Combination of modified FOLFIRINOX with stereotactic body radiotherapy as an induction therapy for locally advanced pancreatic adenocarcinoma - a prospective single-arm study.

Introduction: Radical resection is the only potentially curative treatment for pancreatic adenocarcinoma; however, only a minor fraction of patients are eligible for resection. Induction therapy may be offered to patients, but the response rate in cases with significant vascular involvement is limited. This study aimed to evaluate the efficacy and safety of modified of FOLFIRINOX chemotherapy (mFFX) + stereotactic body radiotherapy (SBRT) in combination as induction therapy for locally advanced pancreatic carcinoma. The primary endpoints were the resection rate and one-year overall survival (OS). The secondary endpoints were progression-free survival (PFS), toxicity, and quality of live (QoL). Material and methods: Thirty patients with locally advanced pancreatic adenocarcinoma were treated with 6 cycles of mFFX, followed by SBRT and additional 3 cycles of mFFX. The response was measured prior to SBRT and after regimen completion. In the absence of disease progression, the patients were referred for surgery. The patients were requested to complete quality of life questionnaires (QLQ)-C30 and QLQ-PAN26 questionnaires biweekly. Results: On the first evaluation, disease control was noted in 26 (86.7%) patients. Stereotactic body radiotherapy was performed in 20 patients. Twelve patients underwent laparotomy, with radical resection possible in 3 cases. The one-year OS rate was 63.3%. Overall, 11 grade ≥ 3 adverse events were noted. No deterioration in the overall QoL was observed. The median PFS was 7.53 months. Conclusions: The expected resection rate of ≥ 30% was not achieved. However, the combination was associated with good local control, low adverse event rate, and good QoL, which advocate its further investigation in this clinical situation.

Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases.

Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematological cancer, as well as higher LOY in CD4 + T-lymphocytes in men with prostate cancer vs. controls. However, nothing is known about LOY in leukocytes infiltrating TME and we address this aspect here. We studied frequency and functional effects of LOY in blood, TME and non-tumorous tissue. Regulatory T-lymphocytes (Tregs) in TME had the highest frequency of LOY (22%) in comparison to CD4 + T-lymphocytes and cytotoxic CD8 + T-lymphocytes. LOY score using scRNA-seq was also linked to higher expression of PDCD1, TIGIT and IKZF2 in Tregs. PDCD1 and TIGIT encode immune checkpoint receptors involved in the regulation of Tregs function. Our study sets the direction for further functional research regarding a probable role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and consequently a possible influence on immunotherapy response in CRC patients.

Tumor Predisposing Post-Zygotic Chromosomal Alterations in Bladder Cancer-Insights from Histologically Normal Urothelium.

Bladder urothelial carcinoma (BLCA) is the 10th most common cancer with a low survival rate and strong male bias. We studied the field cancerization in BLCA using multi-sample- and multi-tissue-per-patient protocol for sensitive detection of autosomal post-zygotic chromosomal alterations and loss of chromosome Y (LOY). We analysed 277 samples of histologically normal urothelium, 145 tumors and 63 blood samples from 52 males and 15 females, using the in-house adapted Mosaic Chromosomal Alterations (MoChA) pipeline. This approach allows identification of the early aberrations in urothelium from BLCA patients. Overall, 45% of patients exhibited at least one alteration in at least one normal urothelium sample. Recurrence analysis resulted in 16 hotspots composed of either gains and copy number neutral loss of heterozygosity (CN-LOH) or deletions and CN-LOH, encompassing well-known and new BLCA cancer driver genes. Conservative assessment of LOY showed 29%, 27% and 18% of LOY-cells in tumors, blood and normal urothelium, respectively. We provide a proof of principle that our approach can characterize the earliest alterations preconditioning normal urothelium to BLCA development. Frequent LOY in blood and urothelium-derived tissues suggest its involvement in BLCA.

Heterogeneity in precision oncology.

Precision oncology is a rapidly evolving concept that holds great promise in cancer treatment. However, a cancer complexity attributed to genomic and acquired tumour heterogeneity limits treatment effectiveness and increases toxicity. These limitations refer to both systemic therapies and radiotherapy, which are two mainstays of non-invasive cancer treatment. By understanding cancer heterogeneity and utilising advanced tools to personalise treatment strategies, precision oncology has the potential to revolutionise cancer care. In this article, we review the current status of precision oncology in solid tumours, specifically focusing on the impact of tumour heterogeneity and genomic patient features on systemic therapies and radiation. We also discuss the implementation of novel tools, such as next-generation sequencing and liquid biopsies, to overcome this problem.

Elevated expression of complement factor I in lung cancer cells associates with shorter survival-Potentially via non-canonical mechanism.

While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients.

Bacterial cellulose as a promising material for pulmonary valve prostheses: In vivo study in a sheep model.

OBJECTIVES: Currently, no consensus exists regarding the most durable prosthesis for pulmonary valve replacement. Bacterial cellulose is a resistant, nonbiodegradable, nonpyrogenic bioimplant with low hemolysis and clotting properties. We hypothesized that bacterial cellulose heart valve prostheses could be an attractive alternative for pulmonary valve replacement. METHODS: We conducted a large animal model experiment in three adult sheep. The animals underwent open-heart surgery and cardiopulmonary bypass for bacterial cellulose conduit implantation in the pulmonary position. The sheep were followed for seven months, and clinical and laboratory parameters were analyzed. Echocardiographic evaluations were performed at 3 and 7 months. After seven months, the sheep were sacrificed and an autopsy was performed. The explanted conduits were radiologically and histopathologically analyzed. RESULTS: All sheep survived the operation, showing good recovery and normal health status; no adverse events were noted during the 7-month postoperative follow-up. Interval laboratory findings were normal with no signs of hemolysis or infection. Echocardiographic analysis after 7 months revealed a normal mean pressure gradient with excellent cusp motion and coaptation; a trace of regurgitation was found in two sheep. X-ray analysis of the explanted conduits revealed no structural defects in the leaflets with minimal calcification. Histological examination showed slight thickening of the conduit by pannus formation. No material failure, no calcification inside the material, and only minor calcification extrinsic to the matrix were observed. CONCLUSIONS: This pilot study provides evidence that bacterial cellulose may be suitable for pulmonary valve prostheses and surgical pulmonary artery plasty. Further studies on the high pressure side of the left heart are needed.

Radiotherapy-induced dynamic changes in the lymphocyte-to-monocyte ratio in patients with laryngeal cancer indicate poor prognosis.

Aim: We hypothesized that markers of inflammation correlate with response to radiotherapy in patients with non-metastatic laryngeal cancer (LC). Our aim was to assess peripheral and local markers of inflammation including lymphocyte to monocyte ratio (LMR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), infiltrating CD8+ lymphocytes (TILsCD8), and programmed death 1 ligand (PD-L1) expression. Methods: We performed a retrospective single-center analysis of LC patients administered definitive (R-RT) or postoperative radiotherapy (PORT). The primary endpoint was overall survival (OS) in relation to peripheral and local inflammatory markers and their dynamic changes during RT. Results: Study group included 215 patients (R-RT, n=116; PORT, n=99). The baseline (t0) NLR and LMR were significantly correlated with OS in the R-RT group. In patients with high and low NLR at t0, the five-year OS was 33% and 56% (p=0.010) and in high and low LMR at t0, the five-year OS was 56% and 27% (p=0.003), respectively. The LMR increase during R-RT predicted better prognosis: the five-year OS in high and low LMR was 57% and 31% at t2 (after 2 weeks of RT) (p=0.015), 49% and 26% at t4 (p< 0.001), and 50% and 25% at t6 (p=0.013), respectively. Multivariable analysis shows that the worse performance status (p=0.003), the presence of nodal metastases (p=0.0001), and low baseline LMR (p=0.049) in the R-RT group, and the presence of nodal metastases (p=0.035) and completion treatment on time (p=0.042) in PORT group were associated with poor prognosis. The PD-L1 expression had no significant prognostic value in any of the examined patients. Conclusion: The baseline LMR and its dynamic changes during R-RT and baseline NLR are independent prognostic factors in patients with nonmetastatic LC. PD-L1 expression and number of TILsCD8 have no prognostic value in R-RT and PORT group.

Prostate Cancer and Its Mimics-A Pictorial Review.

BACKGROUND: Multiparametric prostate MRI (mpMRI) is gaining wider recommendations for diagnosing and following up on prostate cancer. However, despite the high accuracy of mpMRI, false positive and false negative results are reported. Some of these may be related to normal anatomic structures, benign lesions that may mimic cancer, or poor-quality images that hamper interpretation. The aim of this review is to discuss common potential pitfalls in the interpretation of mpMRI. METHODS: mpMRI of the prostates was performed on 3T MRI scanners (Philips Achieva or Siemens Magnetom Vida) according to European Society of Urogenital Radiology (ESUR) guidelines and technical requirements. RESULTS: This pictorial review discusses normal anatomical structures such as the anterior fibromuscular stroma, periprostatic venous plexus, central zone, and benign conditions such as benign prostate hyperplasia (BPH), post-biopsy hemorrhage, prostatitis, and abscess that may imitate prostate cancer, as well as the appearance of prostate cancer occurring in these locations. Furthermore, suggestions on how to avoid these pitfalls are provided, and the impact of image quality is also discussed. CONCLUSIONS: In an era of accelerating prostate mpMRI and high demand for high-quality interpretation of the scans, radiologists should be aware of these potential pitfalls to improve their diagnostic accuracy.

Metastasis to the ureter as the first manifestation of occult pulmonary adenocarcinoma. Case report and review of the literature.

Lung cancer is a major epidemiological threat worldwide, which commonly metastasizes to distant sites. Often, the presence of metastasis is the first manifestation of lung cancer. Some of the most common sites for lung cancer metastasis are bones, adrenal glands, liver, brain, and lungs. However, metastases to unusual locations pose a diagnostic and therapeutic challenge. We present a case of a 74-year-old woman in whom the first manifestation of lung cancer was metastasis to the right ureter. We also analyse the available literature on lung cancer metastases to the ureter, taking into account the possible mechanisms of their spread in the ureter.

Current and future applications of liquid biopsy in non-small-cell lung cancer-a narrative review.

Background and Objective: Lung cancer remains the leading cause of cancer-related mortality and constitutes a significant societal burden. Recent advancements in targeted therapies and immunotherapy have considerably broadened therapeutic options in lung cancer, particularly in non-small-cell lung cancer (NSCLC). However, these novel methods necessitate sophisticated molecular diagnostics. Liquid biopsy, which refers to the cytological and molecular analysis of cancer markers shed by the tumor into the body fluids, may offer an attractive diagnostic tool at the individual patient level. This approach is particularly relevant for lung cancer, as the anatomical location of tumor lesions frequently makes them inaccessible for tissue biopsy. Apart from minimal invasiveness, the major advantages of liquid biopsy include better reflection of the tumor clonal heterogeneity (spatial heterogeneity), the possibility of sequential sampling, and real-time monitoring of tumor load and its evolving mutational status (temporal heterogeneity). Methods: This article reviews the available data in this field, current applications, and future perspectives in accordance with the Narrative Review reporting rules. Key Content and Findings: We discuss the most used approaches, i.e., circulating DNA and tumor cells, but also emerging liquid biopsy techniques, such as plasma DNA methylation, plasma metabolites and RNA, extracellular vesicles, and tumor-educated platelets in NSCLC. Finally, we highlight the current limitations of liquid biopsy techniques hampering their clinical applications. Conclusions: Due to their advantages, liquid biopsy-based approaches have recently gained immense interest in oncology. Potential applications of this method include early detection, informing precision medicine-based individualized treatment, and real-time monitoring of disease evolution and treatment. The development of next-generation sequencing has vastly extended genetic profiling, thus enabling better identification of druggable alterations. However, the clinical application of liquid biopsy techniques is still limited due to their suboptimal specificity and sensitivity, lack of standardization, and relatively high costs. Addressing these issues may allow further integration of liquid biopsies in the routine clinical setting, thus making a profound and permanent change in NSCLC management.

Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer.

Advances in drug treatments for brain metastases of breast cancer have improved progression-free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: transferrin receptor (TfR) peptide, low-density lipoprotein receptor 1 (LRP1) peptide, albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P < 0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor, galectin-3, and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other central nervous system (CNS) cancers.In conclusion, drug therapy for brain metastasis needs improvement. We surveyed three transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel endocytic mechanism.

Molecular aspects of brain metastases in breast cancer.

Brain metastases (BM) are a common and devastating manifestation of breast cancer (BC). BM are particularly frequent in the HER2-positive and triple-negative breast cancer phenotypes and usually occur following the metastatic spread to extracranial sites. Several genes mediating BM and biomarkers predicting their risk in BC have been reported in the past decade. These findings have advanced the understanding of BM pathobiology and paved the way for developing new therapeutic strategies but they still warrant a thorough clinical validation. Hence, a better understanding of the mechanistic aspects of BM and delineating the interactions of tumor cells with the brain microenvironment are of utmost importance. This review discusses the molecular basis of the metastatic cascade: the epithelial-mesenchymal transition, cancer, and tumor microenvironment interaction and intravasation, priming of the metastatic niche in the brain, and survival in the new site. We also outline the postulated mechanisms of BC cells' brain tropism. Finally, we discuss advances in the field of biomarkers (both tissue-based and liquid-based) that predict BM from BC.

Glucose-6-phosphate dehydrogenase and 8-iso-prostaglandin F2α as potential predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a serious complication of aneurysmal subarachnoid hemorrhage (aSAH), which is responsible for significant death and disability. The dynamic balance between the production and elimination of reactive oxygen species (ROS) in patients with DCI is suspected be shifted to favor ROS formation. The authors assessed the relationship between F2-isoprostanes (F2-IsoPs), oxidative stress biomarkers, and glucose-6-phosphate dehydrogenase (G6PD), which are responsible for nicotinamide adenine dinucleotide phosphate (NADPH) production for glutathione system function, with post-aSAH DCI. METHODS: The authors assessed 45 aSAH patients for F2-IsoP and G6PD concentration using commercial ELISA on days 2, 4, and 6 after aSAH. The authors examined the correlation between plasma F2-IsoP and G6PD concentrations and clinical factors with DCI occurrence and aSAH outcome. RESULTS: Expectedly, the most important clinical predictors of DCI were Hunt and Hess grade and modified Fisher (mFisher) grade. Plasma F2-IsoP and G6PD concentrations were greater in aSAH patients than the control group (p < 0.01). F2-IsoP concentrations were greater and G6PD concentrations were lower in patients with DCI than those without (p < 0.01). Plasma F2-IsoP and G6PD concentrations on day 2 were correlated with DCI occurrence (p < 0.01). Plasma F2-IsoP concentrations on days 2 and 6 were correlated with outcome at 1 and 12 months (p < 0.01). CONCLUSIONS: Decreased G6PD indirectly informs the reduced antioxidant response, especially for the glutathione system. G6PD concentration was lower in patients with DCI than those without, which may explain the increased F2-IsoP concentrations. mFisher grade, plasma F2-IsoP concentration, and G6PD concentration on day 2 after aSAH, in combination, may serve as predictors of DCI. Further research is necessary to investigate the therapeutic utility of F2-IsoPs and antioxidants in clinical practice.

Pathway-level mutation analysis in primary high-grade serous ovarian cancer and matched brain metastases.

Brain metastases (BMs) in ovarian cancer (OC) are a rare event. BMs occur most frequently in high-grade serous (HGS) OC. The molecular features of BMs in HGSOC are poorly understood. We performed a whole-exome sequencing analysis of ten matched pairs of formalin-fixed paraffin-embedded samples from primary HGSOC and corresponding BMs. Enrichment significance (p value; false discovery rate) was computed using the Reactome, the Kyoto Encyclopedia of Genes and Genomes pathway collections, and the Gene Ontology Biological Processes. Germline DNA damage repair variants were found in seven cases (70%) and involved the BRCA1, BRCA2, ATM, RAD50, ERCC4, RPA1, MLHI, and ATR genes. Somatic mutations of TP53 were found in nine cases (90%) and were the only stable mutations between the primary tumor and BMs. Disturbed pathways in BMs versus primary HGSOC constituted a complex network and included the cell cycle, the degradation of the extracellular matrix, cell junction organization, nucleotide metabolism, lipid metabolism, the immune system, G-protein-coupled receptors, intracellular vesicular transport, and reaction to chemical stimuli (Golgi vesicle transport and olfactory signaling). Pathway analysis approaches allow for a more intuitive interpretation of the data as compared to considering single-gene aberrations and provide an opportunity to identify clinically informative alterations in HGSOC BM.

Diagnostically misleading aberrant terminal deoxynucleotidyl transferase expression in germ cell tumors.

Terminal deoxynucleotidyl transferase (TdT) is a unique type of DNA polymerase predominantly expressed in precursor lymphoid cells and acute lymphoblastic leukemia. It participates in the junctional diversity of T-cell receptors and immunoglobulins. Recently, aberrant TdT expression was found in seminomas. Here, we evaluated the expression of TdT in our cohort of germ cell tumors (GCTs) with two anti-TdT antibody clones. We included 173 cases of testicular GCTs, 5 ovarian dysgerminomas, and one gonadoblastoma in the study. Tissue microarrays containing representative tumor samples were constructed and subsequently stained with anti-TdT monoclonal rabbit antibody EP266 (Dako) and TdT rabbit polyclonal antibody (Cell Marque). Expression was assessed with the H-score. No specific nuclear reaction was observed for the polyclonal anti-TdT antibody. The H-score values varied between the histological subtypes for the EP266 antibody. Positive nuclear staining was consistently seen in germ cell neoplasia in situ , seminoma, dysgerminoma, and embryonal carcinoma. Pure tumors had higher TdT H-scores than the mixed ones. Teratomas, yolk sac tumors, and choriocarcinomas were almost uniformly negative. Our study confirms that aberrant expression of TdT by testicular and ovarian GCTs exemplifies a potential diagnostic pitfall in histopathological diagnostics.

Impact of Activation of EGFL7 within Microenvironment of High Grade Ovarian Serous Carcinoma on Infiltration of CD4+ and CD8+ Lymphocytes.

Background: It has been demonstrated that Egfl7 promotes tumor cell escape from immunity by downregulating the activation of tumor blood vessels. Aim: to analyze mRNA expression of EGFL7 within the tumor microenvironment of high-grade ovarian serous carcinoma and its association with a number of intraepithelial CD4+/CD8+ lymphocytes and ICAM-1 expression. Methods: qPCR analysis of EGFL7 mRNA in cancer cells and adjacent stromal endothelium microdissected from formalin-fixed paraffin-embedded tumors of 59 high-grade ovarian serous carcinoma patients, was performed. Infiltration of intraepithelial lymphocytes (CD4+/CD8+) and expression of ICAM-1 were evaluated by immunohistochemistry and compared between tumors with different statuses of EGFL7 expression. Results: EGFL7 was expressed in cancer cells (9/59, 15.25%), endothelium (8/59, 13.56%), or both cancer cells and adjacent endothelium (4/59, 6.78%). ICAM-1 was expressed on cancer cells (47/59, 79.66%), stromal endothelium (46/59, 77.97%), or both epithelium and endothelium (40 of 59, 67.8%). EGFL7-positivity of cancer cells and endothelium was associated with lower intraepithelial inflow of CD4+ (p = 0.022 and p = 0.029, respectively) and CD8+ lymphocytes (p = 0.004 and p = 0.031, respectively) but impact neither epithelial nor endothelial ICAM-1 expression (p = 0.098 and p = 0.119, respectively). The patients' median follow-up was 23.83 months (range 1.07-78.07). Lack of prognostic significance of EGFL7-status and ICAM-1 expression was notified. Conclusion: EGFL7 is activated in the cancer cells as frequently as in the endothelium of human high-grade ovarian serous carcinoma. Activation of EGFL7 in cancer cells and/or endothelial cells could negatively impact diapedesis regardless of localization.

Comprehensive cancer-oriented biobanking resource of human samples for studies of post-zygotic genetic variation involved in cancer predisposition.

The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver. The choice was based on the high incidence of these cancers and/or frequent fatal outcome. We also collect age-matched normal controls. Our still ongoing collection originates from five clinical centers and after nearly 2-year cooperation reached 1711 patients and controls, yielding a total of 23226 independent samples, with an average of 74 donors and 1010 samples collected per month. The predominant diagnosis is breast carcinoma, with 933 donors, followed by colorectal carcinoma (383 donors), prostate carcinoma (221 donors), bladder carcinoma (81 donors), exocrine pancreatic carcinoma (15 donors) and metachronous colorectal cancer metastases to liver (14 donors). Forty percent of the total sample count originates from macroscopically healthy cancer-neighboring tissue, while contribution from tumors is 12%, which adds to the uniqueness of our collection for cancer predisposition studies. Moreover, we developed two program packages, enabling registration of patients, clinical data and samples at the participating hospitals as well as the central system of sample/data management at coordinating center. The approach used by us may serve as a model for dispersed biobanking from multiple satellite hospitals. Our biobanking resource ought to stimulate research into genetic mechanisms underlying the development of common cancers. It will allow all available "-omics" approaches on DNA-, RNA-, protein- and tissue levels to be applied. The collected samples can be made available to other research groups.

PARP inhibitors for metastatic castration-resistant prostate cancer: Biological rationale and current evidence.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are the first clinically approved agents designed to exploit synthetic lethality. Based on the recent approvals, PARPi became available for patients with metastatic castration-resistant prostate cancer (mCRPC). Unlike breast or ovarian cancers, where the approvals are limited to patients with BRCA1/2 alterations, in mCRPC PARPi are offered to patients with a broader spectrum of aberrations. A growing body of data indicates that alterations in specific homologous recombination repair (HRR) genes may confer different sensitivities to PARPi. Another challenging issue is the optimal testing methodology for identifying these aberrations. This comprehensive review presents the current place of PARPi in the treatment of mCRPC, provide biological rationale explaining mechanisms of their action and resistance, and discuss current clinical challenges along with avenues for future research.

Diagnostic Accuracy of Liquid Biopsy in Endometrial Cancer.

BACKGROUND: Liquid biopsy is a minimally invasive collection of a patient body fluid sample. In oncology, they offer several advantages compared to traditional tissue biopsies. However, the potential of this method in endometrial cancer (EC) remains poorly explored. We studied the utility of tumor educated platelets (TEPs) and circulating tumor DNA (ctDNA) for preoperative EC diagnosis, including histology determination. METHODS: TEPs from 295 subjects (53 EC patients, 38 patients with benign gynecologic conditions, and 204 healthy women) were RNA-sequenced. DNA sequencing data were obtained for 519 primary tumor tissues and 16 plasma samples. Artificial intelligence was applied to sample classification. RESULTS: Platelet-dedicated classifier yielded AUC of 97.5% in the test set when discriminating between healthy subjects and cancer patients. However, the discrimination between endometrial cancer and benign gynecologic conditions was more challenging, with AUC of 84.1%. ctDNA-dedicated classifier discriminated primary tumor tissue samples with AUC of 96% and ctDNA blood samples with AUC of 69.8%. CONCLUSIONS: Liquid biopsies show potential in EC diagnosis. Both TEPs and ctDNA profiles coupled with artificial intelligence constitute a source of useful information. Further work involving more cases is warranted.