Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Integrated dia-gnostics of diffuse gliomas.

Recently, the World Health Organization (WHO) classification of tumours of the central nervous system (CNS) has brought essential changes. The currently valid revised WHO 2016 classification of CNS tumours introduced the concept of integrated dia-gnostics, which incorporated not only histopathological morphological finding and immunophenotype but also molecular-genetic characteristics of the tumour. Thus, the final integrated dia-gnosis comprises the traditional morphological and growth pattern characteristics of a tumour including histopathological grade and also specific molecular bio-markers. The classification of tumour based on a combination of both tumour phenotype and genotype enables more precise prognostic stratification, increases the objectivity of dia-gnostics and prediction of response to treatment. In 2017, an international platform, The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy - not official WHO (cIMPACT-NOW), was established to create and formulate practical recommendations for integrated dia-gnostics of CNS tumours and upcoming WHO classification. The incorporation of molecular bio-markers into the integrated dia-gnostics radically changed the classification of diffuse gliomas, which include entities with different morphological characteristics, genetic alterations and bio-logical behaviour. This review article summarizes essential morphological, immunophenotypical and molecular genetic characteristics of diffuse gliomas within the scope of integrated dia-gnostics according to the valid WHO classification of tumours of the CNS and subsequent recommendations of dia-gnostic approaches. This work was supported by grant of the Ministry of Health of the Czech Republic - Conceptual Development of a Research Organization (MMCI 00209805) and Grant Agency of Masaryk University (MUNI/A/1562/2018). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Effect of Tumor Size and p16 Status on Treatment Outcomes - Achievement of Complete Remission in Prospectively Followed Patients with Oropharyngeal Tumors.

BACKGROUND: Oropharyngeal squamous cell tumors associated with human papillomavirus infection (p16 positive tumors) have better prognosis than p16 negative tumors regardless of the more advanced stage of the disease. Tumor volume (GTVt+n) is generally an important factor affecting treatment results of ionizing radiation. The aim of this prospective non-randomized study is to evaluate the effect of tumor volume on the (chemo)radiation treatment results in a group of patients with p16 negative and p16 positive oropharyngeal tumors. PATIENTS AND METHODS: Patients with confirmed squamous cell tumor of the oropharynx of stages III and IV, according to the 7th version of the TNM (tumor-nodes-metastases) classification, were eligible for this study. The main exclusion criteria were palliative treatment, neoadjuvant chemotherapy or planned concomitant therapy with cetuximab. Patients were treated according to standardized protocols with curative intent. Primary tumor volume (GTVt) and involved nodes volume (GTVn) were obtained from radiotherapy planning system for further statistical analysis. The differences in tumor volumes between the groups according to p16 expression were assessed with subsequent testing of probability to achieve complete remission (CR) of the disease in both groups. RESULTS: In total, 49 patients - 84% men, median age 60.5 years, 25 (51%) patients p16 positive, 40 (82%) underwent concomitant chemoradiotherapy. Median of GTVt in the whole patients group is 40.2 ccm, GTVn 11.78 ccm and median volume of the whole tumor burden (GTVt+n) 70.21 ccm (range 11.05-249). Median of GTVn was greater in the p16 positive cohort (p = 0.041). In the entire group, the median time to reach CR was 91 days (95% CI 86-107 days) from the end of radiotherapy. In the group of p16 negative patients, 14 achieved CR (61%) out of 23 patients, in p16 positive group 20 (80%) out of 25 patients (p = 0.111). P16 negative patients had a longer time to CR (p = 0.196, HR 1.58, 95% CI 0.79-3.18). None of the independently assessed volumetric parameters of the tumor (GTVt, GTVn, GTVt+n) affected CR in the p16 positive patients group, while there was a significant impact of the whole tumor burden (GTVt+n) in the p16 negative cohort (median 58.1 ccm in CR patients vs. 101.9 ccm, p = 0.018). CONCLUSION: We have showed less GTVt+n dependence to achieve CR in p16 positive tumors in comparison with p16 negative tumors. Thus, p16 positive oropharyngeal squamous cell cancers should not be withdrawn from the curative treatment intent based on the greater GTVt+n. Key words oropharyngeal neoplasms - p16 status - treatment outcome - tumor burden - complete remission This work was supported by grant of the Ministry of Health of the Czech Republic AZV 15-31627A and by grant of the Ministry of Health of the Czech Republic - Conceptual development of a research organization (MMCI 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 11. 2018 Accepted: 11. 11. 2018.

[Dysregulation of Long Non-coding RNAs in Glioblastoma Multiforme and Their Study Through Use of Modern Molecular-Genetic Approaches]. / Dysregulace dlouhých nekódujících RNA u multiformního glioblastomu a jejich studium s vyuzitím moderních molekulárne-genetických prístupu.

BACKGROUND: Glioblastoma (GBM) is the most frequent primary brain tumor characterized by an unfavourable prognosis despite multimodal therapy. Therefore, a lot of efforts and financial resources are dedicated to the research of new therapeutic targets and prognostic or predictive biomarkers. Long non-coding RNAs (lncRNAs) are regulators of gene expression which play a significant role in GBM pathology and, thus, present promising candidates. MATERIAL AND METHODS: Our study included 14 patients with GBM and 8 patients with intractable epilepsy from whom we acquired brain tissues during surgical intervention. Ribosomal RNA depleted RNA was used for sequencing by NextSeq 500 instrument (Illumina). Statistical analysis evaluated 24,087 protein-coding and 8,414 non-coding RNAs and their sequential variants with non-zero reads per kilobase per million mapped reads (RPKM) at least in one sample. CLC Genomic Workbench was used for the alignment and target counts. Targeted downregulation of up-regulated ZFAS1, one of the identified lncRNA, level has been carried out by the transient transfection of specific small interfering RNA (siRNA) in GBM stable cell lines (A172, U87MG, T98G). The success of transfection and viability were analyzed in vitro using quantitative real time polymerase chain reaction and MTT assay, resp. RESULTS: Statistical analysis has revealed 274 (p < 0.01) dysregulated lncRNAs in GBMs in comparison with non-tumor brain tissues. Moreover, the results have showed 489 dysregulated mRNAs (p < 0.0001) and 26 mRNAs (p < 0.000001). Transfection of ZFAS1 inhibitor led to successful downregulation of ZFAS1 expression level, although it did not have a significant effect on proliferation of GBM cells. CONCLUSION: We described a significant dysregulation of lncRNAs and mRNAs in GBM tissue in comparison with non-tumor tissue. We also succesfully decreased expression level of ZFAS1, which in turn, however, had no impact on the viability of GBM cell lines.Key words: glioblastoma - long non-coding RNA - next-generation sequencing The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. This tudy was supported by Ministry of Health of the Czech Republic, grant No. 15-33158A. All rights reserved.Submitted: 19. 3. 2018Accepted: 10. 4. 2018.

[MicroRNAs in Prediction of Response to Radiotherapy in Head and Neck Cancer Patients - Pilot Study]. / MikroRNA v predikci odpovedi na radioterapii u pacientu s nádory hlavy a krku - pilotní studie.

BACKGROUND: Radiotherapy plays a key role in the treatment of squamous cell head and neck cancers (HNSCC). The effectivity of radiation therapy is often limited by radioresistance of these tumours. microRNAs (miRNAs) are endogenous, evolutionary conserved, small non-coding RNAs involved in regulation of cellular processes associated with radioresistance. The objective of this study was to identify miRNA profile enabling to predict the radiation treatment outcomes in HNSCC patients. MATERIAL AND METHODS: The retrospective study included HNSCC patients who underwent a definitive radiotherapy. Patients were divided into two groups according to loco-regional control (LRC) as follows - short LRC (n = 22; median 5.1 months (min. 1.3, max, 18.6)) vs. long LRC (n = 21; 60.4 (min. 46.8, max. 98.8)) group. Global miRNA expression profiles were obtained by use of Affymetrix microarray technology (GeneChip miRNA 4.0 Array). RESULTS: We identified 24 miRNAs to be significantly associated with LRC (p < 0.05), all of these miRNAs were upregulated in patients with short LRC. Out of these miRNAs, 12 miRNAs with p < 0.025 and 4 miRNAs with p < 0.01 have been identified. CONCLUSION: miRNAs seems to be promising as potential biomarkers predicting radiotherapy treatment outcomes in patients with HNSCC.Key words: microRNAs - radiotherapy - head and neck cancer The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Supported by Ministry of Health of the Czech Republic, grant No. 15-31627A. All rights reserved.Submitted: 19. 3. 2018Accepted: 20. 3. 2018.

Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding.

Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

[The Impact of Corticotherapy on the Diagnostic Yield of Stereotactic Biopsy in Patients with Brain Lymphoma]. / Vliv kortikoterapie na diagnostickou výteznost stereotaktické biopsie u nemocných s lymfomem mozku.

Backround: Because of the dismal prognosis of untreated brain lymphoma early histological verification using stereobiopsy is decisive for patient with this disease. The study analysed the diagnostic yield of stereobiopsy in brain lymphoma patients with respect to prebiopsy corticosteroid administration. PATIENTS AND METHODS: Patients with brain lymphomas were identified in a group of 162 stereotactic biopsies (108 frame-based and 54 frameless) of patients harboring suspected brain tumor. Non conclusive biopsies were reevaluated to exclude the possibility of missed lymphoma. RESULTS: Total 9 patients (8.3%) and 4 patients (7.4%) had lymphomas in the frame-based and frameless stereobiopsy groups, resp. In 10 patients, corticosteroid treatment of perifocal brain oedema was conducted continually up until biopsy (including one patient with corticotherapy for pulmonary disease). Lesion regression was observed in 6 of these patients. Transient lesion remission was observed during corticotherapy in one patient with lesion recurrence after steroid discontinuation. In 2 patients, corticosteroids were not administered before biopsy. The results of stereobiopsy were inconclusive in 8 patients (4.9%). Before biopsy, the possibility of brain lymphoma was considered in 3 patients, but the final diagnoses were autoimmune vasculitis, histological changes after embolic events from the thrombosed pulmonary veins in pulmonary malformation and local inflammation. CONCLUSION: Although the extent of brain lymphoma decreased after corticosteroid administration, corticotherapy does not exclude valid diagnostic biopsy.Key words: brain lymphoma - stereotaxic techniques - frameless stereotaxy - stereotactic biopsy - corticosreroids Part of the message was presented on XLI. Brno Oncological Days within the Glio Meeting and published in the form of a short abstract. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 27. 5. 2017Accepted: 2. 7. 2017.

[Prognostic and Predictive Factors for Pancreatic Adenocarcinoma]. / Prognostické a prediktivní faktory u adenokarcinomu pankreatu.

BACKGROUND: Pancreatic ductal adenocarcinoma is a highly aggressive disease with 5-year overall survival not exceeding 5%. In the Czech Republic, the incidence of this tumor has been increasing; according to recent statistics, the Czech Republic is already number one worldwide in the occurrence of this malignancy. Delayed diagnosis due to asymptomatic course of the disease in the early stages is characteristic for this disease. AIM: The objective of this article is to give an overview of the most important factors, which according to current knowledge of pancreatic adenocarcinoma have a prognostic and predictive potential. This work describes both traditional prognostic factors, such as tumor resectability, its extent and localization, application of adjuvant chemotherapy, microscopically positive resection margin, presence of metastases in lymph nodes, histological grade, vascular and perineural invasion. Further, the paper lists a number of different biological markers that could contribute to early detection of cancer, better prognosis and optimization of treatment, for example hENT1 (human equilibrative nucleoside transporter-1), SPARC (secreted protein acidic and rich in cysteine), AGR2, Bcl-2, VEGF, Ki-67, COX-2 and more. Also, genetic mutations and significance of microRNA are discussed. CONCLUSION: Despite great efforts that have been devoted to the research of biological markers, so far the only clinically accepted and used marker is CA 19-9. Its use is primarily in patients already diagnosed with adenocarcinoma of the pancreas. A lot of attention has recently been focused on other potential biomarkers, their application in clinical practice would however still require further research.Key words: carcinoma pancreatic ductal biological tumor markers prognosis prognostic factorsThe authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 16. 2. 2016Accepted: 17. 2. 2016.

[Parametric monitoring of the quality of total mesorectal excision and surgical treatment of rectal carcinoma results of a multicenter study]. / Parametrické sledování kvality totální mezorektální excize a chirurgické lécby karcinomu rekta výsledky multicentrické studie.

INTRODUCTION: Tumour size and the quality of its complete surgical removal are the main prognostic factors in rectal cancer treatment. The number of postoperative local recurrences depends on whether the mesorectum has been completely removed - total mesorectal excision (TME) - and whether tumour-free resection margins have been achieved. The surgery itself and its quality depend on the accuracy of preoperative diagnosis and detection of risk areas in the rectum and mesorectum, on the surgeons skills, and finally on pathological assessment evaluating whether complete tumour excision has been accomplished including circumferential margins of the tumour, and whether mesorectal excision is complete. The aim of our study was to implement and standardize a new method of evaluation of the quality of the surgical procedure - TME - in rectal cancer treatment using an assessment of its circumferential margins (CRO) and completeness of the excision. METHODS: The study consisted of two parts. The first, multi-centre retrospective phase with 288 patients analysed individual partial parameters of the diagnosis, operations and histological examinations of the rectal cancer. Critical points were identified and a unified follow-up protocol was prepared. In the second, prospective part of this study 600 patients were monitored parametrically focusing on the quality of the TME and its effect on the oncological treatment results. RESULTS: The proportion of patients with restaging following neoadjuvant therapy increased from 60.0% to 81.7% based on preoperative diagnosis. The number of specimens missing an assessment of the mesorectal excision quality decreased from 52.9% in the retrospective part of to the study to 22.8% in the prospective part. The proportion of actually complete TMEs rose from 22.6% to 26.0%, and that of nearly complete TMEs from 10.1% to 24.0%. CONCLUSION: The introduction of parametric monitoring into routine clinical practice improved the quality of pre-treatment and preoperative diagnosis, examination of the tissue specimen, and consequently improved quality of the surgical procedure was achieved. KEY WORDS: rectal cancer TME - parametric monitoring - quality control.

[Intraoperative sentinel lymph node detection in colon cancer resection - preliminary results]. / Peroperacní detekce sentinelové uzliny pri resekci pro karcinom kolon - predbezné výsledky.

INTRODUCTION: The aim of this paper is to evaluate the results of intraoperative sentinel node detection in colon cancer patients and to compare the number of nodes retrieved per specimen in comparison with standard resection. METHODS: Patients undergoing elective colon cancer resection were included in the study. The specimen and the sentinel lymph node were sent for histopathological examination. A group of patients from 2011 who underwent elective resection served as the study control. RESULTS: The control group comprised 56 patients. The average node count was 12.73 (4-27). The study group included 102 patients; 29 patients had to be excluded because of protocol deviation. Out of the remaining 73 (46 male and 27 female) patients, 24 were N-positive and 2 of them were pN1c. In the remaining 22 patients, the sentinel node was positive in 8 cases, corresponding to a sensitivity of 36.36%. The average lymph node count was 15.97(3-30) after patent blue dye injection. CONCLUSION: Intraoperative sentinel lymph node detection is an easy and feasible method. Despite the low sensitivity, the main positive effect of the method is the increased lymph node count per resection specimen.

Perigraft seroma as a rare angiosurgical complication.

Perigraft seroma is quite a rare complication that may occur after implantation of Dacron or expanded polytetrafluoroethylene (ePTFE) vascular grafts. We report a case of a 54-year-old patient with perigraft seroma around an axillofemoral bypass (ePTFE graft). Definitive treatment involved the explantation of this extraanatomic bypass with perigraft seroma and the implantation of an aortobiiliac bypass using vascular prosthesis made of a different material. Based on published studies, therapeutic options for this complication are discussed. No guidelines or recommendations are available. In conclusion, the approach to perigraft seroma treatment remains strictly individual. Vascular graft replacement using grafts made of different material seems to be the best option in the case of recurring perigraft seroma, where less invasive procedures were not successful.

[Evaluation of safe resection margins in tumours of parenchymatous organs]. / Problematika stanovení bezpecných resekcních okraju u nádoru parenchymatózních orgánu

The definition of a safe surgical margin in tumours of parenchymatous organs has been the subject of frequent debates and a number of studies. This topic is not generally unified for parenchymatous organs and has many organ specifics. Moreover, there are still controversies in the diagnostic criteria and the definitions of positive resection margins, in indications of perioperative examinations of resection margins, and in the prognostic significance of margin involvement in different parenchymatous organs. The consensus in terminology and standardization of histopathological examination procedures is also very desirable across the diagnostic areas.

[Differential diagnosis of the chronic pancreatitis and the pancreatic ductal adenocarcinoma]. / Diferenciální diagnostika chronické pankreatitidy a duktálního adenokarcinomu pankreatu.

UNLABELLED: The histopathological distinction of pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis represents one of the most difficult differential diagnosis in surgical pathology, especially in small biopsy specimens and frozen sections. Practically usable morphological criteria, which allow an efficient differential diagnosis of these lesions have been determined by a number of authors. The perineural and vascular invasion represent findings, which are entirely diagnostic for PDA; however, they are rarely detectable in small biopsy specimens as well as in the presence of solitary naked ducts in fat without surrounding pancreatic elements or fibrous tissue, which also supports the diagnosis of PDA. The features that are suggestive of PDA include random haphazard distribution of ductal structures, irregular ductal contours, ruptured ducts, nuclear enlargement, pleomorphism, hyperchromatism, and mitoses. Uniterrupted proliferation of numerous ducts (>50), ducts lying adjacent to arterioles, intraluminal cellular debris, and hyperchromatic raisinoid nuclei represent less frequently displayed features that also support the diagnosis of PDA. On the contrary, the preserved lobular arrangement, clusters of uniform ductal units, smooth ductal contours, ducts related to the remaining acini and islets, and finding of intraluminnal mucoprotein plugs favor a benign process over PDA. The combination of presented criteria and features should enable a reliable differential diagnosis of invasive pancreatic cancer and chronic pancreatitis. KEYWORDS: chronic pancreatitis - pancreatic ductal adenocarcinoma - pseudotumor - differential diagnosis.

[Partial regression of CNS lesions of Erdheim-Chester disease after treatment with 2-chlorodeoxadenosine and their full remission following treatment with lenalidomide]. / Parciální regrese lozisek Erdheimovy-Chesterovy nemoci v CNS po lécbe 2-chlorodeoxyadenosinem a jejich kompletní vymizení prn lécbe lenalidomidem.

INTRODUCTION: Erdheim-Chester disease is a very rare syndrome affecting adult population. It typically causes hyperostosis of long bones, retroperitoneal fibrosis and widening of the aortic wall. Patients frequently suffer from disease-associated fevers and pain in the lower limbs. No guidelines are available for the treatment of this rare ailment. Therefore, we describe our experience with lenalidomide in a patient with poor treatment response to 2-chlorodeoxyadenosine. CASE: Diabetes insipidus and neurological problems developing over 4 years were the first signs of the disease. The disease was diagnosed from histology of the bone marrow extracted from the ilium. At diagnosis, the patient had multiple infiltrates in the brain, widened wall of the thoracic and abdominal aorta, fibrotic changes to retroperitoneum and typical hyperostosis of the long bones of lower limbs with high accumulation of technetium pyrophosphate as well as fluorodeoxyglucose. First line treatment involved 2-chlorodeoxyadenosine 5 mg/m2 s.c. for 5 consecutive days every 28 days. There was no clear treatment response identifiable on the MR scan of the brain following the third cycle and thus 4th-6th cycle consisted of 2-chlorodexyadenosine 5 mg/m2 + cyclophosphamide 150 mg/m2 + dexamethasone 24 mg day 1-5 every 28 days. After the 6th cycle, MR showed partial regression of the brain lesions. PET-CT showed an increased accumulation of fluorodeoxyglucose in bone lesions. Second line treatment involved lenalidomide 25 mg/day days 1-21 every 28 days. Lenalidomide tolerance was excellent; the number of neutrophils and thrombocytes was within the physiological range throughout the treatment period. Follow-up MR showed complete remission of the brain lesions, while follow-up PET-CT showed further increase in fluorodeoxyglucose accumulation in the bones of lower limbs. CONCLUSION: Treatment with 2-chlorodeoxyadenosine-based regimen provided partial remission of Erdheim-Chester disease lesions in the brain, while treatment with lenalidomide resulted in complete remission of these lesions. Fluorodeoxyglucose continues to accumulate in the long bones of lower limbs. We are unable to elucidate the reasons for complete remission of the disease in the brain as per the MR and its progression in the long bones according to PET-CT. Further testing of lenalidomide in the treatment of this disease is required to support further use of this perspective treatment option.

Spontaneous duodenal intramural haematoma imitating pancreatic pseudocyst.

Spontaneous intramural duodenal haematoma develops mostly as a complication of anticoagulation therapy. Other causes were reported only as case reports. CT diagnostics has some typical features in an intramural haematoma of the small bowel. This is especially hyperdensity of the bowel wall during the first 10 days from the onset of symptoms (30-80 HU), which could contribute to the differentiation from other infiltrative processes. These features are fully expressed only in a certain part of patients. We reported a 54 year-old female treated for epigastric pain. The patient's history, laboratory data, ultrasonography and CT findings resulted in a mistaken diagnosis of acute pancreatitis, necrosis of the pancreatic body with a subsequent development of pancreatic pseudocyst. The CT guided drainage was performed. The correct diagnosis was made one year later--surgical treatment was indicated for clinical signs of GI obstruction and CT findings of pseudocyst recurrence. During the operation, there was a finding of intramural haematoma in the duodenojejunal border. We performed an evacuation of the haematoma and gastroenteroanastomosis.