Systematic review of comparative transcriptomic studies of cellular resistance to genotoxic stress.

The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes.

Folate hydrolase-1 (FOLH1) is a novel target for antibody-based brachytherapy in Merkel cell carcinoma.

BACKGROUNDS: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. MATERIALS & METHODS: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. RESULTS: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. CONCLUSIONS: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.

[Are multiple trichodiscomas/fibrofolliculomas the Birt-Hogg-Dubé syndrome?] / Mnozhestvennye trikhodiskomy/fibrofollikulomy ­ sindrom Berta­Khogg­D'yuba?

Birt-Hogg-Dubé syndrome is a rare autosomal dominant disease caused by a mutation in the FLCN gene and presents with a triad of multiple fibrofolliculomas, trichodiscomas, and masses that clinically resemble fibroepithelial polyps (acrochordones), accompanied by an increased risk of kidney tumors and lung cysts. The paper provides a literature review supplemented by clinical cases and the morphological pattern of skin lesions. It presents the clinical and morphological features of cutaneous manifestations of the syndrome and gives diagnostic criteria.

[Anogenital mammary-like glands and related diseases. Part 2. Malignant tumors of the anogenital glands]. / Anogenital'nye mammaropodobnye zhelezy i sviazannye s nimi zabolevaniia. Chast' 2. Zlokachestvennye opukholi anogenital'nykh zhelez.

Mammary-like glands are a normal anatomical component of the anogenital region and can give rise to many benign and malignant tumors that morphologically mimic the similar diseases of the breast. The literature review is complemented by a description of 199 cases of malignant tumors of mammary-like glands. The paper presents the clinical and morphological characteristics of various malignant tumors of mammary-like glands, including extramammary Paget's disease, ductal, tubulolobular, adenoid cystic adenocarcinoma, low-grade phyllodes tumor, etc.

[Anogenital mammary-like glands and related lesions. Part 1. Benign tumors and tumor-like disorders]. / Anogenital'nye mammaropodobnye zhelezy i svyazannye s nimi zabolevaniya. Chast' 1. Dobrokachestvennye opukholi i opukholepodobnye protsessy anogenital'nykh zhelez.

Anogenital mammary-like glands represent a normal anatomic constituent of the anogenital area and may give rise to many benign and malignant tumors that morphologically mimic similar breast diseases. The literature review is complemented by a description of 286 cases of benign tumors and tumor-like processes in the mammary-like glands. The paper presents the clinical and morphological characteristics of papillary hidradenoma, fibroadenoma, benign phyllodes tumor, lactating adenoma, sclerosing adenosis, pseudoangiomatous stromal hyperplasia, etc.

[NEW FINDINGS OF RARE SPECIES OF THE MITE GENUS SPINTURNIX VON HEYDEN, 1826 (MESOSTIGMATA: GAMASINA: SPINTURNICIDAE) IN RUSSIA AND TADJIKISTAN].

The article reports new findings of rare and poorly known mite species of the genus Spinturnix von Heyden, 1826 (Gamasina: Spinturnicidae) parasitizing bats of the genera Myotis and Barbastella in Russia and Tadjikistan.

Paediatric cutaneous lymphomas: a review and comparison with adult counterparts.

Primary cutaneous lymphomas (CL) in children is rare. Only a few studies focused specifically on paediatric CL and therefore little is known whether primary CL in children are similar to or different from their adult counterparts with respect to the clinicopathological presentation, behaviour and prognosis. An extensive literature search using PubMed/MEDLINE from January 1995 through July 2014 was undertaken for articles reporting cases of paediatric CL. In addition, we identified 31 children with CL in our institutions. Mycosis fungoides and lymphomatoid papulosis are the two most prevalent lymphoma forms in children. A few entities of cutaneous lymphomas such as cutaneous diffuse large B-cell lymphoma leg type, and Sézary syndrome have not been reported so far in children. Other lymphoma entities such as hydroa vacciniforme-like lymphoma are mostly seen in certain geographic areas (Asia, Central and South America). In the paediatric population, low-malignant indolent forms such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle centre lymphoma are very rare, whereas the more aggressive forms of B-cell lymphomas, precursor lymphoblastic lymphomas, and blastic plasmacytoid dendritic cell neoplasm are the most common forms in children, mostly involving the skin secondarily. Most paediatric lymphomas have similar clinicopathological features and course as their adults counterparts, particularly in the group of cutaneous T-cell lymphomas. The spectrum of cutaneous B-cell lymphomas in children significantly differs from the one in adults. Diagnostic work-up and treatment of paediatric patients with lymphomas are best achieved in close collaboration with paediatric haematopathologists and oncologists.

[Clinical presentation of cutaneous adnexal tumors]. / Klinik der Hautadnextumoren.

Cutaneous adnexal lesions can sometimes be clinically diagnosed even by an experienced clinician or a differential diagnosis can at least be narrowed down. However, clinical findings alone cannot replace histological investigations and diagnosis or make them superfluous. This expertise is based on an algorithm which first differentiates inflammatory pseudo-tumors, such as ruptured infundibular cysts (atheroma) from authentic neoplastic adnexal lesions. In a second step criteria of regularity and/or chaos, such as asymmetry, irregular border, color variation and/or destruction with exulceration help to evaluate the dignity. In a third step criteria of differentiation allow the characterization of lesions varying in size from macules to papules, plaques, nodules and tumors to the subgroups of adnexal differentiation. Infundibular differentiation is characterized by comedones and is skin-colored, yellow or white and hard. Follicular differentiation notifies hair and is skin-colored, pearl-like to occasionally brown-black and variably hard. Sebaceous differentiation signifies lobulation and is yellow to skin-colored or red and soft. Apocrine lesions are reddish and fleshy. Eccrine differentiation shows either papillary reddish-brown (differential diagnosis viral warts) or skin-colored hard lesions. Multiple, monomorphous lesions are characteristic of syndromes, such as Spiegler-Brooke-Fend, Birt-Hogg-Dubé, Muir-Torre, and Gorlin-Goltz.One peculiarity of adnexal lesions is their potential to form cysts. Cysts with horny or hairy material are skin-colored to yellow, with glandular fluid fluctuation, a bluish character, and with illumination a Tyndall phenomenon becomes obvious, while ruptured cysts reveal an erythematous-reddish, ill-defined foreign body reaction. Brown to bluish-gray and black color is seen by the presence of melanocytes with melanin in lesions with mostly follicular differentiation. Strong vascularization and bleeding are reddish, soft, spongy and compressible and in due course variably dark due to the presence of hemosiderin.

[Synthesis, structure and farmacologycal activity of (7R,8S)-epoxy-(13R,17R)-trioxolaneabietic acid].

The synthesis and X-ray diffraction established the structure of (7R,8S)-(see text for symbol)-(13R,17R)-trioxolaneabietic acid. Predicted by the computer system PASS antineoplastic activity and the ability to induce apoptosis, a mechanism of cell death, is correlated with experimentally shown cytotoxic activity against malignant cell line MeWo. Results of tests on animals have shown that abietic acid and its 9R,11S-epoxy-12R,15R-trioxolane derivative have anti-inflammatory and antiulcer activity in the absence of adverse effects on animal organisms.

Pseudotumors and mimickers of malignancy of the head and neck pathology.

We are summarizing some of the difficult pitfalls in tumors of the head and neck, which we have encountered in our biopsies referred for consultation as well as from our routine praxis in the last 20 years. Shortly we are presenting the following lesions of head and neck: multifocal sclerosing thyroiditis, mucoepidermoid carcinoma of the thyroid, solid cell nests, Chievitz organ, rhomboid glossitis, ectopic parathyroid, signet ring cell change of salivary glands, mucocele, epithelial misplacement of the vocal cord squamous cell epithelium, and angiomatoid nasal polyps.

[Carney complex]. / Carneyho komplex.

Carney complex is a clinically and genetically heterogeneous disease, with at least two genetic loci including the PRKAR1A gene located on chromosome 17 and the CNC2 locus mapped to chromosome 2. Clinically this syndrome is characterized by multiple myxomas occurring in different anatomic sites, mucocutaneous pigmentary lesions, and a variety of non-endocrine and endocrine tumors, often causing endocrine abnormalities, involving various organs. Knowledge of morphological findings in CNC patients with their typical locations is necessary to raise suspicion of this syndrome by pathologists. Confirmation of the diagnosis allows regular clinical check-ups and early treatment of these patients.

[Muir-Torre syndrome--a phenotypic variant of Lynch syndrome]. / Muir-Torre syndrom--fenotypická varianta Lynchova syndromu.

Muir-Torre syndrome (MTS) represents an autosomal dominantly inherited condition and is considered a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC), or Lynch syndrome. MTS combines at least one cutaneous neoplasm with sebaceous differentiation (e.g. sebaceoma, sebaceous adenoma, and sebaceous carcinoma), and at least one visceral malignancy. MTS is a genetic disorder caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors in MTS patients are characteristically associated with the loss of MMR protein expression and/or microsatellite instability (70%). Patients who are suspected to have MTS/Lynch syndrome are often identified by dermatologists, dermatopathologists/pathologists, gastroenterologists and gynecologists. If MTS is suspected on a clinicopathological ground, necessary additional laboratory investigations should be performed only in specialized pathological departments providing immunohistochemistry and molecular biologic analysis service.

[The morphology and differential diagnosis of neuroglial heterotopias and related tumors].

The paper reviews the data available in the literature and a clinicomorphological analysis of 15 cases of neuroglial heteropias and related tumors retrieved from the joint databases of Sikl's Department of Pathology, Pilsen, Czech Republic, and the Department of Pathology, Petrov Oncology Institute, with emphasis on the histological, immunohistochemical and ultrastructural features, as well as differential diagnosis.

[Morphologic and differential diagnosis of sclerosing perineurioma].

The paper discusses morphologic and immunohistochemical characteristics of sclerosing perineurioma. Generally, it is well circumscribed and consists of tiny spindle-shaped plump epitheloid cells embedded in collagenous hyalinized matrix. Immunohistochemically, it was represented by EMA+, S-100, AE1/AE3, CAM 5.2, smooth muscle actin and desmin. Being benign, tumor was identified by differential diagnosis using fibroma of tendon sheath, sclerosing one, glomal tumor, giant cell tumor and sclerosing epitheloid cell sarcoma.

Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity.

We present a series of a distinct tumorous entity named renal angiomyoadenomatous tumor (RAT). Five cases were retrieved from the consultation files of the authors. Histologic and immunohistochemical features were evaluated. Sequencing analysis of coding region of the VHL gene was carried out in all cases. The tumors were composed of admixture of an epithelial clear cell component and prominent leiomyomatous stroma. Epithelial cells formed adenomatous tubular formations endowed with blister-like apical snouts. All tubular/glandular structures were lined by a fine capillary network. The epithelial component was positive for epithelial membrane antigen, CK7, CK20, AE1-AE3, CAM5.2, and vimentin in all cases. In all analyzed samples, no mutation of the VHL gene was found. RAT is a distinct morphologic entity, being different morphologically, immunohistochemically, and genetically from all renal tumors including conventional clear cell carcinoma and mixed epithelial and stromal tumor of kidney.

[Small-cell variant of CD30+ -anaplastic large-cell lymphoma of the skin].

Three cases of the so-called variant of primary cutaneous CD30+ anaplastic large cell lymphoma (ALCL) are presented. All patients were males aged 52, 59, and 78 years old; they had a solitary cutaneous tumor nodule. Their sites included the axilla, thigh, and shoulder. There was no extracutaneous involvement. Microscopically, the tumors were composed of small cells with irregular nuclei that were immunohistochemically positive for CD3, CD5, CD7, and CD30 and negative for B-cell markers; there was focal ALK-1 positivity in 1 case. Two cases had CD4+/CD8-phenotype, while the remaining one exhibited a CD4-/CD8+ immunoprofile. Fhedium to large CD30+ cells were rarely found scattered in the infiltrate. Monoclonal TCR gamma gene rearrangement was detected in 2 cases and rearrangement of IgH (lineage infidelity) was in one case. The tumors were surgically removed in all the patients. Two patients were alive and well 4 and 6 years after surgery, without evidence of cutaneous and extractaneous involvement (including the ALK+ patient). The third patient experienced several relapses of the skin tumor and developed axillary and inguinal lymph node involvement. Chemotherapy was performed and finally the patient underwent allogenic bone marrow transplantation; he died 3 years after the original diagnosis due to acute graft-versus-host disease and sepsis.

[Current approaches to diagnosing and treating primary cutaneous lymphomas on the basis of a new WHO-EORTC classification, cutaneous T-cell lymphomas].

This two-part review addresses the current diagnostic approaches towards primary cutaneous lymphomas. In this part, main T and NK-cell lymphomas are described with reference to clinical presentation, histological and immunohistochemical features, and genetic alterations based on the new WHO-EORTC classification of cutaneous lymphomas.

[Current approaches to the diagnosis and treatment of primary cutaneous lymphomas based on the new WHO-EORTC classification of B-cell cutaneous lymphomas].

The review concerns the current approaches to the diagnosis of primary cutaneous lymphomas. B-cell lymphomas are described with the reference to their clinical presentation, histological, and immunohistochemical features and genetic alterations based on the new WHO-EORTC classification of cutaneous lymphomas.

Tumoral, quasitumoral and pseudotumoral lesions of the superficial and somatic soft tissue: new entities and new variants of old entities recorded during the last 25 years. Part XII: appendix.

In an eleven part series published in Pathologica, we have presented various tumoral, quasitumoral and pseudotumoral lesions of the superficial and somatic soft tissue (ST), which emerged as new entities or as variants of established entities during the last quarter of a century. Detailed clinicomorphological and differential diagnostic features of approximately sixty entities were chosen on the basis of their clinical significance and morphologic distinctiveness. The series included fibrous and myofibroblastic tumors (e.g. solitary fibrous tumor, high grade classic and pigmented dermatofibrosarcoma protuberans, inflammatory myofibroblastic tumor and myofibrosarcomas), fibromyxoid and fibrohistiocytic neoplasms (e.g., Evans' tumor, phosphaturic mesenchymal tumor, inflammatory myxohyaline tumor), special adipocytic/vascular/and smooth muscle lesions (e.g., chondroid lipoma, Dabska's tumor, ST hemangioblastoma, lipoleiomyosarcoma), epithelioid mesenchymal malignancies of diverse lineages (e.g., epithelioid liposarcoma, proximal-type epithelioid sarcoma, neuroendocrine extraskeletal chondromyxoid sarcoma), ST Ewing's tumor and peripheral nerve sheath tumors (perineuriomas and pigmented and rosetting tumors of the schwannoma/neurofibroma group), extranodal dendritic or histiocytic proliferative processes (follicular dendritic cell sarcoma, Rosai-Dorfman disease, Castleman's disease, and plexiform xanthomatous tumor), and tumors with myoepithelial differentiation. The section devoted to selected pseudotumoral entities considered representatives of the hamartoma group (neural fibrolipomatous hamartoma, ectopic hamartomatous thymoma, rudimentary meningocele), metabolic diseases (amyloid tumor, nephrogenic fibrosing dermopathy, tophaceous pseudogout, pseudoinfiltrative parathyromatosis), stromal tissue reactions to trauma (fibroosseous pseudotumors of digits) and infections (bacillary angiomatosis), and normal organs (glomus coccygeum). To conclude the descriptive phase, supplementary material has now been collected and appended in an attempt to provide a quick digest of essential knowledge both for comparison and differential diagnosis. The data have been tailored to synthesize diverse sources, integrating clinical elements and references to articles that previously appeared in Part I ("Introduction"), Part II ("The List and Review of New Entities") and Parts III to XI ("Excerpta"). At the very least we hope this final part ("Appendix") will provide the reader with a useful tabular organization of ST lesions and a reference resource.