Rapid Fatal Outcome from Pulmonary Arteries Compression in Transitional Cell Carcinoma

Transitional cell carcinoma of the urinary bladder is a malignancy that metastasizes frequently to lymph nodes including the mediastinal lymph nodes. This occurrence may produce symptoms due to compression of adjacent structures such as the superior vena cava syndrome or dysphagia from esophageal compression. We report the case of a 59-year-old man with metastatic transitional cell carcinoma for whom mediastinal lymphadenopathy led to pulmonary artery compression and a rapidly fatal outcome. This rare occurrence has to be distinguished from pulmonary embolism, a much more frequent event in cancer patients, in order that proper and prompt treatment be initiated

Factors influencing psychological wellbeing of early breast cancer patients

AimThis paper aims to identify factors that influence the psychological wellbeing of patients newly diagnosed with localized breast cancer.BackgroundPsychological wellbeing plays a significant part in the personal experience of patients during their cancer journey. However, despite progress in treatments and outcomes in breast cancer, psychosocial services and emotional support of cancer patients have been given less attention.Materials and methodsData were collected through a retrospective review of 274 charts of women diagnosed with breast cancer between 2012 and 2017 that received care in a single cancer center. Disease specific parameters, social and demographic variables, and Edmonton Symptom Assessment System (ESAS) scores were extracted from the patient charts.ResultsSelf-reported scores of psychological-related symptoms were low (suggesting no or minimal psychological distress) at baseline and remained low in the majority of patients with breast cancer. Pain, depression, anxiety and wellbeing scores of 0–2 were observed in 78.5%, 81.4%, 63.5% and 70.1% of patients, respectively. Higher scores of anxiety at baseline were observed in patients with physical restrictions on the Eastern Cooperative Oncology Group performance status (ECOG PS) (14.9%), current smoking (20.5%) and history of mental illness (19.1%). Increasing scores for pain were observed in older patients during treatment as compared to baseline. Mastectomy was associated with increased scores for wellbeing (worsening wellbeing) as compared to lumpectomy. Of the patients with a history of mental illness (17.3%), 19.1% had more often increased scores for anxiety.ConclusionsThe findings highlight patients that may benefit from additional social and psychological supports at diagnosis and while undergoing treatment

Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration-resistance in prostate cancer (PC) is a critical event hallmarking a switch to a more aggressive phenotype. Neuroendocrine differentiation and upregulation of NFκB transcriptional activity are two mechanisms that have been independently linked to this process.</p> <p>Methods</p> <p>We investigated these two pathways together using <it>in vitro </it>models of androgen-dependent (AD) and androgen-independent (AI) PC. We measured cellular levels, activity and surface expression of Neutral Endopeptidase (NEP), levels of secreted Endothelin-1 (ET-1), levels, sub-cellular localisation and DNA binding ability of NFκB, and proteasomal activity in human native PC cell lines (LnCaP and PC-3) modelling AD and AI states.</p> <p>Results</p> <p>At baseline, AD cells were found to have high NEP expression and activity and low secreted ET-1. In contrast, they exhibited a low-level activation of the NFκB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFκB activation, and minimal NEP activity with increased levels of secreted ET-1.</p> <p>Conclusions</p> <p>Our results seem to support evidence for divergent patterns of expression of the NFκB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFκB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.</p

Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations

PI3KCA Mutations in Uterine Cervix Carcinoma

Background: Squamous cervical carcinoma represents an infection-associated malignancy that produces a high mortality when metastatic or recurrent after primary local treatment. There is an urgent need for new therapies for this cancer. Molecular lesions in cervical cancer may provide opportunities for targeted therapies development. Methods: Publicly available data from the Cancer Genome Atlas (TCGA) were analyzed to define the molecular landscape of squamous cervical carcinomas with and without mutations of PIK3CA, the gene encoding the alpha catalytic subunit of phosphatidylinositol 3 kinase (PI3K). Associations with alterations in other critical genes and pathways of cancer and the total mutation burden and copy number alteration burden of cervical cancers were examined. Results: Mutations in PIK3CA are observed in 27.1% of squamous cervical cancers. PIK3CA represents the most frequently mutated gene in these cancers. Mutations in PIK3CA are associated with higher rates of mutations in other genes of important cancer-associated pathways such as the tyrosine kinase receptors/K-Ras/BRAF/MAPK and the Wnt/&beta; catenin pathway. In addition, PIK3CA mutated cervical cancers display a higher tumor mutation burden (TMB) than non-mutated cancers. Conclusion: Frequent mutations of PIK3CA gene in squamous cervical carcinomas may represent an opportunity for targeted therapies development both inhibiting the PI3K kinase and associated pathway defects. Increased TMB may additionally confer immunotherapy sensitivity

8p11.23 Amplification in Breast Cancer: Molecular Characteristics, Prognosis and Targeted Therapy

Background: Amplification of the locus 8p11.23 has been observed in cancer and genes of this locus, including ZNF703 (Zinc finger protein 703), NSD3 (Nuclear receptor binding SET domain protein 3) and FGFR1 (Fibroblast growth factor receptor 1), have been put forward as dominant oncogenes conferring pathophysiologic benefit in cancers with amplifications. However, there is no consensus on the importance of each of them or any other genes of the amplicon or even a consensus on which genes are part of the amplicon. Methods: Publicly available data were used to characterize the locus amplified at 8p11.23 and derive information on each of the genes and roles as oncogenes. The frequency of the amplifications in the locus was examined in the cBioportal platform, and expression levels of the amplicon genes in amplified cases were derived from genomic studies reported in the platform. Examination of the influence of mRNA expressions of each gene of the locus for Recurrence-free survival in breast cancer was performed using K-M plotter. Results: The 8p11.23 amplicon is present in higher frequency in squamous cell lung carcinomas, breast cancers and bladder carcinomas and is only rarely observed in other cancers. The most frequently amplified genes within the amplicon vary between different types of cancers. In breast cancer, amplified cases are most commonly of the luminal B type. Amplified genes are not always over-expressed and there is a low correlation of amplification with over-expression in amplicon genes with variation between genes. The presence of the amplicon does not influence the aneuploidy score or the tumor mutation burden of breast cancers. Regarding prognosis, the two genes of the amplicon whose mRNA hyper-expression portends adverse relapse-free survival in breast cancer are EIF4EBP1 (Eukaryotic transcription initiation factor 4E binding protein 1) and LSM1 (LSM1 homolog, mRNA degradation associated). Conclusion: Besides the previously proposed genes to play a role as dominant oncogenes in the 8p11.23 cancer amplified locus, other genes may also be important in breast cancer based on the high correlation of their amplification and mRNA expression and adverse prognosis conferred by over-expression, consistent with an oncogenic role

A Systematic Review and Meta-Analysis of Trifluridine/Tipiracil plus Bevacizumab for the Treatment of Metastatic Colorectal Cancer: Evidence from Real-World Series

Background: Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. Methods: A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. Results: Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11–4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06–67.21%). Summary PFS was 4.56 months (95% CI: 3.57–5.55 months), and summary OS was 11.17 months (95% CI: 10.15–12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. Conclusion: The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit

Molecular predictors of gemcitabine response in pancreatic cancer

Gemcitabine is one of the most used anti-neoplastic drugs with documented activity in almost all major localizations of cancer. In pancreatic cancer treatment, gemcitabine occupies a prominent place as a first line chemotherapy, partly because of the paucity of other efficacious chemotherapy options. In fact, only a minority of pancreatic cancer patients display a response or even stability of disease with the drug. There are currently no clinically applicable means of predicting which patient will derive a clinical benefit from gemcitabine although several proposed markers have been studied. These markers are proteins involved in drug up-take, activation and catabolism or proteins that define the ability of the cell to undergo apoptosis in response to the drug. Several of these markers are reviewed in this paper. We also briefly discuss the possible role of stem cells in drug resistance to gemcitabine

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers

Background: Tumor mutation burden (TMB) is arising as a useful marker of checkpoint inhibitors&rsquo; effectiveness in cancer patients in general and has been proposed as predictive in breast cancers. Despite the initial success of checkpoint inhibitors in triple-negative breast cancer, ER-positive breast cancers are less amenable to immunotherapy treatments due to the lower immunogenicity of this subset, associated with lower TMB and less pronounced inflammatory cell infiltration. However, a minority of ER-positive breast cancers do have a higher TMB and could be targets of immune checkpoint inhibitors. Methods: This investigation uses publicly available genomic data to examine ER-positive/HER2-negative or luminal breast cancers with high mutation numbers and compare them with cancers of the same subtype and low mutation numbers. Clinical characteristics and molecular correlates according to mutation numbers are described. Results: ER-positive/HER2-negative and luminal breast cancers with high mutation numbers have a higher prevalence of PIK3CA mutations and in some of the series examined mutations in TP53 and CDH1. A significant proportion of cancers with high mutation numbers carry mutations in microsatellite instability genes and genes involved in DNA damage response. Despite these differences, the prognosis of ER-positive/HER2-negative and luminal breast cancers with high mutation numbers is not significantly different compared to counterparts with lower mutation counts. Conclusions: These data may inform the potential suitability of these cancers for immunotherapy and could guide the development of rational combination therapies based on immune checkpoint inhibitors with other targeted drugs