Testicular cancer is the most common form of cancer in young men of reproductive age and its incidence is increasing globally. With the currently successful treatment and 95% survival rate, there is a need for deeper understanding of testicular cancer-related infertility. Most patients with testicular cancer experience semen abnormalities prior to cancer therapy. However, the exact mechanism of the effect of testicular cancer on sperm anomalies is not known. Mitochondria are organelles that play a crucial role in both tumorigenesis and spermatogenesis and their malfunction may be an important factor resulting in sperm abnormalities in testicular cancer patients. Within the scope of this review, we will discuss current knowledge of testicular cancer-related alterations in the ATP production pathway, a possible pathophysiological switch from oxidative phosphorylation (OXPHOS) to glycolysis, as well as the role of oxidative stress promoting sperm dysfunction. In this regard, the review provides a summary of the impact of testicular cancer on sperm quality as a possible consequence of impaired mitochondrial function including the energy metabolic pathways that are known to be altered in the sperm of testicular cancer patients.
Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.
- MeSH
- dědičné nádorové syndromy * MeSH
- DNA-helikasy genetika metabolismus MeSH
- dospělí MeSH
- epiteliální ovariální karcinom MeSH
- jaderné proteiny genetika MeSH
- karcinom * patologie MeSH
- kolorektální nádory * MeSH
- lidé středního věku MeSH
- lidé MeSH
- malobuněčný karcinom * MeSH
- mladý dospělý MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory endometria * patologie MeSH
- nádory mozku * MeSH
- nádory vaječníků * genetika patologie MeSH
- senioři MeSH
- transkripční faktory genetika metabolismus MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.
- MeSH
- antigen CA-125 MeSH
- časná detekce nádoru metody MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádorové biomarkery genetika MeSH
- nádory vaječníků * diagnóza genetika MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- transkripční faktory Krüppel-like genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
- MeSH
- biologické přípravky * MeSH
- genomika MeSH
- germinální a embryonální nádory * genetika MeSH
- lidé MeSH
- lidské chromozomy, pár 12 metabolismus MeSH
- seminom * genetika MeSH
- senioři MeSH
- testikulární nádory * metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Normalizing growth in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) requires a long-term maintenance of a fragile balance between hydrocortisone (HC) replacement and androgen suppression. The growth pattern in children with 21OHD-CAH diagnosed by clinical symptoms has been evaluated in numerous retrospective studies. The aim of this study was to evaluate growth of patients with 21OHD-CAH detected by newborn screening (NBS), prior to clinical symptoms. METHODS: Nation-wide NBS for 21OHD-CAH was implemented in the Czech Republic in 2006. Since then, 1,317,987 neonates were screened (2006-2017) and 21OHD-CAH was confirmed in 108 patients. Growth was evaluated as height-standard deviation score (SDS) at regular time-points, related to bone age and compared to recent population standards. In 88 patients, available data allowed long-term evaluation of growth, HC and fludrocortisone doses (in half-year intervals), with a median observation period of ten years. RESULTS: Body height in affected children was shorter between years 1-9 of life with a nadir at age 1-3 years. Their height did not differ from general population at the age 10-12 years. There were not found differences according to 21OHD-CAH severity. CONCLUSIONS: NBS is an effective secondary prevention tool for the early detection of 21OHD-CAH which improves growth patterns. A significant growth deceleration was observed during infancy and early childhood periods but with following height normalization. Growth pattern was not associated with the genotype of 21OHD, if patients have been detected by NBS.
- MeSH
- dítě MeSH
- genotyp MeSH
- hydrokortison terapeutické užití MeSH
- kojenec MeSH
- kongenitální adrenální hyperplazie * diagnóza genetika MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- hormonální substituční terapie * škodlivé účinky MeSH
- hypogonadismus komplikace MeSH
- kardiovaskulární nemoci chemicky indukované epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prostaty chemicky indukované epidemiologie MeSH
- randomizované kontrolované studie jako téma MeSH
- rizikové faktory kardiovaskulárních chorob * MeSH
- senioři MeSH
- testosteron krev škodlivé účinky MeSH
- urologické nemoci chemicky indukované epidemiologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- komentáře MeSH
High-grade serous carcinoma of the ovary, fallopian tube and peritoneum (HGSC), the most common type of ovarian cancer, ranks among the deadliest malignancies. Many HGSC patients have excess fluid in the peritoneum called ascites. Ascites is a tumour microenvironment (TME) containing various cells, proteins and extracellular vesicles (EVs). We isolated EVs from patients' ascites by orthogonal methods and analyzed them by mass spectrometry. We identified not only a set of 'core ascitic EV-associated proteins' but also defined their subset unique to HGSC ascites. Using single-cell RNA sequencing data, we mapped the origin of HGSC-specific EVs to different types of cells present in ascites. Surprisingly, EVs did not come predominantly from tumour cells but from non-malignant cell types such as macrophages and fibroblasts. Flow cytometry of ascitic cells in combination with analysis of EV protein composition in matched samples showed that analysis of cell type-specific EV markers in HGSC has more substantial prognostic potential than analysis of ascitic cells. To conclude, we provide evidence that proteomic analysis of EVs can define the cellular composition of HGSC TME. This finding opens numerous avenues both for a better understanding of EV's role in tumour promotion/prevention and for improved HGSC diagnostics.
- MeSH
- ascites metabolismus patologie MeSH
- extracelulární vezikuly * metabolismus MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory vaječníků * diagnóza MeSH
- proteomika MeSH
- serózní cystadenokarcinom * diagnóza genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
An international joint statement about the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer was published in 2016, warning about the uncritical use of HIPEC outside controlled studies. This statement has now been updated after the most recent literature was reviewed by the participating study groups and societies. HIPEC became a treatment option in patients with advanced colon cancer after positive results of a randomized trial comparing surgery and HIPEC versus palliative treatment alone. Although this trial did not compare the added value of HIPEC to surgery alone, HIPEC for the treatment of peritoneal metastases was in the subsequent years generalized to many other cancer types associated with peritoneal carcinomatosis including epithelial ovarian cancer (EOC). In the meantime, new evidence from prospective randomized trials specifically for EOC-patients emerged, with however contradicting results and several quality aspects that made the interpretation of their findings critical. Moreover, three additional trials in colorectal cancer failed to confirm the previously presumed survival benefit through the implementation of HIPEC in peritoneally disseminated colorectal cancers. Based on a still unclear and inconsistent landscape, the authors conclude that HIPEC should remain within the remit of clinical trials for EOC-patients. Available evidence is not yet sufficient to justify its broad endorsement into the routine clinical practice.
- MeSH
- epiteliální ovariální karcinom patologie MeSH
- hypertermická intraperitoneální peroperační chemoterapie MeSH
- indukovaná hypertermie * metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- nádory vaječníků * farmakoterapie patologie MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Rakousko MeSH
- Švýcarsko MeSH
Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.
- MeSH
- CD8-pozitivní T-lymfocyty MeSH
- ektopické lymfoidní struktury * MeSH
- fenotyp MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory plic * MeSH
- nádory vaječníků * patologie MeSH
- nemalobuněčný karcinom plic * MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Karcinom vaječníku je heterogenní onemocnění s celkově špatnou prognózou, jehož léčba by měla být nastavena s ohledem na kvalitu života a přežití pacientky. Základem správného nastavení léčebné strategie je kvalitní předoperační diagnostika a mezioborová spolupráce. V časném stadiu onemocnění představuje chirurgická léčba primárně léčebný a stagingový účel a v pokročilém stadiu onemocnění je chirurgická léčba primárně léčebnou modalitou se snahou dosáhnout optimální resekce. Chirurgická léčba by měla být koncentrována do onkogynekologických center se zkušenostmi s danou problematikou. U pacientek s pokročilým onemocněním je stále diskutováno provedení primární cytoredukční operace nebo intervalové cytoredukční operace, avšak stále platí, že cytoredukční chirurgická léčba je primární léčebná modalita, jejíž extenzi a radikalitu je vždy nutné zvážit individuálně.
Ovarian cancer is a heterogeneous group of diseases with an overall poor prognosis, whose treatment is necessary to manage well keeping in mind the quality of life and overall survival of the patient. Preoperative diagnosis and treatment in a multidisciplinary setting play an important role in setting the optimal treatment strategy. Surgical treatment in the early stages of ovarian cancer has a curative and staging purpose while in advanced stages it has primarily a goal of optimal resection of macroscopic tumors. Surgical treatment of ovarian cancer should be performed by experienced gynecological oncologists in centers with expertise. The discussion between primary cytoreductive surgery versus interval cytoreductive surgery in advanced ovarian cancer remains very active and alive, however surgical treatment remains the gold standard of treatment in ovarian cancer, the extension and radicality of which needs to be always individualized.
- MeSH
- gynekologické chirurgické výkony metody MeSH
- lidé MeSH
- nádory vaječníků * chirurgie MeSH
- staging nádorů MeSH
- zachování plodnosti MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
