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This article discusses the clinicopathological and molecular features of mesonephric-like adenocarcinoma (MLA) of the endometrium. MLAs are high-grade tumors that can recur and metastasize to the lungs. They are similar to true mesonephric carcinomas (MC) but do not have an association with mesonephric remnants. The article presents a case study of a woman with endometrial neoplasm that consisted of three distinct neoplastic components, including MLA. The study found that the MLA component showed loss of mismatch repair (MMR) proteins, which is a novel finding. This suggests a common link between endometrioid carcinoma, MLA, and undifferentiated/de-differentiated carcinoma of the uterus. The authors suggest that further studies should investigate microsatellite instability in MLA, as endometrial carcinomas with MMR deficiency can be targeted with immunotherapy. [Extracted from the article]

Simple Summary: Histologic type is an important prognostic determinant in the clinical workup of uveal melanoma (UM), with different histologic types being related to different metastatic risk and hence mortality rates. The diagnosis of UM is predominantly clinical, whereas biopsy, although capable of providing the histologic type, is not routinely performed due to its invasiveness and complications. Moreover, biopsy often provides contradictory results because of the heterogeneity of UMs. In this context, recently the interest has grown as regards to noninvasive biomarkers, which can represent alternative methods of prognostication. We verified whether magnetic resonance imaging and, in particular, one of its functional techniques, diffusion-weighted imaging, could be helpful in distinguishing the different histologic types of UMs and therefore play a prognostic role. Whilst negative, our preliminary results could represent a starting point for future research in the context of a patient-centered approach of healthcare. Histopathologically, uveal melanomas (UMs) can be classified as spindle cell, mixed cell and epithelioid cell type, with the latter having a more severe prognosis. The aim of our study was to assess the correlation between the apparent diffusion coefficient (ADC) and the histologic type of UMs in order to verify the role of diffusion-weighted magnetic resonance imaging (DWI) as a noninvasive prognostic marker. A total of 26 patients with UMs who had undergone MRI and subsequent primary enucleation were retrospectively selected. The ADC of the tumor was compared with the histologic type. The data were compared using both one-way analysis of variance (ANOVA) (assessing the three histologic types separately) and the independent t-test (dichotomizing histologic subtypes as epithelioid versus non-epithelioid). Histologic type was present as follows: the epithelioid cell was n = 4, and the spindle cell was n = 11, the mixed cell type was n = 11. The mean ADC was 1.06 ± 0.24 × 10−3 mm2/s in the epithelioid cells, 0.98 ± 0.19 × 10−3 mm2/s in the spindle cells and 0.96 ± 0.26 × 10−3 mm2/s in the mixed cell type. No significant difference in the mean ADC value of the histopathologic subtypes was found, either when assessing the three histologic types separately (p = 0.76) or after dichotomizing the histologic subtypes as epithelioid and non-epithelioid (p = 0.82). DWI-ADC is not accurate enough to distinguish histologic types of UMs. [ABSTRACT FROM AUTHOR]

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of our study is to provide a wide perspective on the available literature data on the immune landscape of breast cancers, focusing on TILs and PD-L1 expression across different breast cancer subtypes. Moreover, treatment options such as immunotherapy and chemotherapy in adjuvant and neoadjuvant settings are discussed, along with the most relevant cut-offs and scores for TILs and PD-L1 pathological assessment. With the rise of novel immunotherapies able to stimulate the antitumor immune response, increasing literature concerning the immunogenicity of breast cancer has been published in recent years. Numerous clinical studies have been conducted in order to identify novel biomarkers that could reflect the immunogenicity of BC and predict response to immunotherapy. In this regard, TILs have emerged as an important immunological biomarker related to the antitumor immune response in BC. TILs are more frequently observed in triple-negative breast cancer and HER2+ subtypes, where increased TIL levels have been linked to a better response to neoadjuvant chemotherapy and improved survival. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in breast cancer is observed in about 10–30% of cases and is extremely variable based on tumor stage and molecular subtypes. Briefly, TNBC shows the highest percentage of PD-L1 positivity, followed by HER2+ tumors. On the other hand, PD-L1 is rarely expressed (0–10% of cases) in hormone-receptor-positive BC. The prognostic role of PD-L1 expression in BC is still controversial since different immunohistochemistry (IHC) clones, cut-off points, and scoring systems have been utilized across published studies. In the present paper, an extensive review of the current knowledge of the immune landscape of BC is provided. TILS and PD-L1 expression across different BC subtypes are discussed, providing a guide for their pathological assessment and reporting. [ABSTRACT FROM AUTHOR]

Simple Summary: We are going to highlight new prognostic and predictive factors, CD44, PDL1, and ATG7, in surgical samples from patients with laryngeal squamous cell carcinoma (LSCC). Immunohistochemical analysis with primary antibodies anti-CD44, PD-L1 and ATG7 was performed using the tissue microarray (TMA) technique. Considering follow-up data, the 5-year disease-free survival (DFS) was 85.71% and 36% for CD44-negative and -positive tumors. The 5-year DFS was 60% and 33.33% for negative and positive PDL1 tumors, respectively. At the follow-up, 5-year DFS was 58.06% and 37.50% for negative and positive ATG7 tumors. We focus on the new prognostic and predictive factors CD44, PDL1, and ATG7 in our study of surgical samples of patients with laryngeal squamous cell carcinoma (LSCC) using tissue microarray (TMA). Thirty-nine previously untreated patients affected by laryngeal carcinoma who then underwent surgical treatment were considered in this retrospective study. All surgical specimens were sampled, embedded in paraffin blocks, and stained with hematoxylin and eosin. A representative sample of the tumor was chosen and transferred into a new block of paraffin, the recipient block, to perform immunohistochemical analysis with the primary antibodies anti-CD44, PD-L1, and ATG7. At follow-up, 5-year disease-free survival (DFS) for negative and positive tumors was determined as 85.71% and 36% for CD44, 60% and 33.33% for PDL1, and 58.06% and 37.50% for ATG7, respectively. Multivariate analysis revealed that CD44 expression is an independent predictive factor of low-grade tumors (p = 0.008), lymph node metastasis at the time of diagnosis, and AGT7 negativity. Thus, CD44 expression is a potential marker for more aggressive forms of laryngeal cancer. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. To date, the main strategies to counteract its progression consist of focal radiation on the tumor site and ocular enucleation. Furthermore, many UM patients develop liver metastasis within 10 years following diagnosis, eventually resulting in a poorer prognosis for those patients. Dissecting the molecular mechanism involved in UM progression may lead to identify novel prognostic markers with significative clinical applications. The aim of the present study was to evaluate the role of Heme Oxygenase 1 (HO-1) in regulating UM progression. UM cell lines (92.1) were treated with Hemin (CONC e time), a strong inducer of HO-1, and VP13/47, a selective inhibitor of its enzymatic activity. Interestingly, our results showed an enhanced 92.1 cellular proliferation and wound healing ability following an HO-1 increase, overall unveiling the role played by this protein in tumor progression. Similar results were obtained following treatment with two different CO releasing molecules (CORM-3 and CORM-A1). These results were further confirmed in a clinical setting using our UM cohort. Our results demonstrated an increased median HO-1 expression in metastasizing UM when compared to nonmetastasizing patients. Overall, our results showed that HO-1 derived CO plays a major role in UM progression and HO-1 protein expression may serve as a potential prognostic and therapeutical factor in UM patients. [ABSTRACT FROM AUTHOR]

Peripheral nerve sheath tumors encompass a wide spectrum of lesions with different biological behavior, including both benign and malignant neoplasms as well as the recent diagnostic category, i.e., "atypical neurofibromatous neoplasm with uncertain biologic potential" to be used only for NF1 patients. Neurofibromas and schwannomas are benign Schwann-cell-derived peripheral nerve sheath tumors arising as isolated lesions or within the context of classical neurofibromatosis or schwannomatoses. Multiple tumors are a hallmark of neurofibromatosis type 1(NF1) and related forms, NF2-related-schwannomatosis (formerly NF2) or SMARCB1/LZTR1-related schwannomatoses. Perineuriomas are benign, mostly sporadic, peripheral nerve sheath tumors that show morphological, immunohistochemical, and ultrastructural features reminiscent of perineurial differentiation. Hybrid tumors exist, with the most common lesions represented by a variable mixture of neurofibromas, schwannomas, and perineuriomas. Conversely, malignant peripheral nerve sheath tumors are soft tissue sarcomas that may arise from a peripheral nerve or a pre-existing neurofibroma, and in about 50% of cases, these tumors are associated with NF1. The present review emphasizes the main clinicopathologic features of each pathological entity, focusing on the diagnostic clues and unusual morphological variants. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM. [ABSTRACT FROM AUTHOR]

Abstract Background The main cause of treatment failure and death in laryngeal squamous cell carcinoma is metastasis to the regional lymph nodes. The current clinical staging criteria fail to differentiate patients with occult metastasis from patients without metastasis. Identifying molecular markers of the disease might improve our understanding of the molecular mechanisms underlying the pathogenesis and development of laryngeal carcinoma and may help improve clinical staging and treatment. Methods Sixty-four previously untreated patients who underwent surgical excision of laryngeal squamous cell carcinoma with neck dissection were included in this study. The expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) was examined immunohistochemically on formalin-fixed paraffin-embedded primary tissue specimens. Results Nuclear expression of BMI-1 (nBMI-1) was detected in 32 of the 64 tumors (50%), cytoplasmic expression of BMI-1 (cBMI-1) was detected in 22 (34.4%), and 10 tumors (15.6%) showed no BMI-1 immunoreactivity. High nBMI-1 expression levels (≥10) were detected in 28 of the 32 (87.5%) nBMI-1-positive patients. Multivariate analysis including age at diagnosis, grade, tumor location, TNM status, and nBMI-1 expression showed that a high nBMI-1 expression level was an independent prognostic factor for lymph node metastasis. Conclusion The expression of BMI-1 in patients with laryngeal carcinoma seems to correlate with lymph node metastasis.

Therapy of uveal melanoma aims to preserve the eye and its function and to avoid metastatic dissemination. The treatment choice is difficult and must keep into account several factors; the therapeutic strategy of uveal melanoma should therefore be personalized, sometimes requiring to combine different treatment techniques. Nowadays globe-sparing radiotherapy techniques are often preferred to enucleation. Plaque brachytherapy, the most commonly used eye-preserving therapy, is suitable for small- and medium-sized uveal melanomas. Proton beam radiotherapy is indicated for tumours with noticeable size, challenging shape and location, but is more expensive and less available than brachytherapy. Enucleation is currently restricted to advanced tumours, uveal melanomas with orbital or optic nerve involvement, blind and painful eyes because of treatment-related complications (neovascular glaucoma, chronic inflammatory processes). The effect of proton beam therapy on neoplastic tissue is related to direct cytotoxic action of the radiations, impairment of neoplastic vascular supply and immunologic response. Complications after radiotherapy are frequent and numerous and mainly related to tumour thickness, radiation dose and distance between the tumour and optic nerve. The purpose of this pictorial review is to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the present second section, we discuss the therapeutic management of uveal melanoma, describing the main ocular-conserving radiotherapic techniques. We subsequently present an overview of the effects of radiations on neoplastic tissue. Lastly, we review ocular complications following radiotherapy that should be evaluated by radiologists during follow-up MRI examinations. [ABSTRACT FROM AUTHOR]

Uveal melanoma is a malignant neoplasm that derives from pigmented melanocytes of the uvea and involves, in order of decreasing prevalence, the choroid, ciliary body and iris. Its prognosis is related to histopathologic and genetic features, tumor size and location, extraocular extension. The diagnosis is fundamentally based on clinical evaluation (ophthalmoscopy, biomicroscopy) and ultrasonography. MRI is useful in case of untransparent lens or subretinal effusion. Moreover, MRI has a significant role to confirm the diagnosis, in the evaluation of the local extent of the disease with implications for treatment planning, and in the follow-up after radiotherapy treatment. Uveal melanoma can show different morphologic features (lentiform, dome or mushroom shape) and often determines retinal detachment. MR appearance of uveal melanoma mainly depends on the melanin content. Uveal melanoma typically displays high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Nevertheless, imaging appearance may be variable based on the degree of pigmentation and the presence of areas of necrosis or cavitation. Differential diagnosis includes other uveal lesions. The radiologists and in particular MRI play a significant role in the clinical management of uveal melanoma. The purpose of this pictorial review is to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the present first section we summarize the MR anatomy of the eye and describe ophthalmological and radiological imaging techniques to diagnose uveal melanomas, with emphasis on the role of MR imaging. Additionally, we review MR imaging appearance of uveal melanomas. [ABSTRACT FROM AUTHOR]

Background: Currently, radiotherapy represents the most widely employed therapeutic option in patients with uveal melanoma. Although the effects of proton beam radiotherapy on uveal melanoma end ocular tissues have been histologically documented, their appearance at MR imaging is still poorly understood. The purpose of our study was to elucidate the magnetic resonance (MR) semiotics of radiotherapy-induced changes to neoplastic tissues and ocular structures in patients with uveal melanoma undergoing secondary enucleation after proton beam radiotherapy. Methods: Nine patients with uveal melanoma who had undergone proton beam radiotherapy, MR imaging, and subsequent secondary enucleation were retrospectively selected. The histopathologic findings evaluated for irradiated tumors were necrosis, fibrosis, and viable tumor, while the histopathologic findings evaluated for extratumoral ocular/periocular tissues were radiation-related intraocular inflammation, vitreous hemorrhage, optic nerve degeneration, iris neovascularization, and periocular fibrotic adhesions. On MR images, the appearance of the abovementioned histologic features was assessed on conventional and diffusion-weighted sequences. Results: T2-weighted sequences performed better in detecting radiation-induced necrosis, fibrosis, optic nerve degeneration, and periocular fibrotic adhesions. T1-weighted sequences were preferable for identifying cataracts, vitreous hemorrhage, and inflammatory complications. Contrast-enhanced T1-weighted sequences were irreplaceable in assessing iris neovascularization, and in confirming inflammatory complications. Conclusions: In the light of their increasing role in the multidisciplinary management of patients with uveal melanoma, radiologists should be aware of the MR appearance of the effects of radiotherapy on neoplastic and ocular tissue, in order to improve the accuracy of follow-up MR examinations. [ABSTRACT FROM AUTHOR]

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected. [ABSTRACT FROM AUTHOR]

The human Wilms' tumor gene (WT1) was originally isolated in a Wilms' tumor of the kidney as a tumor suppressor gene. Numerous isoforms of WT1, by combination of alternative translational start sites, alternative RNA splicing and RNA editing, have been well documented. During human ontogenesis, according to the antibodies used, anti-C or N-terminus WT1 protein, nuclear expression can be frequently obtained in numerous tissues, including metanephric and mesonephric glomeruli, and mesothelial and sub-mesothelial cells, while cytoplasmic staining is usually found in developing smooth and skeletal cells, myocardium, glial cells, neuroblasts, adrenal cortical cells and the endothelial cells of blood vessels. WT1 has been originally described as a tumor suppressor gene in renal Wilms' tumor, but more recent studies emphasized its potential oncogenic role in several neoplasia with a variable immunostaining pattern that can be exclusively nuclear, cytoplasmic or both, according to the antibodies used (anti-C or N-terminus WT1 protein). With the present review we focus on the immunohistochemical expression of WT1 in some tumors, emphasizing its potential diagnostic role and usefulness in differential diagnosis. In addition, we analyze the WT1 protein expression profile in human embryonal/fetal tissues in order to suggest a possible role in the development of organs and tissues and to establish whether expression in some tumors replicates that observed during the development of tissues from which these tumors arise. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) include isolated kidney malformations and urinary tract malformations. They have also been reported in Prune-Belly syndrome (PBS) and associated genetic syndromes, mainly 13, 18 and 21 trisomy. The AA focuses on bladder and urethral malformations, evaluating the structural and histological differences between two different cases of megacystis. Both bladders were examined by routine prenatal ultrasound screening and immunohistochemistry, comparing the different expression of smooth muscular actin (SMA), S100 protein and WT1c in megacystis and bladders of normal control from fetuses of XXI gestational age. Considering the relationship between the enteric nervous system and urinary tract development, the AA evaluated S100 and WT1c expression both in bladder and bowel muscular layers. Both markers were not expressed in the bladder and bowel of PBS associated with anencephaly. In conclusion, megacystis could be considered only a macroscopic definition, concerning the size of the fetal bladder rather than the embryologic origin; it may be a single or multiple malformation; the possible association with the bowel and/or encephalic malformations will decide the outcome and prognosis in fetal megacystis. [ABSTRACT FROM AUTHOR]

MacroH2A is a histone variant whose expression has been studied in several neoplasms, including cutaneous melanomas (CMs). In the literature, it has been demonstrated that macroH2A.1 levels gradually decrease during CM progression, and a high expression of macroH2A.1 in CM cells relates to a better prognosis. Although both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma (UM) is biologically and genetically distinct from the more common cutaneous melanoma. Metastasis to the liver is a frequent occurrence in UM, and about 40%–50% of patients die of metastatic disease, even with early diagnosis, proper treatment, and close follow-up. We wanted to investigate macroH2A.1 immunohistochemical expression in UM. Our results demonstrated that mH2A.1 expression was higher in metastatic UM (21/23, 91.4%), while only 18/32 (56.3%). UMs without metastases showed mH2A.1 staining. These data could suggest a possible prognostic role for mH2A.1 and could form a basis for developing new pharmacological strategies for UM treatment. [ABSTRACT FROM AUTHOR]

Uveal melanoma represents the most common primary intraocular malignancy in adults; it may arise in any part of the uveal tract, with choroid and ciliary bodies being the most frequent sites of disease. In the present paper we studied ABCB5 expression levels in patients affected by uveal melanoma, both with and without metastasis, in order to evaluate if ABCB5 is associated with a higher risk of metastatic disease and can be used as a poor prognostic factor in uveal melanoma. The target population consisted of 23 patients affected by uveal melanoma with metastasis and 32 without metastatic disease. A high expression of ABCB5 was seen in patients with metastasis (14/23, 60.9%), compared to that observed in patients without metastasis (13/32, 40.6%). In conclusion, we found that ABCB5 expression levels were correlated with faster metastatic progression and poorer prognosis, indicating their role as a prognostic factor in uveal melanoma. [ABSTRACT FROM AUTHOR]

Background In the international literature we have never found a long survival in patients treated for a colon cancer with synchronous hepatic metastases and for a metachronous Krukenberg tumor. Presentation of case A 46-year old woman for an advanced colon cancer with a synchronous hepatic metastases was subjected to a left hemicolectomy and a resection of liver segment V (R0 resection; T4N2bM1; stage IVa according AJCC 2010). After one year a CT of the abdomen revealed an expansive formation of the left ovary. The patient was subjected to a bilateral ovariectomy, hysterectomy and hiperthermic intraperitoneal chemotherapy (HIPEC). The patient, after several cycles of adjuvant chemotherapy, is disease-free 13 years after surgery. Discussion To our knowledge, in the literature there do not appear to be cases of such disease-free survival. The survival of patient despite the prognostic indexes is discussed. The authors discus the importance of an adequate surgical treatment especially for liver metastases simultaneously treated to colon cancer. The authors also focus on chemotherapy (FOLFOX and then FOLFIRI) performed in a pre-biological era. Furthermore, the degree to which the HIPEC may have had an impact is still unknown, although it seems to be the gold standard for the treatment of the microscopic peritoneal neoplastic remnant. Conclusion The authors emphasize that the long term survival in colon cancer with hepatic and ovarian metastases is possible as long as it has an adequate surgical approach, a tailored chemotherapy and an intensive follow-up. Most likely new prognostic markers will have to be identified. [ABSTRACT FROM AUTHOR]

Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood. [ABSTRACT FROM AUTHOR]

Uveal melanoma is the most frequent primary intraocular neoplasm in adults. Although malignant melanoma may be located at any point in the uveal tract, the choroid and ciliary body are more frequent locations than the iris. In the present study, we examined ADAM10 expression levels in primary uveal melanoma both with and without metastasis, and we evaluated their association with other high risk characteristics for metastasis in order to assess if ADAM10 can be used to predict metastasis. This study included a total of 52 patients, 23 men and 29 women, with uveal melanoma. A significantly high expression of ADAM-10 was seen in patients with metastasis (11/13, 84.6%), but not in patients without metastasis (15/39, 38.5%). In conclusion we found that ADAM10 expression was associated with a more rapid metastatic progression confirming its role in uveal melanoma metastasis. [ABSTRACT FROM AUTHOR]

Osteoarthritis is the most common human arthritis characterized by degeneration of articular cartilage. Several studies reported that levels of human cartilage glycoprotein chitinase 3-like-1 (CHI3L1) are known as a potential marker for the activation of chondrocytes and the progression of Osteoarthritis (OA), whereas lubricin appears to be chondroprotective. The aim of this study was to investigate the co-expression and co-localization of CHI3L1 and lubricin in normal and osteoarthritic rat articular cartilage to correlate their modified expression to a specific grade of OA. Samples of normal and osteoarthritic rat articular cartilage were analyzed by the Kellgren-Lawrence OA severity scores, the Kraus' modified Mankin score and the Histopathology Osteoarthritis Research Society International (OARSI) system for histomorphometric evaluations, and through CHI3L1 and lubricin gene expression, immunohistochemistry and double immuno-staining analysis. The immunoexpression and the mRNA levels of lubricin increased in normal cartilage and decreased in OA cartilage (normal vs. OA, p < 0.01). By contrast, the immunoexpression and the mRNA levels of CHI3L1 increased in OA cartilage and decreased in normal cartilage (normal vs. OA, p < 0.01). Our findings are consistent with reports suggesting that these two glycoproteins are functionally associated with the development of OA and in particular with grade 2/3 of OA, suggesting that in the future they could be helpful to stage the severity and progression of the disease. [ABSTRACT FROM AUTHOR]

Emerging studies show that BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) has an important function as a biomarker of cancer stem cells (CSCs), i.e. cells with self-renewal characteristics, capable of tumor initiation, progression, invasion, metastasis, tumor recurrence and resistance to chemotherapy and radiotherapy. The failure of current anticancer therapies can be attributed to the relative ineffectiveness of drug and radiation treatments on CSCs, thereby preserving the full capacity of the cells to reproduce tumors. The development of new strategies is currently hindered by the lack of reliable markers for the identification of these CSCs. At present, they have been isolated from solid tumors at various locations using a variety of surface markers, including CD34, CD133, CD24, CD44, CD29 and CD31, in addition to the methods of isolation and cell culture via the Wnt, BMI1, Notch and Hedgehog pathways. The discovery of specific tumor targets for CSCs would constitute a big step in the research for the definitive therapy against cancer. More studies are being conducted that consider the role of CSCs in head and neck cancers with potential for an impact on clinical-surgical outcomes from the knowledge that is being gained. A promising intracellular marker of CSCs in head and neck cancer is the oncoprotein BMI1, with specific data about its prognostic value based on the specific location. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Developmental expression of Wilms’ tumor gene (WT1) and protein is crucial for cell proliferation, apoptosis, differentiation and cytoskeletal architecture regulation. Recently, a potential role of WT1 has been suggested in the development of neural tissue and in neurodegenerative disorders. We have investigated immunohistochemically the developmentally regulated expression and distribution of WT1 in the human fetal peripheral sympathetic nervous system (PSNS) and the gastro-enteric nervous system (GENS) from weeks 8 to 28 gestational age. WT1 expression was restricted to the cytoplasm of sympathetic neuroblasts, while it progressively disappeared with advancing morphologic differentiation of these cells along both ganglionic and chromaffin cell lineages. In adult tissues, both ganglion and chromaffin cells lacked any WT1 expression. These findings show that WT1 is a reliable marker of human sympathetic neuroblasts, which can be used routinely in formalin-fixed, paraffin-embedded tissues. The progressive loss of WT1 in both ganglion and chromaffin cells, suggests its potential repressor role of differentiation in a precise temporal window during the development of the human PSNS and GENS. [Copyright &y& Elsevier]

Simple Summary: Uveal melanomas may undergo necrosis, both spontaneously or following radiotherapy. Nowadays radiotherapy is the preferred treatment, whereas enucleation of the eye is used in selected cases. In order to differentiate the effects of radiotherapy from spontaneous degenerative changes in uveal melanomas, we compared the appearance of necrosis, both from a histopathological point of view and from the perspective of MR imaging, in two groups of patients with uveal melanoma: a group who had undergone previous proton beam radiotherapy (secondary enucleation); a control group who had undergone enucleation without any previous radiotherapy treatment (primary enucleation). Irradiated and nonirradiated uveal melanomas differ on the basis of the histological appearance, the MR imaging appearance and the distribution of necrosis. We hope that the findings we observed could be extended to all patients with uveal melanomas treated with radiotherapy, and may enhance the accuracy of radiologists in evaluating MR examinations after radiotherapy. Necrosis in uveal melanomas can be spontaneous or induced by radiotherapy. The purpose of our study was to compare the histopathologic and MRI findings of radiation-induced necrosis of a group of proton beam-irradiated uveal melanomas with those of spontaneous necrosis of a control group of patients undergoing primary enucleation. 11 uveal melanomas who had undergone proton beam radiotherapy, MRI and secondary enucleation, and a control group of 15 untreated uveal melanomas who had undergone MRI and primary enucleation were retrospectively identified. Within the irradiated and nonirradiated group, 7 and 6 eyes with histological evidence of necrosis respectively, were furtherly selected for the final analysis; the appearance of necrosis was assessed at histopathologic examination and MRI. Irradiated melanomas showed a higher degree of necrosis as compared with nonirradiated tumors. Irradiated and nonirradiated lesions differed based on the appearance and distribution of necrosis. Irradiated tumors showed large necrotic foci, sharply demarcated from the viable neoplastic tissue; nonirradiated tumors demonstrated small, distinct foci of necrosis. Radiation-induced necrosis, more pigmented than surrounding viable tumor, displayed high signal intensity on T1-weighted and low signal intensity on T2-weighted images. The hemorrhagic/coagulative necrosis, more prevalent in nonirradiated tumors (4 out of 6 vs. 1 out of 7 cases), appeared hyperintense on T2-weighted and hypointense on T1-weighted images. Our study boosts the capability to recognize radiation-induced alterations in uveal melanomas at MRI and may improve the accuracy of radiologists in the evaluation of follow-up MR examination after radiotherapy. [ABSTRACT FROM AUTHOR]

Background/Aims: We evaluated the diagnostic variability and reproducibility of endoscopic signs in two populations with a different pretest likelihood of celiac disease (CD). Methods: We recruited 289 CD patients (both adults and children) in a multicenter prospective study. Group 1 (high risk) included 111 patients referred for positive serology. Group 2 (low risk) included 178 unselected patients. Mosaic pattern, reduction/loss of Kerckring's folds, scalloping of the valvulae conniventes and a nodular pattern were the endoscopic findings looked for in the duodenum. Results: In group 1, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of endoscopic findings were 100, 84.6, 94.2 and 100% in adults, and 86.8, 9.1, 82.1 and 12.5% in children. In group 2, the sensitivity, specificity, PPV and NPV of endoscopic findings were 33.3, 91.4, 7.7 and 98.5% in adults, and noncalculable, 78.3, 0.0 and 100% in children. Comparing group 1 and group 2, there was a statistically significant difference in sensitivity and PPV in adults, and in specificity, PPV and NPV in children. Concerning the reproducibility of endoscopic findings, a wide variability of κ values was found. Conclusion: Endoscopic signs have low reproducibility for CD, and their diagnostic value in selecting patients for multiple intestinal biopsies is unacceptable, especially in populations with low disease prevalence. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Pediatric small round blue cell tumors (SRBCTs) are a heterogeneous group of neoplasms with overlapping morphological appearance. Accordingly, their diagnosis is one of the most difficult in the field of surgical pathology. The most common tumors include rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma, lymphoblastic lymphoma and Wilms' tumor (the blastemal component). Over time their diagnosis has become more difficult due to the increasing use of small biopsies. However, the advent of immunohistochemistry has improved the quality of diagnosis in most cases by the application of an adequate panel of immunomarkers. Recently, WT1 and Cyclin D1 have been shown to be useful in the differential diagnosis of SRBCTs on surgically-resected specimens, showing a diffuse cytoplasmic positivity of the former in all RMSs and a diffuse nuclear staining of the latter in both EWS and NB. The aim of the present study was to investigate the expression of WT1 and Cyclin D1 on small biopsies from a series of 105 pediatric SRBCTs to evaluate their diagnostic utility. Both immunomarkers were differentially expressed, with a diffuse and strong cytoplasmic staining for WT1 limited to all cases of RMS, and a diffuse nuclear staining for cyclin D1 restricted to all cases of EWS and NB. Notably, the expression of WT1 and cyclin D1 was also retained in those cases in which the conventional tumor markers (myogenin, desmin and MyoD1 for RMS; CD99 for EWS; NB84 for NB) were focally expressed or more rarely absent. The present study shows that WT1 and Cyclin D1 are helpful immunomarkers exploitable in the differential diagnosis of pediatric SRBCTs on small biopsies, suggesting their applicability in routine practice. [ABSTRACT FROM AUTHOR]

Intestinal ischemia is reported to be the most common gastrointestinal complication of renal transplantation and a potential cause of morbidity and mortality. The recent use of more potent immunosuppressive drug regimens has reduced the incidence of acute rejection, increasing the incidence of potentially fatal infectious complications, such as clinically important cytomegalovirus (CMV) infection. A 42-year-old kidney transplant recipient experienced on postoperative day 10 a dehiscence of the ureterovesical anastomosis, associated with a 7-cm longitudinal tear graft on the lower pole of the kidney and an ureteral ischemia. A graft biopsy demonstrated a mild acute rejection for which the patient received an unsuccessful administration of steroids, with progression of the rejection, so that 1 mg/kg/day antithymocyte globulin was administered. Two days later the patient presented with fever (39.5°C), diffuse abdominal pain with tenderness and bloody diarrhea, and diagnosis of CMV colitis was achieved; rectal samples were taken for histologic examination, and Clostridium difficile toxin was isolated. A subtotal colectomy with Hartmann’s procedure was performed, but the patient died 13 days later of a multiple organ failure. The risk of lethal CMV colitis is increased in patients being treated with anti-rejection therapy for severe acute rejection; the occurrence of simultaneous infection, such as pseudomembranous colitis, usually characterized by a favorable prognosis, increases the mortality rate in these patients. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The incidence of colorectal cancer in kidney transplant recipients has been previously reported with conflicting results. In this study, we investigated if the incidence of colorectal advanced neoplasms in kidney transplant recipients, evaluated with screening colonoscopy, was higher than in healthy individuals. One-hundred sixty kidney transplant recipients undergoing screening colonoscopy were compared with 594 age- and sex-matched healthy individuals. Advanced colorectal neoplasia was found in 22 patients (13.7%), including four patients (2.5%) with colorectal cancer. Compared with the healthy population, kidney transplant recipients did not have an increased risk of developing a colorectal cancer (OR 0.69; 95% CI 0.236–2.063, p = 0.688) although it developed at a younger age. In contrast, kidney transplant recipients had a higher risk of developing an advanced adenoma compared with the control group (OR 1.65; 95% CI 0.930–2.981, p = 0.04). In conclusion, kidney transplant recipients did not have an increased incidence of colorectal cancer compared with healthy population. However, transplant patients displayed a higher incidence of colorectal adenomas, suggesting that screening colonoscopy in kidney transplant recipients should be expanded to include even younger recipients (<50 years old). [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal melanoma (UM) is the most frequent primary tumor of the eye in adults. Although molecular alterations on protein-coding genes have been associated with the development of UM, the role of non-coding RNAs and their competitive endogenous networks remain poorly investigated. Starting from a computational analysis on UM expression dataset deposited in The Cancer Genome Atlas, we identified the long non-coding RNA LINC00518 as a potential oncogene. We then experimentally evaluated LINC00518 and its supposed RNA signaling in human biopsies and in vitro functional assays. The results obtained suggest that LINC00518, under potential transcriptional control by MITF, regulates an RNA–RNA network promoting cancer-related processes (i.e., cell proliferation and migration). These findings open the way to the characterization of the unknown RNA signaling associated with UM and pave the way to the exploitation of a potential target for RNA-based therapeutics. Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults; little is known about the contribution of non-coding RNAs (ncRNAs) to UM pathogenesis. Competitive endogenous RNA (ceRNA) networks based on RNA–RNA interactions regulate physiological and pathological processes. Through a combined approach of in silico and experimental biology, we investigated the expression of a set of long non-coding RNAs (lncRNAs) in patient biopsies, identifying LINC00518 as a potential oncogene in UM. The detection of LINC00518 dysregulation associated with several in vitro functional assays allowed us to investigate its ceRNA regulatory network and shed light on its potential involvement in cancer-related processes, such as epithelial to mesenchymal transition (EMT) and CoCl2-induced hypoxia-like response. In vitro transient silencing of LINC00518 impaired cell proliferation and migration, and affected mRNA expression of LINGO2, NFIA, OTUD7B, SEC22C, and VAMP3. A "miRNA sponge" and "miRNA protector" model have been hypothesized for LINC00518-induced regulation of mRNAs. In vitro inhibition of MITF suggested its role as a potential activator of LINC00518 expression. Comprehensively, LINC00518 may be considered a new oncogene in UM and a potential target for RNA-based therapeutic approaches. [ABSTRACT FROM AUTHOR]

Ductal carcinoma in situ (DCIS) shows overlapping epidemiology with invasive ductal carcinoma of the breast, sharing similar risk factorssuch as age, mammographic density, family history, and hormonal therapy as well as genetic factors such as BRCA1/BRCA2, histotypes, and molecular subtypes such as luminal A and B, HER2 enriched, and basal-type, thus suggesting its potential precursor role. A small percentage of patients with a history of DCIS die without a documented intermediate diagnosis of invasive breast carcinoma (IBC). The increased risk of death is usually associated with ipsilateral recurrence such as IBC. The slightly variable incidence of DCIS in different countries is mainly due to a different diffusion of mammographic screening and variability of the risk factors. The majority of DCIS lesions are not palpable lesions, which can be only radiologically detected because of the association with microcalcifications. Mammography is a highly sensitive diagnostic procedure for detecting DCIS with microcalcifications, while magnetic resonance imaging (MRI) is considered more sensitive to detect DCIS without calcifications and/or multifocal lesions. The aim of the present overview was to focus on the clinical, radiological, and pathological features of DCIS of the breast, with an emphasis on the practical diagnostic approach, predictive prognostic factors, and therapeutic options. [ABSTRACT FROM AUTHOR]

Uveal melanoma is a rare disease but it is the most common primary intraocular malignant tumor in adults with poor late prognosis. About 50% of patients will develop liver metastasis far from the enucleation within 10–15 years. Our study examined SPANX-C expression levels in primary uveal melanoma both with and without metastasis to assess if they can be used to predict metastasis. This study included a total of 55 patients, 28 males and 27 females, with uveal melanoma. A significantly high expression of SPANX-C was seen in 19/23 (82.6%) patients with metastasis, and only in 11/32 (38.5%) patients without metastasis. In conclusion, we found that SPANX-C expression could play a role in tumor progression of uveal melanoma. [ABSTRACT FROM AUTHOR]

We describe the case of a 67-year-old woman affected by pemphigus vulgaris with a dry whitish scaly lesion in the upper lip. Clinically, this lesion resembled an actinic keratosis. Although histological examination revealed a focal acantholysis, the finding of a moderate-to-severe dysplastic epithelium was consistent with the diagnosis of acantholytic actinic keratosis with moderate/severe dysplasia. Nevertheless, the complete resolution of the lip lesion after systemic therapy for pemphigus vulgaris led us to reconsider the possibility that we were dealing with a pemphigus vulgaris with unusual clinical and histological features. The previously reported cytological dysplasia was better regarded reactive rather than neoplastic, likely as the result to the inflammatory injury. [ABSTRACT FROM AUTHOR]

There is increasing evidence that WT1 protein expression is found not only at nuclear, but also at cytoplasmic, level in several developing and neoplastic tissues. In order to better understand the possible role of WT1 protein in human skeletal myogenesis and oncogenesis of rhabdomyosarcoma, we assessed immunohistochemically its comparative expression in a large series of human developing, adult and neoplastic skeletal muscle tissues. The present study shows that WT1 protein is developmentally expressed in the cytoplasm of human myoblasts from the 6 weeks of gestational age. This expression was maintained in the myotubes of developing muscles of the trunk, head, neck, and extremities, while it was down-regulated in fetal skeletal fibers from 20 weeks of gestational age as well as in adult normal skeletal muscle. Notably, WT1 immunostaining disappeared from rhabdomyomas, whereas it was strongly and diffusely re-expressed in all cases (27/27) of embryonal and alveolar rhabdomyosarcoma. The comparative evaluation of the immunohistochemical findings revealed that WT1 cytoplasmic expression in rhabdomyosarcoma may represent an ontogenetic reversal, and this nuclear transcription factor can also be considered an oncofetal protein which can be exploitable as an additional, highly sensitive immunomarker, together with desmin, myogenin and MyoD1, of this tumor. Moreover, our observations support the rationale for the use of WT1 protein-based target therapy in high risk rhabdomyosarcomas in children and adolescents. [ABSTRACT FROM AUTHOR]