Publications by authors named "Pavel Dundr"

117 Publications

Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases.

Virchows Arch 2021 Oct 9. Epub 2021 Oct 9.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 12800, Prague 2, Czech Republic.

Cellular leiomyoma (CL) represents an uncommon variant of uterine leiomyoma with limited data concerning its immunohistochemical and molecular profile. We performed a comprehensive analysis of 52 CL cases all of which were analyzed immunohistochemically. Molecular analysis was possible in 32 cases with sufficient DNA, and 38 cases with sufficient RNA. The immunohistochemical results showed a high expression of smooth muscle markers (calponin (100%), desmin (100%), smooth muscle actin (98.1%), caldesmon (96.1%), transgelin (96.1%), smooth muscle myosin heavy chain (86.5%), and smoothelin (61.5%)). Concerning markers of endometrial stromal differentiation, the expression of CD10 was observed in 65.4% cases (42.2% with H-score > 50), and IFITM1 in 36.5% cases (1.9% with H-score > 50). 36.5% showed HMGA2 overexpression at the IHC level, associated with increased mRNA expression in 14/14 cases. The rearrangement of the HMGA2 gene was detected in 13.2%. Chromosome 1p deletion was found in 19.3%, while 9.4% of tumors showed a pathogenic mutation in the MED12 gene. In conclusion, CL is immunohistochemically characterized by a high expression of "smooth muscle" markers commonly associated with a co-expression of "endometrial stromal" markers, where IFITM1 shows superior performance compared to CD10 regarding its specificity for differentiation from endometrial stromal tumors. The sensitivity of smoothelin in CL seems rather low, but no data is available to assess its specificity. On a molecular level, the most common mutually exclusive aberration in CL affects HMGA2, followed by chromosome 1p deletions and MED12 mutations.
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http://dx.doi.org/10.1007/s00428-021-03217-zDOI Listing
October 2021

Molecular testing in endometrial carcinoma (Joint recommendation of Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists).

Cesk Patol 2021 ;57(3):181-187

Molecular classification of endometrial carcinoma is becoming an important part of the diagnostic process with direct therapeutic implications. Recent international guidelines, including the joint ESGO-ESTRO-ESP recommendation, include the molecular classification into standard diagnostic algorithms. Molecular testing of endometrial carcinomas is also recommended in the latest (5th) edition of the WHO classification of Female Genital Tumors. Due to the need to implement these recommendations in practice, representatives of four professional societies of Czech Medical Association of J. E. Purkyně (Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists) organized a meeting focused on this topic. The result of this meeting is a joint recommendation for molecular testing of endometrial carcinoma in routine diagnostic practice in the Czech Republic.
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September 2021

Review of tumor infiltrating lymphocytes assessment in breast cancer in routine diagnostic practice.

Cesk Patol 2021 ;57(3):161-166

Evaluation of tumor infiltrating lymphocytes (TIL) is gaining importance in many cancers not only because of their prognostic, but also predictive significance. One of the tumors in which the evaluation of TIL is of prognostic importance and has potential predictive impact on the modification of treatment procedures is breast cancer, especially its so-called triple negative, and HER2 positive variants.The aim of this review is to provide an overview of the issue of TIL evaluation in breast cancer, focusing not only on the clinical significance of this evaluation, but especially on the methodological aspects of evaluation and standardized reporting of the results.
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September 2021

The possibilities of molecular testing of somatic aberrations in tumor tissue using NGS in routine practice - current situation in the Czech Republic.

Cesk Patol 2021 ;57(3):147-149

Molecular testing of tumor tissue for the detection of somatic aberrations using NGS is increasingly gaining significance in routine practice. The technical aspects of testing are standardized and currently do not pose a problem. However, the situation is evolving very rapidly regarding the indication of testing, which depends on the sometimes rapidly developing medical knowledge and needs in clinical practice. In order to implement NGS testing in practice and arrange its reimbursement by the health care system, first it is necessary to reach an agreement on the level of professional societies concerning the definition of priority and medically clearly justified areas in which molecular testing has a clear impact on therapeutical choices. The next step is to reach an agreement with the health insurance companies regarding NGS testing. The aim of this article is to provide an overview of the issue of routine tumor tissue testing using the NGS method covered by public health insurance, with a summary of the current situation in the Czech Republic. Only the testing of somatic aberrations in solid tumors performed at pathology departments is discussed. The issue of testing in haemato-oncological centres is not the subject of this review.
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September 2021

The Abscopal Effect in the Era of Checkpoint Inhibitors.

Int J Mol Sci 2021 Jul 4;22(13). Epub 2021 Jul 4.

Department of Dermatovenereology, First Faculty of Medicine and General University Hospital, Charles University, 128 00 Prague, Czech Republic.

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8 T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.
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http://dx.doi.org/10.3390/ijms22137204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267720PMC
July 2021

Gynecological lesions in hereditary cancer predisposition syndromes.

Cesk Patol 2021 ;57(2):96-104

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.
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July 2021

The value of immunohistochemical methods in diagnosing mesenchymal tumours of the uterus.

Cesk Patol 2021 ;57(2):86-95

The goal of this manuscript is to provide a comprehensive overview of the use of immunohistochemical methods in diagnosing mesenchymal tumours of the uterus. The main points discussed include, especially, the issue of determining smooth muscle differentiation, the differential diagnosis between smooth muscle and endometrial stromal tumours, and the diagnosis of inflammatory myofibroblastic tumour. The role of immunohistochemical examination in the diagnosis of some of the only recently definedentities such as YWHAE-altered high grade endometrial stromal sarcoma (HG-ESS), BCOR-altered HG-ESS, tumours with NTRK fusion, and SMARCA4-deficient sarcomas is also discussed. The last aspect of this work is an analysis of the significance of immunohistochemical methods in the determination of the biological behaviour of leiomyocellular tumours. The issue of their molecular classification for those lesions associated with the presence of recurrent molecular aberrations is also discussed.
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July 2021

The value of immunohistochemical methods in diagnosing endometrial carcinoma.

Cesk Patol 2021 ;57(2):73-85

The goal of this manuscript is to provide an overview of the significance of immunohistochemical methods in diagnosing endometrial carcinoma. The main points discussed include: the use of immunohistochemistry in the differential diagnosis of the main histological types of endometrial carcinoma, the difference between primary serous endometrial carcinoma and the involvement with high grade serous carcinoma of another primary source, the diagnosis of undifferentiated/dedifferentiated endometrial carcinoma, and diagnosing tumours with neuroendocrine differentiation. The role of p53 expression evaluation is also emphasized as a special area of interest, not only in the context of differential diagnosis, but also from the point of view of the prognosis and prediction of endometrial carcinoma as an ancillary marker for subtypization of these tumours.
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July 2021

Primary mucinous ovarian tumors vs. ovarian metastases from gastrointestinal tract, pancreas and biliary tree: a review of current problematics.

Diagn Pathol 2021 Mar 11;16(1):20. Epub 2021 Mar 11.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00, Prague 2, Czech Republic.

Background: Making the distinction between primary mucinous and metastatic ovarian tumors is often difficult, especially in tumors with a primary source from the gastrointestinal tract, pancreas and biliary tree. The aim of the following paper is to provide an overview of the problematics, with a focus on the possibilities of the differential diagnosis at the macroscopic, microscopic and immunohistochemical level.

Main Body: The three main aspects of mucinous ovarian tumors are described in detail, including the comparison of the available diagnostic algorithms based on the evaluation of mostly macroscopic features, characterization of the spectrum of microscopic features, and a detailed analysis of the immunophenotype comparing 20 antibodies with the assessment of their statistical significance for differential diagnosis purposes. Specific features, including Krukenberg tumor and pseudomyxoma peritonei, are also discussed.

Conclusion: Despite the growing knowledge of the macroscopic and microscopic features of ovarian mucinous tumors and the availability of a wide range of immunohistochemical antibodies useful in this setting, there still remains a group of tumors which cannot be precisely classified without close clinical-pathological cooperation.
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http://dx.doi.org/10.1186/s13000-021-01079-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953678PMC
March 2021

A comprehensive analysis of the expression, epigenetic and genetic changes of HNF1B and ECI2 in 122 cases of high-grade serous ovarian carcinoma.

Oncol Lett 2021 Mar 6;21(3):185. Epub 2021 Jan 6.

Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12800 Prague, Czech Republic.

High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer, with a poor prognosis; however, most studies concerning ovarian carcinoma have focused mainly on clear cell carcinoma. The involvement of hepatocyte nuclear factor 1β (HNF1B) in the carcinogenesis of HGSC has not yet been fully elucidated. To the best of our knowledge, the present study is the first to analyse the expression of the possible downstream target of HNF1B, enoyl-CoA (Δ) isomerase 2 (ECI2), in HGSC. The present study performed a comprehensive analysis of HNF1B mRNA and protein expression, and epigenetic and genetic changes, as well as an analysis of ECI2 mRNA and protein expression in 122 cases of HGSC. HNF1B protein expression was detected in 28/122 cases, and was positively associated with lymphovascular invasion (P=0.025). Protein expression of ECI2 was detected in 115/122 cases, but no associations with clinicopathological variables were revealed. Therefore, ECI2 does not seem to function as a suitable prognostic marker for HGSC. In the sample set, a positive correlation between HNF1B and ECI2 protein expression was detected (P=0.005). HNF1B mRNA was also positively correlated with HNF1B protein expression (P=0.001). promoter methylation was detected in 26/67 (38.8%) of cases. A novel pathogenic somatic mutation was detected in 1/61 (1.6%) of the analysed HGSC cases. No other correlations between the examined SNPs (rs4430796, rs757210 and rs7405776), HNF1B promoter methylation, HNF1B/ECI2 expression or clinicopathological characteristics were found.
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http://dx.doi.org/10.3892/ol.2021.12446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816296PMC
March 2021

Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery.

Br J Cancer 2021 03 14;124(6):1121-1129. Epub 2020 Dec 14.

Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Apolinarska 18, Prague 2, 12800, Czech Republic.

Background: Models predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice.

Methods: All consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007-12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative.

Results: The best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR.

Conclusions: A newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR.
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http://dx.doi.org/10.1038/s41416-020-01204-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961006PMC
March 2021

Single-Cell RNA Sequencing Unravels Heterogeneity of the Stromal Niche in Cutaneous Melanoma Heterogeneous Spheroids.

Cancers (Basel) 2020 Nov 10;12(11). Epub 2020 Nov 10.

Institute of Anatomy, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic.

Heterogeneous spheroids have recently acquired a prominent position in melanoma research because they incorporate microenvironmental cues relevant for melanoma. In this study, we focused on the analysis of microenvironmental factors introduced in melanoma heterogeneous spheroids by different dermal fibroblasts. We aimed to map the fibroblast diversity resulting from previously acquired damage caused by exposure to extrinsic and intrinsic stimuli. To construct heterogeneous melanoma spheroids, we used normal dermal fibroblasts from the sun-protected skin of a juvenile donor. We compared them to the fibroblasts from the sun-exposed photodamaged skin of an adult donor. Further, we analysed the spheroids by single-cell RNA sequencing. To validate transcriptional data, we also compared the immunohistochemical analysis of heterogeneous spheroids to melanoma biopsies. We have distinguished three functional clusters in primary human fibroblasts from melanoma spheroids. These clusters differed in the expression of (a) extracellular matrix-related genes, (b) pro-inflammatory factors, and (c) TGFβ signalling superfamily. We observed a broader deregulation of gene transcription in previously photodamaged cells. We have confirmed that pro-inflammatory cytokine IL-6 significantly enhances melanoma invasion to the extracellular matrix in our model. This supports the opinion that the aspects of ageing are essential for reliable melanoma 3D modelling in vitro.
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http://dx.doi.org/10.3390/cancers12113324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697260PMC
November 2020

Analysis of expression, epigenetic, and genetic changes of HNF1B in 130 kidney tumours.

Sci Rep 2020 10 13;10(1):17151. Epub 2020 Oct 13.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studnickova 2, 12800, Prague 2, Czech Republic.

Hepatocyte nuclear factor 1 beta (HNF1B) is a transcription factor which plays a crucial role in nephronogenesis, and its germline mutations have been associated with kidney developmental disorders. However, the effects of HNF1B somatic exonic mutations and its role in the pathogenesis of kidney tumours has not yet been elucidated. Depending on the type of the tumour HNF1B may act as a tumour suppressor or oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using an immunohistochemical approach, and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B in 130 cases of renal tumours (121 renal cell carcinomas, 9 oncocytomas). In the subset of clear cell renal cell carcinoma (ccRCC), decreased HNF1B expression was associated with a higher tumour grade and higher T stage. The mutation analysis revealed no mutations in the analysed samples. Promoter methylation was detected in two ccRCCs and one oncocytoma. The results of our work on a limited sample set suggest that while in papillary renal cell carcinoma HNF1B functions as an oncogene, in ccRCC and chRCC it may act in a tumour suppressive fashion.
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http://dx.doi.org/10.1038/s41598-020-74059-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555858PMC
October 2020

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes.

Biomedicines 2020 Oct 9;8(10). Epub 2020 Oct 9.

Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, 128 53 Prague, Czech Republic.

Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected and variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; = 2.0 × 10). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (, , ) and 22 (8.3%) patients in other cancer syndrome genes (, , , , , ). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6-413.1; = 3.2 × 10) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4-3.8; = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2-6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.
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http://dx.doi.org/10.3390/biomedicines8100404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601281PMC
October 2020

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

J Clin Oncol 2020 11 8;38(31):3638-3651. Epub 2020 Sep 8.

Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada.

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).

Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.

Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high low], 0.48; 95% CI, 0.32 to 0.71; = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high low], 0.41; 95% CI, 0.25 to 0.67; .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high low], 0.36; 95% CI, 0.21 to 0.62; .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; = .0011) and high-risk (HR [chemotherapy no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; = .0015) patients, in contrast to the low-Immunoscore group ( > .12).

Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.03205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605397PMC
November 2020

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study.

Sci Rep 2020 09 1;10(1):14365. Epub 2020 Sep 1.

Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 2, Czech Republic.

Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target.
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http://dx.doi.org/10.1038/s41598-020-71427-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463257PMC
September 2020

Microscopic extraovarian sex cord proliferation: report of a case with bilateral Fallopian tube involvement and a comprehensive molecular analysis.

Pol J Pathol 2020 ;71(2):175-180

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.

We report a case of a 58-year-old female with microscopic extraovarian sex cord proliferations affecting both Fallopian tubes. Molecular analysis showed likely pathogenic germline missense mutations of the KDM5A and KMT2D genes. However, mutations of other genes, including FOXL2 and STK11, were not detected. Our case represents the 12th case of extraovarian sex cord proliferation reported in the literature to date. This is the first time that a molecular genetic analysis of the lesion has been performed, and it showed a wild-type FOXL2 gene, which represents another argument supporting the estimated benign nature of these rare lesions.
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http://dx.doi.org/10.5114/pjp.2020.97023DOI Listing
October 2020

Ovarian mesonephric-like adenocarcinoma arising in serous borderline tumor: a case report with complex morphological and molecular analysis.

Diagn Pathol 2020 Jul 21;15(1):91. Epub 2020 Jul 21.

Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Apolinarska 18, 12808, Prague 2, Czech Republic.

Background: Mesonephric-like adenocarcinoma (M-LAC) is a rare, recently described tumor occurring in the uterine corpus and ovary, which shares the same morphological and immunohistochemical features with the more common mesonephric adenocarcinoma (MAC), which mostly arises the uterine cervix. Despite the similarities between these tumors, the histogenesis of M-LAC is still disputable.

Case Presentation: Sixty-one-year-old woman presented with an advanced tumor of the left ovary with intraabdominal spread and liver metastases. After receiving 5 cycles of neoadjuvant chemotherapy, she underwent a hysterectomy with bilateral salpingo-oophorectomy, and resection of the liver metastasis, omentum, and appendix. Histologically, the ovarian tumor consisted of two components, whose morphology and immunohistochemical results were typical of either a serous borderline tumor (immunohistochemical positivity for PAX8, WT1, ER and PR) or a mesonephric-like carcinoma (immunohistochemical positivity for PAX8, TTF1 and GATA3). Only the component of the mesonephric-like adenocarcinoma metastasized to the omentum and liver. A molecular analysis with a panel of 271 genes (size 1020 kbp) was performed separately on samples from the borderline tumor, primary ovarian mesonephric-like adenocarcinoma, and liver metastasis. The results showed the clonal origin of all samples, which shared the same KRAS (NM_004985.3:c.34G > T, p.(G12C)) and PIK3CA (NM_006218.2:c.1633G > A, p.(E545K)) somatic mutations. Moreover, in the sample from the primary mesonephric-like carcinoma and its liver metastasis a likely pathogenic somatic MYCN mutation (NM_005378.4:c.131C > T, p.(P44L) was found. In all samples, the deletion of exons 9-10 in the CHEK2 gene was present, which is in concordance with the previously performed genetic testing of the blood specimen which revealed the hereditary CHEK2 mutation in this patient.

Conclusions: Our result support the theory that at least some mesonephric-like ovarian adenocarcinomas are of Müllerian origin. The serous borderline tumor seems to be a precursor of mesonephric-like adenocarcinoma, which has been proven in our case by both tumors sharing the same mutations, and the presence of cumulative molecular aberrations in the mesonephric-like adenocarcinoma.
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http://dx.doi.org/10.1186/s13000-020-01012-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372838PMC
July 2020

Secretory carcinoma of salivary type in a lymph node presenting as a neck cyst diagnosed by cytology: A case report.

Diagn Cytopathol 2021 Jan 20;49(1):E1-E6. Epub 2020 Jul 20.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Secretory carcinoma (SC) is a relatively recently described salivary gland adenocarcinoma characterized by ETV6-NTRK3 gene fusion and, in most cases, indolent clinical behavior. Morphologically, the tumor shows a glandular architecture and the presence of monophasic tumor cells with vacuolated cytoplasm, low-grade nuclear atypia, and mucin production, with possibly a tubular, papillary, or cystic arrangement. In this article, we describe a case of a 52-year old man with SC involving a neck lymph node clinically manifesting as a slowly growing cystic neck mass without recent proof of the primary tumor, but with a history of a parotid gland "cystadenopapilloma," which had been removed 35 years prior. A fine-needle aspiration biopsy revealed a diagnosis of SC. Subsequent histopathological examination after lymph node dissection confirmed the diagnosis. The tumor showed typical features of SC, including immunohistochemical positivity for NTRK and NTRK3 gene rearrangement, detected using in situ hybridization. We discuss that the tumor may be a late metastasis occurring 35 years after resection of undiagnosed salivary SC or a primary SC arising from heterotopic salivary tissue within a lymph node. Differential diagnostic considerations and review of relevant literature are included.
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http://dx.doi.org/10.1002/dc.24550DOI Listing
January 2021

Expression, Epigenetic, and Genetic Changes of HNF1B in Colorectal Lesions: an Analysis of 145 Cases.

Pathol Oncol Res 2020 Oct 1;26(4):2337-2350. Epub 2020 Jun 1.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studnickova 2, 12800, Prague 2, Czech Republic.

Hepatocyte nuclear factor 1 beta (HNF1B) is transcription factor which plays a crucial role in the regulation of the development of several organs, but also seems to be implicated in the development of certain tumours, especially the subset of clear cell carcinomas of the ovary and kidney. Depending on the type of the tumour, HNF1B may act as either a tumour suppressor or an oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using immunohistochemical approach and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B on 40 cases of colorectal adenomas and 105 cases of colorectal carcinomas. The expression of HNF1B was correlated with the benign or malignant behaviour of the lesion, given that carcinomas showed significantly lower levels of expression compared to adenomas. In carcinomas, lower levels of HNF1B expression were associated with recurrence and shortened disease-free survival. The mutation analysis revealed three somatic mutations (two frameshift and one nonsense) in the carcinoma sample set. Promoter methylation was detected in three carcinomas. These results suggest that in colorectal cancer, HNF1B may play a part in the pathogenesis and act in a tumour suppressive fashion.
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http://dx.doi.org/10.1007/s12253-020-00830-2DOI Listing
October 2020

Micrometastases in Sentinel Lymph Nodes Represent a Significant Negative Prognostic Factor in Early-Stage Cervical Cancer: A Single-Institutional Retrospective Cohort Study.

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, 128 00 Prague, Czech Republic.

The data on the prognostic significance of low volume metastases in lymph nodes (LN) are inconsistent. The aim of this study was to retrospectively analyze the outcome of a large group of patients treated with sentinel lymph node (SLN) biopsy at a single referral center. Patients with cervical cancer, stage T1a-T2b, common tumor types, negative LN on preoperative staging, treated by primary surgery between 01/2007 and 12/2016, with at least unilateral SLN detection were included. Patients with abandoned radical surgery due to intraoperative SLN positivity detected by frozen section were excluded. All SLNs were postoperatively processed by an intensive protocol for pathological ultrastaging. Altogether, 226 patients were analyzed. Positive LN were detected in 38 (17%) cases; macrometastases (MAC), micrometastases (MIC), isolated tumor cells (ITC) in 14, 16, and 8 patients. With the median follow-up of 65 months, 22 recurrences occurred. Disease-free survival (DFS) reached 90% in the whole group, 93% in LN-negative cases, 89% in cases with MAC, 69% with MIC, and 87% with ITC. The presence of MIC in SLN was associated with significantly decreased DFS and OS. Patients with MIC and MAC should be managed similarly, and SLN ultrastaging should become an integral part of the management of patients with early-stage cervical cancer.
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http://dx.doi.org/10.3390/cancers12061438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352782PMC
May 2020

Central Pathology Review in SENTIX, A Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2).

Cancers (Basel) 2020 Apr 29;12(5). Epub 2020 Apr 29.

Department of Obstetrics and Gynaecology, Hospital Ceske Budejovice, JSC, 37001 Ceske Budejovice, Czech Republic.

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.
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http://dx.doi.org/10.3390/cancers12051115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281480PMC
April 2020

Identification of novel HNF1B mRNA splicing variants and their qualitative and semi-quantitative profile in selected healthy and tumour tissues.

Sci Rep 2020 04 24;10(1):6958. Epub 2020 Apr 24.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12808, Czech Republic.

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor crucial for the development of several tissues, and a promising biomarker of certain solid tumours. Thus far, two HNF1B alternative splicing variants (ASVs) have been described, however, the complete spectrum, prevalence and role of HNF1B ASVs in tumorigenesis are unclear. Considering the equivocal data about HNF1B ASVs and expression presented in literature, our aim was to characterize the spectrum of HNF1B mRNA splicing variants across different tissues. Here, we characterize HNF1B ASVs with high sensitivity in carcinomas of the uterine corpus, large intestine, kidney, pancreas, and prostate, with selected paired healthy tissues, using the previously described multiplex PCR and NGS approach. We identified 45 ASVs, of which 43 were novel. The spectrum and relative quantity of expressed ASVs mRNA differed among the analysed tissue types. Two known (3p, Δ7_8) and two novel (Δ7, Δ8) ASVs with unknown biological functions were detected in all the analysed tissues in a higher proportion. Our study reveals the wide spectrum of HNF1B ASVs in selected tissues. Characterization of the HNF1B ASVs is an important prerequisite for further expression studies to delineate the HNF1B splicing pattern, potential ASVs functional impact, and eventual refinement of HNF1B's biomarker role.
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http://dx.doi.org/10.1038/s41598-020-63733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181708PMC
April 2020

Impact of sentinel lymph node frozen section evaluation to avoid combined treatment in early-stage cervical cancer.

Int J Gynecol Cancer 2020 06 9;30(6):744-748. Epub 2020 Apr 9.

Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic

Background: The need for radical surgery followed by adjuvant chemoradiation may be reduced by abandoning radical surgery in patients in whom lymph node involvement is detected intra-operatively.

Objectives: To analyze, in a retrospective cohort study, the efficacy of the algorithm using intra-operative pathological assessment of sentinel lymph nodes.

Methods: A retrospective single-institution study was carried out, which analyzed data from all consecutive patients with cervical cancer who were referred for primary surgical treatment between May 2005 and December 2015. Inclusion criteria were as follows: (1) TNM stage T1a1 with lymphovascular space invasion, T1a2, T1b, T2a, and selected T2b with incipient parametrial invasion; (2) adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma; (3) no evidence of enlarged suspicious nodes or distant metastases on pre-operative imaging; (4) primary surgery with curative intent; (5) successful detection of sentinel lymph node, at least, unilaterally. All patients had at least one sentinel lymph node detected and submitted for frozen section evaluation. When sentinel lymph node involvement was detected intra-operatively, the cervical procedure was abandoned and the patient was referred for definitive chemoradiation. Radical surgery was completed in patients with intra-operative negative sentinel lymph nodes. The reliability of intra-operative sentinel lymph node assessment was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio.

Results: The study included a total of 309 patients. Sentinel lymph nodes were detected bilaterally in 86% of the patients. Lymph node positivity was detected intra-operatively in 18 (6%) patients in whom the cervical procedure was abandoned. Adjuvant radiotherapy after completed radical surgery was given to 29 (9%) patients, including 20 patients with macrometastases (8) or micrometastases (12) reported from the final histology, eight patients with positive parametria (all ≤3 mm), and one patient with a positive vaginal resection margin. The sensitivity, specificity, positive predictive value, and negative predictive value for the intra-operative detection of lymph node positivity (macrometastases or micrometastases) was 47% (95% CI 31% to 64%), 100%, 100%, and 93% (95% CI 90% to 96%), respectively. A total of 18 (6%) patients were spared combined treatment owing to the intra-operative sentinel lymph node triage; 29 patients (9%) received combined treatment with both radical surgery and adjuvant radiotherapy CONCLUSIONS: Of 47 patients with high-risk prognostic risk factors (lymph node, parametria, or surgical margin involvement), combined treatment was successfully avoided in 18 (38%). Despite an effort to triage the patients intra-operatively, 9% received a combination of cervical procedure and adjuvant chemoradiation, mostly owing to the low sensitivity of the frozen section in the detection of micrometastases and macrometastases.
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http://dx.doi.org/10.1136/ijgc-2019-001113DOI Listing
June 2020

Metformin Treatment for Diabetes Mellitus Correlates with Progression and Survival in Colorectal Carcinoma.

Transl Oncol 2020 Feb 30;13(2):383-392. Epub 2019 Dec 30.

Third Faculty of Medicine, Charles University, Prague, Czech Republic.

Background: Diabetes mellitus is unfavorably associated with cancer risk. The purpose of this multidisciplinary project was to evaluate a possible association of diabetes mellitus and other comorbidities and their treatment with progression of colorectal cancer.

Patients And Methods: We investigated the correlation between pathological characteristics and clinical course, including comorbidities in 1004 Czech patients diagnosed and surgically treated for colorectal adenocarcinoma (CRC) between 1999 and 2016.

Results: In our data set, CRC patients treated with metformin due to coexisting diabetes mellitus type 2 (T2DM) developed fewer distant metastases which clinically correlates with slower CRC progression. Survival in metformin subgroup was longer, particularly in men with CRC. Osteoporosis may be a negative factor of survival in CRC patients.

Conclusions: Our findings also indicate that aging, higher tumor grade and TNM stage, coexistence of selected endocrine disorders, and metabolic abnormalities may change the tumor microenvironment and impact survival in colorectal cancer, although mechanism of these observations yet to be explained. Patients with diabetes mellitus type 2 treated with metformin may represent the altered microenvironment with specifically tuned metabolic molecular responses and with various epigenetic characteristics. More awareness and increased understanding of the mechanisms underlying the positive effect of metformin on patients' survival could offer insight into new treatment methods and permit more individualized treatment plans.
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http://dx.doi.org/10.1016/j.tranon.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940647PMC
February 2020

Practical instructions for testing and targeted therapy in adult patients with solid tumours with NTRK gene fusion in common clinical practice.

Klin Onkol 2020 ;33(6):414-419

Background: Tropomyosin receptor kinase inhibitors (TRKi) have been shown to produce a dramatic and long-lasting effect on tumours harbouring fusions of neurotrophic receptor tyrosine kinase (NTRK) genes. Due to the low incidence of these molecular aberrations in common types of solid adult tumours, the identification of patients eligible for the treatment with TRK inhibitors in routine clinical practice is a major challenge. The current methods for NTRK gene fusion testing include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and several genomic assays using next-generation sequencing (NGS). After considering the characteristics of these tests, we recommend two-step testing for clinical practice in tumours with a low incidence of NTRK gene fusions. In the first step, a fresh or archival formalin fixed paraffin embedded (FFPE) sample is tested using a validated IHC method. If the IHC result is positive, verification using RNA-based should follow, preferably using fresh tissue sample. If fresh tissue bio-psy cannot be obtained, e.g. due to a disproportionate risk or discomfort for the patient, an archival FFPE sample may be used for testing. For tumours with high incidence of NTRK gene fusions, we recommend upfront NGS sequencing. Larotrektinib is currently the only TRK inhibitor registered in the EU. Although entrektinib, another TRK inhibitor, is not yet registered in the EU, it is currently available in the Czech Republic within an Early Access Programme.

Purpose: The aim of this paper is to provide concise and clear guidance on testing for the presence of NTRK gene fusions and indications for the treatment with TRK inhibitors in the routine clinical oncology practice.
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October 2021

Pathologic Protocols for Sentinel Lymph Nodes Ultrastaging in Cervical Cancer.

Arch Pathol Lab Med 2019 Dec 23. Epub 2019 Dec 23.

From Institute of Pathology (Drs Dundr, Němejcová, Tichá, Bártů, and Jakša) and Gynecologic Oncology Center, Department of Obstetrics and Gynecology (Dr Cibula), First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.

Context.—: Ultrastaging of sentinel lymph nodes (SLNs) is a crucial aspect in the approach to SLN processing. No consensual protocol for pathologic ultrastaging has been approved by international societies to date.

Objective.—: To provide a review of the ultrastaging protocol and all its aspects related to the processing of SLNs in patients with cervical cancer.

Data Sources.—: In total, 127 publications reporting data from 9085 cases were identified in the literature. In 24% of studies, the information about SLN processing is entirely missing. No ultrastaging protocol was used in 7% of publications. When described, the differences in all aspects of SLN processing among the studies and institutions are substantial. This includes grossing of the SLN, which is not completely sliced and processed in almost 20% of studies. The reported protocols varied in all aspects of SLN processing, including the thickness of slices (range, 1-5 mm), the number of levels (range, 0-cut out until no tissue left), distance between the levels (range, 40-1000 μm), and number of sections per level (range, 1-5).

Conclusions.—: We found substantial differences in protocols used for SLN pathologic ultrastaging, which can impact sensitivity for detection of micrometastases and even small macrometastases. Since the involvement of pelvic lymph nodes is the most important negative prognostic factor, such profound discrepancies influence the referral of patients to adjuvant radiotherapy and could potentially cause treatment failure. It is urgent that international societies agree on a consensual protocol before SLN biopsy without pelvic lymphadenectomy is introduced into routine clinical practice.
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http://dx.doi.org/10.5858/arpa.2019-0249-RADOI Listing
December 2019

A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants.

Sci Rep 2019 11 19;9(1):17050. Epub 2019 Nov 19.

Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum of somatic mutations developed in those lesions and all potential druggable targets have not yet been fully elucidated. We present the results of a sequence capture NGS analysis of 114 primary nodular and superficial spreading melanomas identifying driver mutations using biostatistical, immunohistochemical and/or functional approach. The spectrum and frequency of pathogenic or likely pathogenic variants were identified across 54 evaluated genes, including 59 novel mutations, and the newly identified TP53 loss-of-function mutations p.(L194P) and p.(R280K). Frequently mutated genes most commonly affected the MAPK pathway, followed by chromatin remodeling, and cell cycle regulation. Frequent aberrations were also detected in the genes coding for proteins involved in DNA repair and the regulation and modification of cellular tight junctions. Furthermore, relatively frequent mutations were described in KDR and MET, which represent potential clinically important targets. Those results suggest that with the development of new therapeutic possibilities, not only BRAF testing, but complex molecular testing of cutaneous melanoma may become an integral part of the decision process concerning the treatment of patients with melanoma.
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http://dx.doi.org/10.1038/s41598-019-53636-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863855PMC
November 2019

Laparoscopic myomectomy after or without pre-treatment with ulipristal acetate.

Minim Invasive Ther Allied Technol 2021 Feb 16;30(1):55-62. Epub 2019 Oct 16.

Department of Obstetrics and Gynecology, General Faculty Hospital and 1st Medical Faculty, Charles University, Prague, Republic of Czech.

Introduction: The aim was to compare the surgical experience and the clinical results of laparoscopic myomectomy (LM) with or without pre-treatment with ulipristal acetate (UPA).

Material And Methods: Fifty-four women who underwent LM for intramural myomas and were pre-treated with three months of UPA were matched with 54 patients with the same procedure but no hormonal pre-treatment. All operations were performed by one team. The technical features of the procedures were reviewed and evaluated by two other laparoscopists, unaware of the eventual use of UPA. The clinical, histological, and reproductive outcomes of each patient were assessed and the results of both groups were compared.

Results: The groups did not significantly differ in operation time, intra-operative blood loss, drop in hemoglobin concentration, number of complications, pregnancy rate, and delivery rate. Women pre-treated with UPA had significantly longer hospital stays, higher numbers of histologically abnormal leiomyomas, and higher rates of fibroids peri-procedurally assessed as soft and disintegrating. The other four technical parameters of LM were comparable in both groups.

Conclusions: The surgeons performing LM in women pre-treated with UPA should be aware of the abnormal texture of enucleated myomas. Nevertheless, this does not negatively affect the other surgical and clinical outcomes of these patients.
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http://dx.doi.org/10.1080/13645706.2019.1674337DOI Listing
February 2021

Serum proteomic analysis of melanoma patients with immunohistochemical profiling of primary melanomas and cultured cells: Pilot study.

Oncol Rep 2019 Nov 17;42(5):1793-1804. Epub 2019 Sep 17.

Department of Dermatovenereology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague 128 00, Czech Republic.

The steadily increasing incidence of malignant melanoma (MM) and its aggressive behaviour makes this tumour an attractive cancer research topic. The tumour microenvironment is being increasingly recognised as a key factor in cancer biology, with an impact on proliferation, invasion, angiogenesis and metastatic spread, as well as acquired therapy resistance. Multiple bioactive molecules playing cooperative roles promote the chronic inflammatory milieu in tumours, making inflammation a hallmark of cancer. This specific inflammatory setting is evident in the affected tissue. However, certain mediators can leak into the systemic circulation and affect the whole organism. The present study analysed the complex inflammatory response in the sera of patients with MM of various stages. Multiplexed proteomic analysis (Luminex Corporation) of 31 serum proteins was employed. These targets were observed in immunohistochemical profiles of primary tumours from the same patients. Furthermore, these proteins were analysed in MM cell lines and the principal cell population of the melanoma microenvironment, cancer‑associated fibroblasts. Growth factors such as hepatocyte growth factor, granulocyte‑colony stimulating factor and vascular endothelial growth factor, chemokines RANTES and interleukin (IL)‑8, and cytokines IL‑6, interferon‑α and IL‑1 receptor antagonist significantly differed in these patients compared with the healthy controls. Taken together, the results presented here depict the inflammatory landscape that is altered in melanoma patients, and highlight potentially relevant targets for therapy improvement.
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http://dx.doi.org/10.3892/or.2019.7319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787991PMC
November 2019
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