Ninety-Day Mortality of Thoracoscopic vs Open Lobectomy: A Large Multicenter Cohort Study.

BACKGROUND: Studies have demonstrated a lower incidence of complications after video-assisted thoracoscopic surgery (VATS) lobectomy compared with thoracotomy, but the data on in-hospital and 90-day mortality are inconclusive. This study analyzed whether surgical approach, VATS or thoracotomy, was related to early mortality of lobectomy in lung cancer and determined the differences between in-hospital and 90-day mortality. METHODS: Data of all patients with non-small cell lung cancer who underwent lobectomy between January 1, 2007, and July 30, 2018, were retrieved from Polish National Lung Cancer Registry. Included were 31 433 patients who met all study criteria. After propensity score matching, 4946 patients in the VATS group were compared with 4946 patients in the thoracotomy group. RESULTS: Compared with thoracotomy, VATS lobectomy was related to lower in-hospital (1.5% vs 0.9%, P = .004) and 90-day mortality (3.4% vs 1.8%, P < .001). Mortality at 90 days was twice as high as in-hospital mortality in both the VATS (1.8% vs 0.9%, P < .001) and thoracotomy groups (3.4% vs 1.5%, P < .001). Postoperative complications were less common after VATS compared with thoracotomy (23.6% vs 31.8%, P < .001). CONCLUSIONS: VATS lobectomy is associated with lower in-hospital and 90-day mortality compared with thoracotomy and should be recommended for lung cancer treatment, if feasible. Patients should also be closely monitored after discharge from the hospital, because 90-day mortality is significant higher than in-hospital mortality.

Glioma 2021 WHO Classification: The Superiority of NGS Over IHC in Routine Diagnostics.

INTRODUCTION: The accurate detection of genetic variants such as single substitutions (IDH1/2, TERT), chromosomal abnormalities (CDKN2A, 1p/19q deletions, and EGFR amplifications), or promoter methylations (MGMT) is critical for glioma patient management, as emphasized in the World Health Organization's (WHO's) most recent classification in 2021 (WHO CNS5). The purpose of this study was to evaluate novel innovative methods for determining IDH1/2 status in the context of WHO CNS5. METHODS: Multiple biomarkers were simultaneously screened using next-generation sequencing (NGS) on 34 glioma samples. In cases where the IDH1/2 status determined by immunohistochemistry (IHC) or multiplex ligation-dependent probe amplification (MLPA) was inconsistent with the NGS results, quantitative polymerase chain reaction (qPCR) and Sanger sequencing were performed to resolve the adjudicated discrepancy. RESULTS: IDH1/2 NGS results differ from IHC (7/13 samples) as well as MLPA reports (1/4 samples). All NGS findings were confirmed by qPCR and Sanger sequencing. WHO CNS5 requires assessment of multiple mutations for glioma classification. CONCLUSIONS: We demonstrated that qPCR or NGS performed in reference genetic laboratories, rather than IHC, is the most reliable method for IDH1/2 analysis. Clinicians should be aware of discrepancies in MLPA or IHC results and seek reconsultation in facilities with extensive access to advanced molecular technologies. Moreover, we proposed a new algorithm for the molecular diagnostic procedures in glioma patients based on the WHO CNS5.

HPV RNA and DNA testing in Polish women screened for cervical cancer - A single oncological center study.

OBJECTIVES: To evaluate the incidence of HPV infection, and the frequency of the various genotypes, using mRNA and DNA testing; to assess their relationship with the cervical lesions and women's age in the Polish patients. STUDY DESIGN: A group of 1840 women, most of whom had abnormal cytology, from the Franciszek Lukaszczyk Oncology Centre in Bydgoszcz, Poland were screened for presence of at least one of 13 high risk HPV. Following that, 545 HPV DNA positive women were tested for HPV infection using HPV mRNA with the Nucleic Acid Sequence-Based Amplification Assay (NASBA) method. RESULTS: In our study group, 70.1% had DNA HPV positive results. Only 4% of the women had normal cytology. Among 545 HPV DNA positive patients, 36.3% had HPV mRNA positive tests. Moreover, 48% of the HPV mRNA positive patients were infected with HPV 16, followed by 18 (12.6%), 31 (10.1%), 33 (8.6%%), 45 (4.5%), and 16.2% of HPV mRNA positive women were infected with more than one HPV genotype. Furthermore, we found that in women under 30, HPV DNA positivity was higher than HPV mRNA positivity, supporting the hypothesis that younger women's infections are mostly temporary. CONCLUSIONS: The differences in HPV prevalence and genotype distribution observed in our study may have an impact on the efficacy of HPV vaccinations for cervical cancer and the development of screening programs, which should be examined further in future studies.

Prognostic and Predictive Biomarkers in Gliomas.

Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic approach to the patient and reveal new points of treatment options. Moreover, the 2021 World Health Organization Classification of Tumors of the Central Nervous System has fundamentally changed the classification of gliomas and incorporated many molecular biomarkers. Given the rapid progress in neuro-oncology, here we compile the latest research on prognostic and predictive biomarkers in gliomas. In adult patients, IDH mutations are positive prognostic markers and have the greatest prognostic significance. However, CDKN2A deletion, in IDH-mutant astrocytomas, is a marker of the highest malignancy grade. Moreover, the presence of TERT promoter mutations, EGFR alterations, or a combination of chromosome 7 gain and 10 loss upgrade IDH-wildtype astrocytoma to glioblastoma. In pediatric patients, H3F3A alterations are the most important markers which predict the worse outcome. MGMT promoter methylation has the greatest clinical significance in predicting responses to temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype predicting poor response to TMZ. Finally, we discussed liquid biopsies, which are promising diagnostic, prognostic, and predictive techniques, but further work is needed to implement these novel technologies in clinical practice.

BRCA1/2 Mutation Detection in the Tumor Tissue from Selected Polish Patients with Breast Cancer Using Next Generation Sequencing.

(1) Background: Although, in the mutated BRCA detected in the Polish population of patients with breast cancer, there is a large percentage of recurrent pathogenic variants, an increasing need for the assessment of rare BRCA1/2 variants using NGS can be observed. (2) Methods: We studied 75 selected patients with breast cancer (negative for the presence of 5 mutations tested in the Polish population in the prophylactic National Cancer Control Program). DNA extracted from the cancer tissue of these patients was used to prepare a library and to sequence all coding regions of the BRCA1/2 genes. (3) Results: We detected nine pathogenic variants in 8 out of 75 selected patients (10.7%). We identified one somatic and eight germline variants. We also used different bioinformatic NGS software programs to analyze NGS FASTQ files and established that tertiary analysis performed with different tools was more likely to give the same outcome if we analyzed files received from secondary analysis using the same method. (4) Conclusions: Our study emphasizes (i) the importance of an NGS validation process with a bioinformatic procedure included; (ii) the importance of screening both somatic and germline pathogenic variants; (iii) the urgent need to identify additional susceptible genes in order to explain the high percentage of non-BRCA-related hereditary cases of breast cancer.

Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors.

Fluorescence in situ hybridization (FISH) is a standard technique used in routine diagnostics of genetic aberrations. Thanks to simple FISH procedure is possible to recognize tumor-specific abnormality. Its applications are limited to designed probe type. Gene rearrangements e.g., ALK, ROS1 reflecting numerous translocational partners, deletions of critical regions e.g., 1p and 19q, gene fusions e.g., COL1A1-PDGFB, genomic imbalances e.g., 6p, 6q, 11q and amplifications e.g., HER2 are targets in personalized oncology. Confirmation of genetic marker is frequently a direct indication to start specific, targeted treatment. In other cases, detected aberration helps pathologists to better distinguish soft tissue sarcomas, or to state a final diagnosis. Our main goal is to show that applying FISH to formalin-fixed paraffin-embedded tissue sample (FFPE) enables assessing genomic status in the population of cells deriving from a primary tumor or metastasis. Although many more sophisticated techniques are available, like Real-Time PCR or new generation sequencing, FISH remains a commonly used method in many genetic laboratories.

Detection of somatic mutations in ctDNA derived from adenocarcinoma patients - EGFR tyrosine kinase inhibitor monitoring preliminary study.

AIM OF THE STUDY: The main purpose of this study was to assess detection of mutations in the epidermal growth factor receptor (EGFR) gene in circulating tumor DNA (ctDNA) as a tool for EGFR tyrosine kinase inhibitor (TKI) monitoring therapy. MATERIAL AND METHODS: The study was conducted using 20 samples from 7 adenocarcinoma patients treated with TKIs. Blood samples for ctDNA analysis were collected in 2015-2016. ctDNA was isolated using the QIAamp Circulating Nucleic Acid Kit (Qiagen) and analyzed using the ctEGFR Mutation Detection Kit (EntroGen). RESULTS: The most common exon 19 deletion and p.Leu858Arg mutation in exon 21 of the EGFR gene were detected. We observed a correlation between stabilization of patient condition and the lack of p.Thr790Met mutation detection in ctEGFR during TKI treatment (2 out of 7 patients). We also observed a correlation between progression of the disease and p.Thr790Met mutation detection in ctEGFR (3 out of 7 cases). We did not detect ctDNA p.Thr790Metp in two patients in whom progression occurred shortly thereafter. Last but not least, we noticed that good organization during plasma collection and transportation (average time of 6 minutes and 30 seconds) allows to use K2EDTA tubes. CONCLUSIONS: When tissue is limited or insufficient, analysis of the ctEGFR mutational status can be considered as an alternative tool for qualifying patients with non-small cell lung cancer (NSCLC) for TKI therapy, also as a potential monitoring tool. The plasma p.Thr790Met-negative result needs to be verified for the presence of p.Thr790Met-positive tumor tissue.

Differential gene methylation patterns in cancerous and non­cancerous cells.

Large­scale projects, such as The Cancer Genome Atlas (TCGA), Human Epigenome Project (HEP) and Human Epigenome Atlas (HEA), provide an insight into DNA methylation and histone modification markers. Changes in the epigenome significantly contribute to the initiation and progression of cancer. The goal of the present study was to characterize the prostate cancer malignant transformation model using the CpG island methylation pattern. The Human Prostate Cancer EpiTect Methyl II Signature PCR Array was used to evaluate the methylation status of 22 genes in prostate cancer cell lines: PC3, PC3M, PC3MPro4 and PC3MLN4, each representing different metastatic potential in vivo. Subsequently, it was ascertained whether DNA methylation plays a role in the expression of these genes in prostate cancer cells. Hypermethylation of APC, DKK3, GPX3, GSTP1, MGMT, PTGS2, RASSF1, TIMP2 and TNFRSF10D resulted in downregulation of their expression in prostate cancer cell lines as compared to WT fibroblasts. Mining of the TCGA data deposited in the MetHC database found increases in the methylation status of these 9 genes in prostate cancer patients, further supporting the role of methylation in altering the expression of these genes in prostate cancer. Future studies are warranted to investigate the role of these proteins in prostate cancer development.

Transcathether aortic valve implantation with the new repositionable self-expandable Medtronic Evolut R vs. CoreValve system: evidence on the benefit of a meta-analytical approach.

AIMS: To compare transcatheter aortic valve replacement TAVR with self-expandable first-generation Medtronic CoreValve with new-generation Evolut R devices in patients with aortic stenosis. METHODS: Multiple databases were screened for all available reports directly or indirectly comparing CoreValve vs Evolut R. Primary endpoint was device success. Procedural, functional and clinical outcomes were assessed as well. RESULTS: Ten retrospective series including 12 294 pts. were found. Overall device success rate was 95.5% and was statistically higher in the Evolut R treated patients as compared with CoreValve: 96.6 vs. 94.8%, respectively; RR (risk ratio) 95%CIs (confidence intervals): 1.02 (1.00-1.04); P = 0.01. There were no statistical differences with regard to postoperative mean aortic gradients 8.5 +/- 5.3 vs 7.9 +/- 4.6 with Evolut R and CoreValve. Evolut R valve demonstrated nearly 50% reduction of the risk for moderate-to-severe paravalvilar leak 0.55 (0.39-0.79); P = 0.001; 60% statistically significant lower risk of developing myocardial injury 0.40 (0.22-0.72); P = 0.002 and numerical reductions in the risk of acute kidney injury, vascular complications and bleeding. Together with significantly reduced risk of permanent pacemaker implantation (0.80 [0.67-0.96]; P = 0.02) the above benefits were associated with 40% reduction in the risk of 30-day all-cause mortality with Evolut R as compared to CoreValve: 0.60 (0.37-1.00); P = 0.05. CONCLUSIONS: The use of new-generation Evolut R was associated with improved procedural, functional and clinical outcomes compared with the CoreValve device.

Chromosome Conformation Capture Reveals Two Elements That Interact with the PTBP3 (ROD1) Transcription Start Site.

The long-range control of gene expression is facilitated by chromatin looping and can be detected using chromosome conformation capture-3C. Here we focus on the chromatin architecture of the PTBP3 (Polypyrimidine tract binding protein 3) locus to evaluate its potential role in regulating expression of the gene. PTBP3 expression in prostate cancer cell lines is found significantly higher compared to skin fibroblasts using real-time PCR (p < 0.05) and digital droplet PCR (p < 0.01). Exploration of the chromatin spatial architecture of a nearly 200-kb fragment of chromosome 9 encompassing the PTBP3 gene identified two elements located 63 kb upstream and 48 kb downstream of PTBP3, which looped specifically to the PTBP3 promoter. These elements contain histone acetylation patterns characteristic of open chromatin regions with active enhancers. Our results reveal for the first time that long-range chromatin interactions between the -63 kb and +48 kb loci and the PTBP3 promoter regulate the expression of this gene in prostate cancer cells. These interactions support an open chromatin form for the PTBP3 locus in cancer cells and the three-dimensional structural model proposed in this paper.

Prognostic and Predictive Epigenetic Biomarkers in Oncology.

Epigenetic patterns, such as DNA methylation, histone modifications, and non-coding RNAs, can be both driver factors and characteristic features of certain malignancies. Aberrant DNA methylation can lead to silencing of crucial tumor suppressor genes or upregulation of oncogene expression. Histone modifications and chromatin spatial organization, which affect transcription, regulation of gene expression, DNA repair, and replication, have been associated with multiple tumors. Certain microRNAs (miRNAs), mainly those that silence tumor suppressor genes and occur in a greater number of copies, have also been shown to promote oncogenesis. Multiple patterns of these epigenetic factors occur specifically in certain malignancies, which allows their potential use as biomarkers. This review presents examples of tests for each group of epigenetic factors that are currently available or in development for use in early cancer detection, prediction, prognosis, and response to treatment. The availability of blood-based biomarkers is noted, as they allow sampling invasiveness to be reduced and the sampling procedure to be simplified. The article stresses the role of epigenetics as a crucial element of future cancer diagnostics and therapy.

Application of artificial neural networks for predicting presence of non-sentinel lymph node metastases in breast cancer patients with positive sentinel lymph node biopsies.

INTRODUCTION: The aim of this study was to present a new predictive tool for non-sentinel lymph node (nSLN) metastases. MATERIAL AND METHODS: One thousand five hundred eighty-three patients with early-stage breast cancer were subjected to sentinel lymph node biopsy (SLNB) between 2004 and 2012. Metastatic SLNs were found in 348 patients - the retrospective group. Selective axillary lymph node dissection (ALND) was performed in 94% of cases. Involvement of the nSLNs was identified in 32.1% of patients following ALND. The correlation between nSLN involvement and selected epidemiological data, primary tumor features and details of the diagnostic and therapeutic management was examined in metastatic SLN group. Multivariate analysis was performed using an artificial neural network to create a new nomogram. The new test was validated using the overall study population consisting of the prospective group (365 patients - SLNB between 01-07.2013). RESULTS: Accuracy of the new test was calculated using area under the receiver operating characteristics curve (AUC). We obtained AUC coefficient equal to 0.87 (95% confidence interval: 0.81-0.92). Sensitivity amounted to 69%, specificity to 86%, accuracy - 80% (retrospective group) and 77%, 46%, 66% (validation group), respectively. The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram the calculated AUC value was 0.71, for Stanford - 0.68, for Tenon - 0.67. CONCLUSIONS: In the analyzed group only the MSKCC nomogram and the new model showed AUC values exceeding the expected level of 0.70. Our nomogram performs well in prospective validation on patient series. The overall assessment of clinical usefulness of this test will be possible after testing it on different patient populations.

Systematic review and meta-analysis of randomized controlled trials assessing safety and efficacy of posterior pericardial drainage in patients undergoing heart surgery.

OBJECTIVES: To investigate the potential beneficial effects of posterior pericardial drainage in patients undergoing heart surgery. METHODS: Multiple online databases and relevant congress proceedings were screened for randomized controlled trials assessing the efficacy and safety of posterior pericardial drainage, defined as posterior pericardiotomy incision, chest tube to posterior pericardium, or both. Primary endpoint was in-hospital/30 days' cardiac tamponade. Secondary endpoints comprised death or cardiac arrest, early and late pericardial effusion, postoperative atrial fibrillation (POAF), acute kidney injury, pulmonary complications, and length of hospital stay. RESULTS: Nineteen randomized controlled trials that enrolled 3425 patients were included. Posterior pericardial drainage was associated with a significant 90% reduction of the odds of cardiac tamponade compared with the control group: odds ratio (95% confidence interval) 0.13 (0.07-0.25); P < .001. The corresponding event rates were 0.42% versus 4.95%. The odds of early and late pericardial effusion were reduced significantly in the intervention arm: 0.20 (0.11-0.36); P < .001 and 0.05 (0.02-0.10); P < .001, respectively. Posterior pericardial drainage significantly reduced the odds of POAF by 58% (P < .001) and was associated with significantly shortened (by nearly 1 day) overall length of hospital stay (P < .001). Reductions in postoperative complications translated into significantly reduced odds of death or cardiac arrest (P = .03) and numerically lower odds of acute kidney injury (P = .08). CONCLUSIONS: Posterior pericardial drainage is safe and simple technique that significantly reduces not only the prevalence of early pericardial effusion and POAF but also late pericardial effusion and cardiac tamponade. These benefits, in turn, translate into improved survival after heart surgery.

Clinical Safety and Effectiveness of Endoaortic as Compared to Transthoracic Clamp for Small Thoracotomy Mitral Valve Surgery: Meta-Analysis of Observational Studies.

Controversies remain on the increased rate of neurological events after small thoracotomy mitral valve surgery attributed to endoaortic balloon occlusion (EABO). Systematic literature search of databases identified 17 studies enrolling 6,643 patients comparing safety and effectiveness of EABO versus transthoracic clamp. In a meta-analysis, there was no difference in occurrence of cerebrovascular events, all-cause mortality, and kidney injury. EABO was associated with a significantly higher risk of iatrogenic aortic dissection (0.93% versus 0.13%; risk ratio, 4.67; 95% confidence interval, 1.62 to 13.49; p = 0.004) and a trend toward longer operative times. The data is limited to observational studies.

Meta-analysis of uninterrupted as compared to interrupted oral anticoagulation with or without bridging in patients undergoing coronary angiography with or without percutaneous coronary intervention.

OBJECTIVES: To assess safety and effectiveness of different periprocedural antithrombotic strategies in patients receiving long-term oral anticoagulation and undergoing coronary angiography with or without percutaneous coronary intervention (PCI). METHODS: Studies comparing uninterrupted oral anticoagulation (UAC) with vit. K antagonists vs interrupted oral anticoagulation (IAC) with or without bridging anticoagulation before coronary procedures were eligible for inclusion in the current meta-analysis. Endpoints selected were 30-day composite of major adverse cardiovascular or cerebrovascular and thromboembolic events (MACCE) and major bleeding. RESULTS: Eight studies (7 observational and 1 randomized controlled trial [N=2325pts.]) were included in the analysis. There was no difference in MACCE between UAC and IAC; RR (95%CIs): 0.74 (0.34-1.64); p=0.46 but there was a statistically significant MACCE risk reduction with UAC as compared to IAC with bridging: 0.52 (0.29-0.95); p=0.03. Likewise, there were no statistically significant differences between UAC vs IAC in regard to major bleeding: 0.62 (0.16-2.43); p=0.49; but as compared to IAC with bridging, UAC was associated with statistically significant 65% lower risk of major bleeding: 0.35 (0.13-0.92); p=0.03. Additionally, meta-regression analysis revealed significant linear correlation between log RR of MACCE (ß=-4.617; p<0.001) and major bleeding (ß=6.665; p=0.022) and mean value of target INR suggestive of higher thrombotic and secondary haemorrhagic risk below estimated INR cut-off of 2.17-2.27 within 30days. CONCLUSIONS: Uninterrupted OAC is at least as safe as interrupted OAC, and seems to be much safer than interrupted OAC with bridging anticoagulation in patients undergoing coronary angiography with or without PCI.

Cerebrovascular Events After No-Touch Off-Pump Coronary Artery Bypass Grafting, Conventional Side-Clamp Off-Pump Coronary Artery Bypass, and Proximal Anastomotic Devices: A Meta-Analysis.

BACKGROUND: Off-pump coronary artery bypass (OPCAB) has been shown to reduce the risk of neurologic complications as compared to coronary artery bypass grafting performed with cardiopulmonary bypass. Side-clamping of the aorta while constructing proximal anastomoses, however, still carries substantial risk of cerebral embolization. We aimed to perform a comprehensive meta-analysis of studies assessing 2 clampless techniques: aortic "no-touch" and proximal anastomosis devices (PAD) for OPCAB. METHODS AND RESULTS: PubMed, CINAHL, CENTRAL, and Google Scholar databases were screened for randomized controlled trials and observational studies comparing "no-touch" and/or PAD with side-clamp OPCAB and reporting short-term (≤30 days) outcomes: cerebrovascular accident and all-cause mortality. A total of 18 studies (3 randomized controlled trials) enrolling 25 163 patients were included. Aortic "no-touch" was associated with statistically lower risk of cerebrovascular accident as compared to side-clamp OPCAB: risk ratio 95% CI: 0.41 (0.27-0.61); P<0.01; I(2)=0%. Event rates were 0.36% and 1.28% for "no-touch" and side-clamp OPCAB, respectively. No difference was seen between PAD and side-clamp OPCAB: 0.71 (0.33-1.55); P=0.39; I(2)=39%. A trend towards increased 30-day all-cause mortality with PAD and no difference with "no-touch" were observed when compared to side-clamp OPCAB. In a subset analysis, "no-touch" consistently reduced the risk of cerebrovascular accident regardless of patients' baseline risk characteristics. A benefit with PAD was observed in low-risk patients. CONCLUSIONS: Aortic "no-touch" technique was associated with nearly 60% lower risk of postoperative cerebrovascular events as compared to conventional side-clamp OPCAB with effect consistent across patients at different risk.

Off-pump coronary artery bypass grafting improves short-term outcomes in high-risk patients compared with on-pump coronary artery bypass grafting: Meta-analysis.

OBJECTIVES: To assess the benefits and risks of off-pump coronary artery bypass (OPCAB) versus coronary artery bypass grafting (CABG) through a meta-analysis of randomized controlled trials (RCTs), and to investigate the relationship between outcomes and patient risk profile. METHODS: PubMed, Embase, the Cumulative Index of Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major conference proceedings databases were searched for RCTs comparing OPCAB and CABG and reporting short-term (≤ 30 days) outcomes. Endpoints assessed were all-cause mortality, myocardial infarction (MI), and cerebral stroke. RESULTS: The meta-analysis included 100 studies, with a total of 19,192 subjects. There was no difference between the 2 techniques with respect to all-cause mortality and MI (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.71-1.09; P = .25; I(2) = 0% and OR, 0.90; 95% CI, 0.77-1.05; P = .19; I(2) = 0%, respectively). OPCAB was associated with a significant 28% reduction in the odds of cerebral stroke (OR, 0.72; 95% CI, 0.56-0.92; P = .009; I(2) = 0%). A significant relationship between patient risk profile and benefits from OPCAB was found in terms of all-cause mortality (P < .01), MI (P < .01), and cerebral stroke (P < .01). CONCLUSIONS: OPCAB is associated with a significant reduction in the odds of cerebral stroke compared with conventional CABG. In addition, benefits of OPCAB in terms of death, MI, and cerebral stroke are significantly related to patient risk profile, suggesting that OPCAB should be strongly considered in high-risk patients.