In patients with testicular germ cell tumours (TGCT), sperm cryopreservation prior to anti-cancer treatment represents the main fertility preservation approach. However, it is associated with a low sperm recovery rate after thawing. Since sperm is a high-energy demanding cell, which is supplied by glycolysis and oxidative phosphorylation (OXPHOS), mitochondrial dysfunctionality can directly result in sperm anomalies. In this study, we investigated the bioenergetic pattern of cryopreserved sperm of TGCT patients in comparison with normozoospermic samples using two state-of-the-art methods: the Extracellular Flux Analyzer (XF Analyzer) and two-photon fluorescence lifetime imaging microscopy (2P-FLIM), in order to assess the contributions of OXPHOS and glycolysis to energy provision. A novel protocol for the combined measurement of OXPHOS (oxygen consumption rate: OCR) and glycolysis (extracellular acidification rate: ECAR) using the XF Analyzer was developed together with a unique customized AI-based approach for semiautomated processing of 2P-FLIM images. Our study delivers optimized low-HEPES modified human tubal fluid media (mHTF) for sperm handling during pre-analytical and analytical phases, to maintain sperm physiological parameters and optimal OCR, equivalent to OXPHOS. The negative effect of cryopreservation was signified by the deterioration of both bioenergetic pathways represented by modified OCR and ECAR curves and the derived parameters. This was true for normozoospermic as well as samples from TGCT patients, which showed even stronger damage within the respiratory chain compared to the level of glycolytic activity impairment. The impact of cryopreservation and pathology are supported by 2P-FLIM analysis, showing a significant decrease in bound NADH in contrast to unbound NAD(P)H, which reflects decreased metabolic activity in samples from TGCT patients. Our study provides novel insights into the impact of TGCT on sperm bioenergetics and delivers a verified protocol to be used for the assessment of human sperm metabolic activity, which can be a valuable tool for further research and clinical andrology.
- MeSH
- dospělí MeSH
- energetický metabolismus * MeSH
- germinální a embryonální nádory * metabolismus patologie MeSH
- glykolýza * MeSH
- kryoprezervace * metody MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- oxidativní fosforylace * MeSH
- spermie * metabolismus MeSH
- spotřeba kyslíku fyziologie MeSH
- testikulární nádory * metabolismus patologie MeSH
- uchování spermatu metody MeSH
- zachování plodnosti metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
INTRODUCTION: Piflufolastat F-18 (18F-DCFPyL) prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is approved by the US food and drug administration for initial staging of high-risk prostate cancer, biochemical recurrence (BCR), and restaging of metastatic prostate cancer. Here, we sought to assess how its integration into clinical care may have impacted the management of patients. METHODS: We identified 235 consecutive patients who underwent an 18F-DCFPyL PET scan from August 2021 to June 2022. The median prostate-specific antigen at the time of imaging was 1.8 ng/mL (Range: 0-3740 ng/mL). Descriptive statistics were used to analyze its impact on clinical care for a subset of 157 patients with available treatment information: 22 for initial staging, 109 with BCR, and 26 patients with known metastatic disease. RESULTS: PSMA-avid lesions were detected in 154/235 (65.5% of) patients. In patients undergoing initial staging, 18/39 (46.2% of) patients had extra-prostatic metastatic lesions; 15/39 (38.5% of) scans were negative and 6/39 (15.4%) had equivocal results. 12/22 (54.5% of) patients had a change in their treatment plan post-PSMA PET scan while 10/22 (45.5%) had no change in their treatment plan. In the BCR cohort, 93/150 (62.0%) had a local recurrence or metastatic lesions. Equivocal and negative scans accounted for 11/150 (7.3%) and 46/150 (30.7%) of scans, respectively. 37/109 (33.9% of) patients had a change in their treatment plan, while treatment was not altered in 72/109 (66.1% of) cases. In patients with metastatic disease, 43/46 (93.5%) had PSMA-avid lesions identified; equivocal and negative scans accounted for 2/46 (4.3%) and 1/46 (2.2%) of scan results, respectively. 6/26 (23.1%) had their tentative treatment plan adjusted after the PSMA PET scan. No change in the treatment plan was observed in 20/26 (76.9% of) cases. CONCLUSION: Integration of F-18 PSMA PET imaging impacted clinical decision-making and subsequent management across all stages of prostate cancer. It remains to be seen whether this translates into superior survival outcomes.
Karcinom prostaty patří k vůbec nejčastějším zhoubným nádorovým onemocněním mužů v České republice. Podobně se dá hovořit o karcinomu rekta, jehož incidence v ČR je v mezinárodním srovnání na předních příčkách, není proto až takovou raritou, když dojde k současnému (synchronnímu) výskytu obou malignit u jednoho pacienta. Problémem této tématiky zůstává zejména absence standardizovaných postupů či guidelines odborných společností, pramenící z nedostatečného vzorku této specifické populace, která by byla podkladem pro kvalitní klinické studie. Blízký anatomický vztah obou struktur s sebou nese řadu úskalí, ale i potencionálních příležitostí, které lze při léčbě synchronního postižení využít. Léčba by měla probíhat ideálně v multioborové spolupráci s onkology, urology a chirurgy a vždy zohledňovat aktuální konfiguraci obou malignit i stav a přání pacienta.
Prostate cancer is one of the most common malignancies in men in the Czech Republic. Similarly, we can talk about rectal cancer, the incidence of which in the Czech Republic is at the forefront of international comparison, so it is not such a rarity when there is a simultaneous (synchronous) occurrence of both malignancies in one patient. The problem of this topic remains mainly the absence of standardized procedures or guidelines of professional societies, stemming from the insufficient sample of the specific population, which would be the basis for clinical studies. The close anatomical relationship between the two structures carries a number of problems, but also potential opportunities that can be used in the treatment of synchronous tumors. Treatment should be discussed in a multidisciplinary collaboration with oncologists, urologists and surgeons and always take into account the current configuration of both malignancies and the patient's condition and preferences.
- MeSH
- adenokarcinom chirurgie diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetné primární nádory * diagnóza terapie MeSH
- nádory prostaty chirurgie diagnóza terapie MeSH
- nádory rekta chirurgie diagnostické zobrazování terapie MeSH
- neoadjuvantní terapie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
We investigated the possible associations between leukocyte telomere length, therapy outcomes, and clinicopathological features in patients with colorectal cancer. Additionally, telomerase reverse transcriptase (TERT) expression was evaluated. Telomere length was measured using singleplex qPCR in 478 consecutive leukocyte DNA samples from 198 patients. Blood was drawn at diagnosis prior to any therapy and then at 6-month intervals for 18 months. Following diagnosis, the telomeres gradually shortened during the course of the treatment regardless of the patient's age. The most pronounced decrease was observed 12 months after the diagnosis (p < 0.0001). Based on tumor localization, the decrease in telomere length one year after the diagnosis followed different trajectories (p = 0.03). In patients treated with adjuvant therapy, telomere length correlated with the time elapsed after completion of therapy (p = 0.03). TERT expression did not correlate with the telomere length; however, it was higher in women than men (1.35-fold, 95% CI 1.11-1.65, p = 0.003) and in smokers than non-smokers (1.27-fold, 95% CI 1.01-1.61, p = 0.04). Leukocyte telomere length declines naturally during aging, but the accelerated shortening observed in our patients was age-independent. Telomere length manifestly reflected chemotherapy impact and could be linked to therapy toxicity.
- Publikační typ
- časopisecké články MeSH
Telomeres are complex protective structures located at the ends of linear eukaryotic chromosomes. Their purpose is to prevent genomic instability. Research progress in telomere biology during the past decades has identified a network of telomeric transcripts of which the best-studied is TElomeric Repeat-containing RNA (TERRA). TERRA was shown to be important not only for the preservation of telomere homeostasis and genomic stability but also for the expression of hundreds of genes across the human genome. These findings added a new level of complexity to telomere biology. Herein we provide insights on the telomere transcriptome, its relevance for proper telomere function, and its implications in human pathology. We also discuss possible clinical opportunities of exosomal telomere transcripts detection as a biomarker in cancer precision medicine.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- adjuvantní chemoterapie MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory krev genetika mortalita terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru epidemiologie prevence a kontrola MeSH
- messenger RNA krev genetika MeSH
- mikro RNA krev metabolismus MeSH
- následné studie MeSH
- přenašeče organických aniontů genetika MeSH
- prognóza MeSH
- proteiny přenášející organické kationty genetika MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- transportér organických kationtů 2 genetika MeSH
- vazebná místa genetika MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
Complete tumour devascularisation (CTD) is a surgical technique which entails the complete disruption by ligation or cutting of afferent and efferent tumour vasculature which remains in situ. In some animal models, CTD induces immune responses that lead to regression of distant metastases and protective immunity.
- Publikační typ
- časopisecké články MeSH
