenger RNA expression; 557 patients with adequate tissue were eligible for the analysis. Results: CXCL13 was correlated with CXCL9 (rho = 0.52; P < .001). High-expressing CXL13 and CXCL9 tumors had higher Ki67 and tumor infiltrating lymphocyte density (P-values < .001). High CXCL9 expression was an unfavorable prognosticator for OS among all patients (hazard ratio [HR], 1.73; P = .021), whereas it showed favorable significance for both DFS and OS in patients with triple negative disease (HR, 0.29; P = .027 and HR, 0.32; P = .045). High CXCL13 conferred longer DFS and OS among patients with luminal-human epidermal growth factor receptor 2 disease (HR, 0.31; P = .013 and HR, 0.25; P = .005). Patients with low CXCL13 and high CXCL9 expression had shorter DFS and OS compared with those with high expression of both chemokines (HR, 1.63; P = .006 and HR, 1.61; P = .016). Conclusions: Both biomarkers were associated with poor prognosis characteristics and with tumor infiltrating lymphocyte density. High CXCL9 conferred an improved prognosis in the triple negative subtype, whereas high CXCL13 was associated with improved outcome in the luminal-human epidermal growth factor receptor 2 subtype. Chemokines can be associated with breast cancer subtype and outcome. These data should be evaluated prospectively. © 2019 Elsevier Inc. Chemokines are of increasing interest in breast cancer. A total of 557 tissue samples from patients with early breast cancer treated in the context of a prospective adjuvant chemotherapy trial were tested for CXCL13 and CXCL9 expression, and the results were associated with outcome and other markers. CXCL13 was associated with triple positive disease and CXCL9 with triple negative disease, both conferring improved outcome. © 2019 Elsevier Inc.

BACKGROUND The differences in histopathology and molecular biology between right colon cancer (RCC) and left colon cancer (LCC) were first reported in the literature by Bufill in 1990. Since then, a large number of studies have confirmed their differences in epidemiology, clinical presentation, comorbidities and biological behaviours, which may be related to the difference in prognosis and overall survival (OS) between the two groups. AIM To investigate statistically significant differences between Greek patients with LCC and RCC. METHODS The present observational study included 144 patients diagnosed with colon cancer of any stage who received chemotherapy in a Greek tertiary oncology hospital during a 2.5-year period. Clinical information, comorbidities, histopathologic characteristics and molecular biomarkers were collected from the patients' medical records retrospectively, while administered chemotherapy regimens, targeted agents, progression-free survival (PFS) periods with first-and second-line chemotherapy and OS were recorded retroactively and prospectively. Data analysis was performed with the SPSS statistical package. RESULTS Eighty-six males and 58 females participated in the study. One hundred (69.4%) patients had a primary lesion in the left colon, and 44 (30.6%) patients had a primary lesion in the right colon. Patients with RCC were more likely to display anaemia than patients with LCC [odds ratio (OR) = 3.09], while LCC patients were more likely to develop rectal bleeding (OR = 3.37) and a feeling of incomplete evacuation (OR = 2.78) than RCC patients. Considering comorbidities, RCC patients were more likely to suffer from diabetes (OR = 3.31) and coronary artery disease (P = 0.056) than LCC patients. The mucinous differentiation rate was higher in the right-sided group than in the left-sided group (OR = 4.49), as was the number of infiltrated lymph nodes (P = 0.039), while the percentage of high-grade differentiation was higher in the group of patients with left-sided colon cancer than in RCC patients (OR = 2.78). RAS wild-type patients who received anti-epidermal growth factor receptor (EGFR): Treatment experienced greater benefit (PFS: 16.5 mo) than those who received anti-vascular endothelial growth factor treatment (PFS: 13.7 mo) (P = 0.05), while among RAS wild-type patients who received anti-EGFR treatment, LCC patients experienced greater benefit (PFS: 15.8 mo) than the RCC subgroup (PFS: 5.5 mo) in the first-line chemotherapy setting (P = 0.034). BRAF-mutant patients had shorter PFS (9.3 mo) than BRAF wild-type patients (14.5 mo) (P = 0.033). RCC patients showed a shorter tumour recurrence period (7.7 mo) than those with LCC (14.5 mo) (P < 0.001), as well as shorter (OS) (58.4 mo for RCC patients; 82.4 mo for LCC patients) (P = 0.018). CONCLUSION RCC patients present more comorbidities, worse histological and molecular characteristics and a consequently higher probability of tumour recurrence, poor response to targeted therapy and shorter OS than LCC patients. © The Author(s) 2020.

Aim To compare distinct clinicopathological features between atypical proliferative serous tumors and non-invasive low-grade ovarian serous carcinomas. Methods Our study group comprised 203 cases of serous borderline tumors sub-classified as atypical proliferative serous tumors or as non-invasive low-grade serous carcinomas. All pathological features related to borderline tumors were re-evaluated by two gynecological pathologists. Data concerning recurrences and survival were retrieved from the medical records of the patients. Results When comparing atypical proliferative serous tumors to non-invasive low-grade serous carcinomas, the latter were statistically related to advanced stage at diagnosis, bilateral disease, exophytic pattern of growth, microinvasive carcinoma, and the presence of invasive implants. In univariate analysis, recurrences were statistically related to the exophytic pattern of growth, to microinvasion, and to the presence of implants (both invasive and non-invasive). Nevertheless, in multivariate analysis, only microinvasion and the presence of invasive implants were related to recurrence. Women who eventually succumbed to the disease were only those with invasive implants. Their ovarian tumor was either a non-invasive low-grade serous carcinoma or an atypical proliferative serous tumor with minimal' micropapillary pattern. Neither lymph node involvement nor endosalpingiosis seemed to influence the course of the disease. Conclusions The results of our study underline the increased possibility of non-invasive low-grade serous carcinomas to be related with features indicative of aggressive behavior as opposed to atypical proliferative serous tumors. Nevertheless, irrespective of tumor histology, the presence of invasive implants and microinvasion were the only independent prognostications of recurrence. © 2019 IGCS and ESGO.

BACKGROUND: Src, CDKN1B, and JAK2 play a crucial role in the coordination of cell signaling pathways. In the present study, we aim to investigate the prognostic significance of these biomarkers in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab (T). METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 197 patients with HER2-positive MBC treated with T were retrospectively collected. All tissue samples were centrally assessed for ER, PgR, Ki67, HER2, and PTEN protein expression; EGFR gene amplification; PI3KCA mutational status; and tumor-infiltrating lympocytes density. Src, CDKN1B, and JAK2 mRNA expression was evaluated using quantitative reverse transcription-polymerase chain reaction. RESULTS: Only 133 of the 197 patients (67.5%) were found to be HER2-positive by central assessment. CDKN1B mRNA expression was strongly correlated with Src (rho = 0.71) and JAK2 (rho = 0.54). In HER2-positive patients, low CDKN1B conferred higher risk for progression [hazard ratio (HR) = 1.58, 95% confidence interval (CI) 1.08-2.32, P =.018]. In HER2-negative patients, low Src was associated with longer survival (HR = 0.56, 95% CI 0.32-0.99, P =.045). Upon multivariate analyses, only low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in de novo and relapsed (R)-MBC patients, respectively (HR = 2.36, 95% CI 1.01-5.48, P =.046 and HR = 1.76, 95% CI 1.01-3.06, P =.047, respectively). CONCLUSIONS: Low CDKN1B and JAK2 mRNA expressions were unfavorable prognosticators in a cohort of T-treated MBC patients. Our results suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T resistance, which seems to be associated with distinct pathways in de novo and R-MBC. © 2019

Background: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. Methods: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry. Results: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with non-endometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). Conclusions: In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology. © 2019, Japan Society of Clinical Oncology.

Toll-like receptors (TLRs) are the key regulators of innate and adaptive immunity and are highly expressed during sepsis. Thus, studying the expression of TLRs in an animal septic model might indicate their possible association with acute kidney injury in sepsis. Seventy-two male C57BL/6J mice were used for this study. Randomly, these animals were divided into 6 groups (N = 12/group): 3 control and 3 septic groups depending on the euthanasia time (24 h, 48 h, 72 h). Septic groups underwent cecal ligation and puncture (CLP) to induce peritonitis, while control groups had a sham operation. Hematological tests were performed in serum for immune biomarkers; immunohistochemistry, morphometry and qRT-PCR analysis were used on both kidney and intestine tissues to evaluate the expression of TLR 2, 3, 4 and 7 in a septic process. At the end of each experimental period, we found that TLRs 2, 3, 4 and 7 were expressed in both tissues but there were differences between those at various time points. Also, we found that mRNA levels were significantly higher in qRT-PCR evaluation in septic groups than control groups in both kidney and intestinal tissues (p < 0.05); showing a steady increase in the septic groups as the time to euthanasia was prolonged (p < 0.05). Overall, our study provides a suggestion that TLRs 2, 3, 4 and 7 are highly expressed in the kidneys of septic mice and especially that these TLRs are sensitive and specific markers for sepsis. Finally, our study supports the diagnostic importance of TLRs in AKI and provides an insight on the contribution of septic mice models in the study of multi organ dysfunction syndrome in general. © 2019, The Author(s).

Study Objective: To examine the potential beneficial effect of platelet-rich plasma (PRP) and fibrin sealant (TISSEEL; Baxter Healthcare Corporation, Deerfield, IL) on bowel wound healing after shaving of an experimentally induced endometriotic lesion. Design: A single-blind, randomized study (Canadian Task Force classification I). Setting: A certified animal research facility. Animals: Thirty female Sprague-Dawley rats. Interventions: Experimental colonic endometriosis was induced by transplanting endometrial tissue to all animals (first surgery). Thirty rats were then randomized to 1 of 3 groups according to treatment; PRP (group 1, n = 10), fibrin sealant (group 2, n = 10), or no agent (group 3, n = 10) was applied after shaving of the endometriotic nodule (second surgery). Measurements and Main Results: Colonic endometriosis was successfully induced in all subjects. Four days after the second surgery, the animals were euthanized, and microscopic evaluation was performed. The pathologist was blinded to the treatment method. Histopathologic analysis revealed that compared with the control group, collagen disposition was found in a significantly higher expression in both the PRP and fibrin sealant groups (p =.011 and p =.011, respectively). Distortion of the integrity of the colon layers was statistically more pronounced in the control group compared with the fibrin sealant group (p =.033), whereas greater new blood vessel formation was observed in the fibrin sealant group compared with the control (p =.023). No histologic evidence of residual or recurrent disease was detected. Conclusion: Both PRP and fibrin sealant appear to be safe and associated with improved tissue healing during shaving for the excision of colonic endometriosis, attributed to the enhanced collagen disposition, neovascularization, and protection of the integrity of colon layers. Clinical trials are warranted to confirm the feasibility of PRP and fibrin sealant in the clinical setting. © 2018 AAGL

Purpose: Endometriosis is a disease that affects 6–10% of the female population, mainly women of reproductive age, and causes a variety of cyclic symptoms. Deep infiltrating endometriosis and in particular bowel involvement presents a challenge for modern surgery. To date, there are no experimental animal models in this field, demonstrating experimental induction of endometriosis directly attached to surface of the colon imitating human colorectal endometriosis; hence, the implementation of novel pharmaceutical and surgical strategies for the management of colorectal endometriosis is mainly limited to clinical studies. Aim of the study: To investigate whether induction of colorectal endometriotic lesions in is feasible in rats. Materials and Methods: Twenty, female, adult, non-pregnant Sprague Dawley rats sustained uterine horn resection, which was then placed around the rectum of the rat with the endometrial surface in direct contact with the bowel serosa and approximated in the serosal surface of the colon with two sutures. Results: Two weeks following, surgery rats were euthanized and the bowel was surgically explored. The presence of a cystic lump at the site of the surgical intervention was evaluated macroscopically and microscopically. Histopathology documented the presence of cystic endometriosis. The endometriotic focus was adherent to the bowel wall by large fibrous nodules with concomitant replacement of part of the outer longitudinal muscle layer. Conclusions: The findings of our study support that the proposed experimental model of colorectal endometriosis is feasible, easily reproducible and may be implemented in future research in this field. Copyright © 2018 Taylor & Francis Group, LLC.

Objective: Estrogen receptor, coded by the ESR1 gene, is highly expressed in epithelial ovarian cancer. ESR1 gene is frequently methylated in many types of gynecological malignancies. However, only a few studies attempted to investigate the role of ESR1 methylation and its clinical significance in ovarian cancer so far. The aim of our study was to examine ESR1 methylation status in primary tumors and corresponding circulating tumor DNA of patients with high-grade serous ovarian cancer (HGSC). Methods: ESR1 methylation was detected by a highly specific and sensitive real-time methylation-specific PCR assay. Two groups of HGSC samples were analyzed: group A (n = 66 primary tumors) and group B (n = 53 primary tumors and 50 corresponding plasma samples). Results: ESR1 was found methylated in both groups of primary tumors: in 32/66 (48.5%) of group A and in 15/53 (28.3%) of group B. 19/50 (38.0%) corresponding plasma samples of group B were also methylated for ESR1. A significant agreement for ESR1 methylation was observed between primary tumors and paired plasma ctDNA samples (P = 0.004). Interestingly, the presence of ESR1 methylation in primary tumor samples of group B was significantly correlated with a better overall survival (P = 0.027) and progression-free survival (P = 0.041). Conclusions: We report for the first time the presence of ESR1 methylation in plasma ctDNA of patients with HGSC. The agreement between ESR1 methylation in primary tumors and paired ctDNA is statistically significant. Our results indicate a correlation between the presence of ESR1 methylation and a better clinical outcome in HGSC patients. © 2018 Elsevier Inc.

Aim: The study was conducted to delineate the histological problems in diagnosing uterine mesenchymal tumors in morcellated material. Methods: All cases of morcellated uteri performed between 2008 and 2014 were reviewed. The incidence of unexpected malignancy, defined as any neoplasm with a clear-cut diagnosis of leiomyosarcoma (LMS) or endometrial stromal sarcoma (ESS), was noted. Cases with absolute discrepancy between the diagnosis of the morcellated tumor and the subsequent diagnosis were also included in the study. Results: Out of 631 cases, a final diagnosis of LMS or ESS was made regarding three and five tumors, respectively. Patient age ranged from 25 to 48 years. Two further cases initially diagnosed as ESS proved to be endometrial stromal nodules with smooth muscle differentiation. Two cases were diagnosed as smooth muscle tumors with uncertain malignant potential and the patients remain free of disease. One tumor was diagnosed as an endometrial stromal neoplasm and proved to be benign and finally a leiomyoma variant presented with presumed peritoneal disease. Conclusion: Both endometrial stromal and smooth muscle tumors with malignant behavior can be encountered at a young age. Because of the limitations in histological evaluation, morcellated tumors may be overdiagnosed or underdiagnosed by pathologists. © 2017 Japan Society of Obstetrics and Gynecology

The RASSF1A promoter is frequently methylated in high-grade serous ovarian cancer (HGSC). We examined RASSF1A promoter methylation in primary tumors, adjacent morphologically tumor cell-free tissues and corresponding circulating tumor DNA (ctDNA) samples of patients with HGSC, using a real-time methylation specific PCR (real-time MSP) and a methylation-sensitive high-resolution melting analysis (MS-HRMA) assay for the detection and semi-quantitative estimation of methylation, respectively. Two groups of primary HGSC tumor FFPE samples were recruited (Group A n=67 and Group B n=61), along with matched adjacent morphologically tumor cellfree tissues (n=58) and corresponding plasma samples (n=59) for group B. Using both assays, RASSF1A promoter was found highly methylated in primary tumors of both groups, and at lower percentages in the adjacent morphologically tumor cell-free tissues. Interestingly, RASSF1A promoter methylation was also observed in ctDNA by real-time MSP. Overall survival (OS) was significantly associated with RASSF1A promoter methylation in primary tumor samples using MS-HRMA (P=0.023). Our results clearly indicate that RASSF1A promoter is methylated in adjacent tissue surrounding the tumor in HGSC patients. We report for the first time that RASSF1A promoter methylation provides significant prognostic information in HGSC patients.

Background: The Notch pathway has been implicated in triple-negative breast cancer (TNBC). Herein, we studied the subcellular localization of the less investigated Notch2 and Notch3 and that of the Jagged1 (Jag1) ligand in patients with operable TNBC. Patients and Methods: We applied immunohistochemistry for Notch2, Notch3 and Jag1 in 333 tumors from TNBC patients treated with adjuvant anthracycline-based chemotherapy. We evaluated cytoplasmic (c), membranous (m) and nuclear (n) protein localization. Results: c-Notch2 (35% positive tumors), c-Notch3 (63%), c-Jag1 (43%), m-Notch3 (23%) and n-Jag1 (17%) were analyzed individually and by using hierarchical clustering for prognostic evaluation. Upon multivariate analysis, compared to high m-Notch3 in the absence of n-Jag1 (cluster 4), all other marker combinations (clusters 1, 2, 3) conferred significantly higher risk for relapse (p

Background: Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system and appear as a severity index of the clinical course. Materials and methods: A total of 72 C57BL/6J mice, aged 12–14 weeks, were studied. The animals were divided into 3 sepsis (S) groups (24h, 48h and 72h) and 3 control (C) groups (24h, 48h and 72h), each consisting of 12 mice. The S-groups were subjected to cecal ligation and puncture (CLP) while the C-groups had a sham operation performed. Blood samples were drawn from all groups. Total blood count analysis was performed along with the measurement of certain biochemical markers. Additionally, lung tissues were harvested and the expression of TLRs, namely TLR 2, TLR 3, TLR 4 and TLR 7 were evaluated by means of immunofluorescence (IF) and qRT-PCR (quantitative-Polymerase Chain Reaction). Statistical analysis was performed by using one-way ANOVA followed by student t-test. Results were considered statistically significant when p

Background: The retinoblastoma (RB) gene is a tumor-suppressor gene that plays a central role in regulating the cell cycle. Inactivation of this gene is involved in breast cancer. Patients and Methods: A total of 827 patients with breast cancer treated with taxane-based adjuvant chemotherapy were included in the study. Protein expression of RB, phosphorylated RB (pRB), p16, cyclin D1 and p53 was evaluated by immunohistochemistry. Results: Neither of the retinoblastoma markers (RB and pRB) reached statistical significance in terms of their association with disease-free or overall survival. Nevertheless, when clustering analysis was performed, patients with tumors featuring low levels of p16, cyclin D1 and p53 with concomitantly high levels of pRB had reduced risk for relapse (Wald's p=0.015). Conclusion: The p53-mediated sensitivity of breast cancer cells to chemotherapeutic agents appears to be driven mostly by pRB. Using agents that enhance RB phosphorylation might possibly increase the chemosensitivity of breast cancer cells.

Inflammatory myofibroblastic tumour (IMT) of the bladder is a rare tumour of indeterminate malignant potential with myofibroblastic differentiation, with a generally benign but rarely aggressive behaviour. Vesical IMT is usually treated by transurethral resection or partial cystectomy. Herein we describe a case of a woman who underwent laparoscopic excision of an IMT of the bladder, initially diagnosed as deep infiltrating endometriosis. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved.

Objective: The aim of this study was to evaluate the clinicopathological features related to lymph node metastases in grade 1 endometrial carcinomas. Materials and Methods: Five hundred ninety-nine cases of endometrial carcinoma treated with total hysterectomy bilateral salpingo-oophorectomy and pelvic lyphadenectomy between 2001 and 2015 were retrieved from the pathology files of IASOWomen's Hospital, Athens, Greece. Of these, 345 were grade 1 endometrioid carcinomas and were included in the study. Features such as the age of the patients, the stage, the location, and size of the tumors, as well as the existence of microcystic, elongated, and fragmented pattern invasion or lymph vascular space invasion, were estimated. Results: In our cohort of endometrial carcinomas, features related to an increased risk of lymph node metastases were stages IB or higher; the location of the tumor in the lower uterine segment; the identification of microcystic, elongated, and fragmented pattern of invasion; and the existence of lymph vascular emboli. When considering the size of the tumors, only stage IAmyoinvasive cancers of larger than 4 cmin diameter were significantly associated with nodal disease. In addition, a statistically significant relationship was found between the number of excised lymph nodes and the possibility to detect nodal disease. Conclusions: Full surgical staging carries a substantial risk of operative complications, and, indeed, it can be avoided in most cases of grade 1 endometrial carcinomas. Nevertheless, even in the low-risk group of patients, there are clinicopathological parameters that should alert the clinician for the possibility of a more disseminated disease. Copyright © 2017 by IGCS and ESGO.

Background: Inflammatory myofibroblastic tumor is a rare tumor of a borderline malignancy. Although it is commonly seen in children, the number of childhood cases in the current literature is limited. The lung is the most commonly affected location. However, cases that have been documented in the mesentery-omentum have mostly been located in the mesentery of the small bowel and not in the antimesenteric edge as in our patient. Case presentation: A 6-year-old Greek boy was referred to our hospital with acute abdominal pain mimicking appendicitis. Ultrasound and computed tomography revealed a solid mass in the abdomen. The patient underwent laparoscopic resection of the tumor, and histopathology and immunohistochemical analysis favored an omental-mesenteric myxoid hamartoma, which is a variant of an inflammatory myofibroblastic tumor. The patient's postoperative course was uneventful, and he has been asymptomatic during follow-up. Conclusions: Inflammatory myofibroblastic tumor of the small intestine is a rare, benign neoplasm in children that should be considered as a possible cause of acute abdomen. A precise diagnosis can be made on the basis of histologic findings. Surgical excision is the treatment of choice. © 2016 Oeconomopoulou et al.

Background: Epithelial-mesenchymal transition is one of the mechanisms that contribute to the aggressiveness of cancer. CD44 antigen is an emerging biomarker that is currently being evaluated in the literature in the frame of epithelial-mesenchymal transition. The aim of this study was to evaluate the expression of CD44 in relation to several clinicopathological parameters in gastric and esophageal carcinomas. Materials and Methods: This historical cohort survey was performed on gastric and esophageal tumors obtained from 86 patients who underwent resection from 2003 until 2011. Immunohistochemistry was used for assessing the expression of CD44 with a semiquantitative model. Results: Survival rates were negatively correlated with pT at diagnosis (p

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches. © 2014 Nature America, Inc. All rights reserved.

INTRODUCTION: To investigate the immunohistochemical expression of claudin-1, claudin-3, and claudin-4 in triple-negative breast carcinomas and compare it with several clinicopathologic parameters as well as their expression in luminal cancers. MATERIALS AND METHODS: A total of 128 cases of breast carcinoma were included in the study. For all these cases, immunohistochemistry for estrogen and progesterone receptors, Ki-67, and Her2 had already been performed, whereas Her2 2+ cases had been further characterized as positive or negative for Her2 amplification with the chromogenic in situ hybridization technique. Seventy-six tumors were triple negative. The remaining 52 were luminal cancers. All tumors were evaluated for the expression of claudin-1, claudin-3, and claudin-4. RESULTS: In the triple-negative group, the positive expression of claudin-3 and claudin-4 was related to unfavorable and favorable prognostic factors, respectively. Claudin-1 was not related to any parameter under evaluation. In the luminal cancer group, claudin-4 positivity was related to a shorter disease-free survival, whereas the inverse was observed for claudin-3. Moreover, all 3 claudins increased with increase of the grade and Ki-67 value in the luminal cancers. CONCLUSION: A distinct prognostic significance in the expression of claudin-3 and mostly of claudin-4 between triple-negative and luminal breast carcinomas was identified. Specifically, in triple-negative carcinomas, claudin-4 positivity could probably be considered as a biomarker of favorable prognosis, whereas in luminal cancers with claudin-4-positive expression, the administration of targeted therapy should eventually be part of the patients' management in the near future. Copyright © 2013 by Lippincott Williams &Wilkins.

The aim of the study was to evaluate whether the preoperative intrauterine injection of methylene blue could help in visualizing the endometrium of uterine morcellation specimens. A total of 48 laparoscopic subtotal hysterectomies using the uterine morcellation technique were used for the study. In 19 of these cases, a preoperative intrauterine administration of methylene blue had been performed (study group). The total number of slides for each group, without and with methylene blue, was counted. Moreover, the number of slides comprising endometrial tissue was evaluated. The number of sections included in the control group to adequately assess the endometrium ranged from 6 to 95 (mean 27.24±4.01), whereas the respective number for the study group ranged from 4 to 10 (mean 7.21±0.44). The efficacy of recognizing adequate endometrial tissue (defined by the percentage of slides with adequate endometrial tissue over the overall slides requested to evaluate complete uterine histology) was significantly higher in the study group compared with that in the control group (67.05%±2.36% vs. 17.46%±2.66%, respectively; P

INTRODUCTION Port-site metastasis or peritoneal spread after laparoscopic surgery for urological malignancies is a rare phenomenon accounting for 0.09% and 0.03% of the cases respectively. PRESENTATION OF CASE We present a case of tumor seeding in the omentum found in a female patient after previous transperitoneal robotic-assisted radical nephrectomy (RARN) for papillary renal cell carcinoma (RCC). Two years after the robotic operation, the patient was diagnosed with cervical clear cell carcinoma and underwent radical hysterectomy with lymphadenectomy and omentectomy. A neoplastic omental nodule was incidentally identified intraoperatively. Pathological characteristics and immunohistochemistry revealed features of papillary RCC. Two years after the hysterectomy, the patient is clinically cancer free, without any adjuvant therapy for her cervical cancer. DISCUSSION To the best of our knowledge, we report the first case of tumor seeding in the omentum following RARN for organ confined low grade papillary (T2aN0M0) RCC. No risk factors that could explain the tumor seeding were identified. The neoplastic cells had a low proliferative index (Ki-67 < 5%) and a decreased capability to metastasize. CONCLUSION Tumor seeding as a result of robotic assisted laparoscopic nephrectomy, although rare, might represent a novel way of tumor inoculation deprived of or with low malignant potential. © 2013 Surgical Associates Ltd.

EGFR (epidermal growth factor receptor), cyclin D1 and Akt/mTOR pathways are active in head and neck cancer. The aim of this study was to explore biomarker expression, their correlations with clinicopathological parameters and their prognostic utility in a cohort of patients with localized squamous laryngeal carcinoma. We assessed relative messenger RNA expression of EGFR, Akt1, 2, and 3, mTOR and CCND1, copy number variants of the EGFR and CCND1 genes and immunohistochemical protein expression of EGFR, p-Akt308, p-Akt473, pmTOR, PTEN, p53 and cyclin D1 in paraffin-embedded tissue samples of localized laryngeal carcinomas. In 289 patients with T3-4 (77.8%), node-negative (84.1%) tumors of the larynx, high EGFR and CCND1 mRNA correlated with no or ex-smoking, (p = 0.003 and p = 0.029, respectively), while low Akt3 mRNA correlated with alcohol abuse, N0 stage, total laryngectomy, and absence of neck dissection. At a median follow-up of 74.5 months, high mTOR mRNA expression was marginally associated with shorter disease-free survival (hazard ratio [HR] = 1.54; p = 0.093) and high Akt3 mRNA with shorter overall survival (HR = 1.49; p = 0.0786), in univariate analysis. In multivariate analysis, node-positive status, subglottic-transglottic location, surgery other than total laryngectomy and mTOR/CCND1 mRNA interaction with a hazard ratio of 2.16 (p value for interaction: 0.0010) were independent predictors of relapse, while node-positive status and subglottic-transglottic location were associated with higher risk for death. In localized laryngeal cancer, clinicopathological parameters and an interaction of high mTOR and CCND1 mRNA expression were found to be associated with poor patient outcome.

The ThinPrep cervical smear is widely used in clinical practice for the cytological and molecular screening against abnormal cells and Human Papillomavirus (HPV) infection. Current advancements made to LC-MS proteomics include the use of stable isotope labeling for the in-depth analysis of proteins in complex clinical specimens. Such approaches have yet to be realized for ThinPrep clinical specimens. In this study, an LC-MS method based on isobaric (iTRAQ) labeling and high-resolution FT-Orbitrap mass spectrometry was used for the proteomic analysis of 23 human ThinPrep smear specimens. Tandem mass spectrometry analysis was performed with both nitrogen high collision dissociation (HCD MS/MS) and helium collision induced dissociation (CID MS/MS) peptide fragmentation modes. The analysis of three 8-plex sample sets yielded the identification of over 3200 unique proteins at FDR < 1%, of which over 2300 proteins were quantitatively profiled in at least one of the three experiments. The interindividual variability served to define the required sample size needed to identify significant protein expression differences. The degree of in-depth proteome coverage allowed the detection of 6 HPV-derived proteins including the high-risk HPV16 type in the specimens tested. The presence of the HPV strains of origin was also confirmed with PCR-hybridization molecular methods. This proof-of-principle study constitutes the first ever report on the nontargeted analysis of HPV proteins in human ThinPrep clinical specimens with high-resolution mass spectrometry. A further testament to the sensitivity and selectivity of the proposed study method was the confident detection of a significant number of phosphopeptides in these specimens. © 2013 American Chemical Society.

BACKGROUND: The role of Nitric Oxide (NO) in angiogenesis has not been fully clarified yet. A dual role for NO, either inductive or inhibitory, has been proposed on the basis of different effects that high or low concentrations of NO may exert on the angiogenic process. Additionally, it has been referred that NO may induce VEGF production, while VEGF may induce NO production via up-regulation of the endothelial nitric oxide synthase (eNOS), the two pathways being reverse. The aim of the current study was to investigate the expression of key molecules involved in these opposite pathways in primary breast cancer. METHODS: Representative tumor samples from 242 patients with early-stage breast cancer (invasive ductal breast carcinomas) were investigated for the expression of VEGF, VEGFR-2, HIF1alpha, iNOS, and eNOS using immunohistochemistry. RESULTS: Endothelial NOS was found in 159 cases, VEGF in 131 cases, HIF-1alpha in 139 cases, VEGFR2 in 185 cases and inducible NOS (iNOS) in 22 cases. There was a significant correlation between the expression of VEGF and VEGFR-2, eNOS and VEGF, eNOS and VEGFR-2, eNOS and HIF1alpha. No statistically significant correlation was found between iNOS and the rest of the studied molecules. CONCLUSIONS: In breast cancer cases, the major molecules regulating NO and VEGF production can be co-expressed in the individual carcinomas implying a possibility for the relevant pathways to be active; however appropriate functional experiments remain to be conducted to prove such a hypothesis. Pathol Oncol Res

Intervertebral disc (IVD) degeneration is accompanied by growth factor-overexpression and increased cell proliferation, probably representing a tissue repair process. Accordingly, we studied the effect of exogenous and autocrine growth factors on the proliferation of human IVD cells. We observed that Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin-like Growth Factor-I (IGF-I) stimulate DNA synthesis of human IVD cells, through the activation of the MEK/ERK and the PI-3K/Akt signal transduction pathways. Furthermore, medium conditioned (CM) by IVD cells induced DNA synthesis in the same cells, indicating the secretion of autocrine growth factors. The MEK/ERK and PI-3K/Akt pathways were also induced by CM, while their inhibition reversed in large part the DNA synthesis induction by CM. These responses to the exogenous and autocrine growth factors were qualitatively similar in both nucleus pulposus (NP) and annulus fibrosus (AF) cell cultures. Immunohistochemical studies in human biopsies showed significant activation of both signaling pathways, which was most prominent in the clusters of proliferating cells. These in vitro and in vivo data indicate that the proliferation of human IVD cells is regulated by exogenous and autocrine growth factors mainly via the MEK/ERK and PI-3K/Akt pathways; this may contribute to the design of future interventional approaches. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

AIM: To evaluate the immunohistochemical expression of several benign or malignant mucinous lesions that can be encountered in endometrial curettage material. MATERIALS AND METHODS: Nineteen well-differentiated mucinous endometrial carcinomas, 12 papillary mucinous metaplasias, 11 cervical microglandular hyperplasias, 11 endocervical adenocarcinomas, 2 goblet cell metaplasias, 1 minimal-deviation adenocarcinoma, and 1 lobular endocervical glandular hyperplasia entered the study. Immunohistochemistry was performed with the following antibodies against: estrogen receptors, progesterone receptors, vimentin, p16, p63, carcinoembryonic antigen, and Ki-67. RESULTS: Immunohistochemistry could easily distinguish endocervical adenocarcinoma of usual type from all other lesions under study. A Vim/p16/p63 signature was found to favor a cervical microglandular hyperplasia, whereas both mucinous endometrial carcinoma and mucinous papillary metaplasia would be preferentially characterized by a Vim/p16/p63 immunophenotype. A high Ki-67 expression would be of help in differentiating the latter 2 conditions. Statistically, the expression of estrogen receptors, progesterone receptors, and carcinoembryonic antigen did not aid in the differential diagnosis of these 3 conditions. For the 4 cases representing goblet cell metaplasia, minimal-deviation adenocarcinoma and lobular endocervical glandular hyperplasia, no results could be drawn. CONCLUSIONS: In endometrial curettage material, the differential diagnosis of lesions comprising mucinous epithelium might be rendered by combining the immunohistochemical expression of vimentin, p16, p63, and Ki-67. Of all lesions, endocervical adenocarcinoma of usual type is the most easily identified. Copyright © 2012 by Lippincott Williams & Wilkins.