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INTRODUCTION: Maintaining optimal central venous catheter tip position requires reliable catheter securement. A vital decision about the choice of engineered securement device is often made by what is conveniently available in the insertion kit or default clinical routine. The importance of continuous securement for oncology patients prompted the need for an evaluation of securement options currently available. This study aimed to assess the effectiveness of two engineered securement devices to assist the oncology patient in reaching the end of their catheter need. METHODS: A retrospective study was conducted to assess patients' ability to finish their therapy with one peripherally inserted central catheter. Implant and explant data for adult oncology patients was evaluated spanning 2007-2021. All patients received a PICC with either an adhesive securement device or a subcutaneous anchor securement system. RESULTS: Partial or complete dislodgement causing the unplanned removal of the PICC occurred at 12% for ASD and 0.4% for SASS (p < 0.0001). The probability of reaching the end of need with one PICC, regardless of the reason for premature removal, at 2 years for patients with an adhesive securement device was 68% (n = 944). For patients with a subcutaneous anchored securement device, it was over 95% (n = 8313). The difference in the probability of reaching the end of the need with one PICC between the two securement devices was calculated at (p < 0.0001). CONCLUSION: With over 9200 patients and more than a million catheter days, the results of this retrospective study demonstrate the SASS's superiority in assisting the patient to reach the end of need with a single PICC.
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INTRODUCTION AND HYPOTHESIS: The practice of histopathological assessment of the uterus following hysterectomy for benign indications including pelvic organ prolapse (POP) surgery is common and often routine. While pathology is not anticipated, the finding of pathology requiring further action is always a concern, in particular CIN (cervical intraepithelial neoplasia) or cervical/uterine malignancy. We aimed to perform a systematic review to understand the prevalence of actionable uterine and cervical pathology in hysterectomy specimens performed for POP. METHODS: A literature search was performed in January 2020 of MEDLINE, Embase and CINAHL using the Healthcare Databases Advanced Search platform. Included studies reported CIN and/or uterine/cervical malignancy in histological assessment of hysterectomy specimens performed purely for POP. Meta-analysis of prevalence was performed using the MetaXL ( www.epigear.com ) add-in for Microsoft Excel. RESULTS: Six hundred seventy-seven records were identified, out of which 34 studies were eligible. Overall prevalence (95% confidence interval [CI]) of endometrial cancer in 33 studies was 0.004 (0.003-0.006), I2 = 41%, number needed to treat (NNT) 1:250. Total actionable uterine pathology was 0.005 (0.003-0.006) in 33 studies, I2 = 35%, NNT = 1:200. Overall prevalence of cervical cancer in 19 papers was 0.001 (0.000-0.002), I2 = 18%, NNT = 1:1000. In 16 studies the overall prevalence of CIN was 0.013 (0.001-0.033), I2 = 95%, NNT = 1:77. Prevalence of total actionable pathology was 0.013 (0.006-0.0023), I2 = 86%, NNT = 1:77. CONCLUSION: The risk of actionable pathology is low, but not negligible. The variation between populations is wide. The prevalence of finding such pathology supports the routine practice of sending all hysterectomy specimens performed for POP for histological assessment.
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Neoplasias do Endométrio , Prolapso de Órgão Pélvico , Feminino , Humanos , Histerectomia , Prolapso de Órgão Pélvico/epidemiologia , Prolapso de Órgão Pélvico/cirurgia , Prevalência , Útero/cirurgiaRESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.
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Amianto , Neoplasias Pulmonares , Mesotelioma , Neoplasias Pleurais , Biomarcadores Tumorais , Proteínas de Ligação ao Cálcio , Proteínas da Matriz Extracelular , Proteínas Ligadas por GPI , Humanos , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Mesotelioma/etiologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/etiologia , Proteômica , Estudos RetrospectivosRESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. METHODS AND ANALYSIS: Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13-20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. ETHICS AND DISSEMINATION: The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN10079972, Pre-results.
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Proteínas da Matriz Extracelular/sangue , Proteínas Ligadas por GPI/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico por imagem , Mesotelioma/sangue , Mesotelioma/diagnóstico por imagem , Biomarcadores Tumorais/sangue , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Mesotelina , Mesotelioma Maligno , Prognóstico , Estudos Prospectivos , Proteômica/métodos , Curva ROC , Projetos de Pesquisa , EscóciaRESUMO
Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated ß-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated ß-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells.
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Benzimidazóis/administração & dosagem , Senescência Celular/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Neurais de Computação , Interface Usuário-Computador , Benzimidazóis/metabolismo , Senescência Celular/fisiologia , Relação Dose-Resposta a Droga , Fase G1/fisiologia , Redes Reguladoras de Genes/fisiologia , Células HCT116 , HumanosRESUMO
PURPOSE: This study evaluated the effect of a single 45-mg dose of dacomitinib (PF-00299804), an irreversible small-molecule inhibitor of human epidermal growth factor receptors-1, -2, and -4, on CYP2D6 activity in healthy volunteers (HV) using dextromethorphan (DM), a selective CYP2D6 probe. METHODS: Fourteen male HVs were enrolled in this open-label, randomized, cross-over, single-dose study of DM alone or with dacomitinib. Each HV received both treatments separated by a 14-day washout period. The pharmacokinetics of DM, dextrorphan (DX; the major DM metabolite), dacomitinib and PF-05199265 (an active metabolite of dacomitinib) were calculated. RESULTS: When combined with dacomitinib, the ratio of adjusted geometric means (90% CI) of DM area under the concentration-time curve (AUC)(last) was 955% (90% CI: 560%, 1,630%) and maximum plasma concentration (C (max)) was 973% (90% CI: 590%, 1,606%), compared with DM alone. For dacomitinib plus DM, exposures were consistent with those in patients receiving single-dose dacomitinib. Terminal elimination half-life (t (1/2)) was 51.4 h. Mild and moderate treatment-related adverse events were reported. No HV withdrew from the study. CONCLUSIONS: Single-dose administration of dacomitinib plus DM was safe and well tolerated in HVs and resulted in a significant increase in systemic exposures of DM in extensive metabolizers. No effect was observed on the pharmacokinetics of dacomitinib. Drug-drug interaction may occur when dacomitinib is concomitantly administered with therapeutic agents metabolized by cytochrome P450 (CYP) 2D6. Administration of drugs which are highly dependent on CYP2D6 metabolism may require dose adjustment, or substitution with an alternative medication.
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Inibidores do Citocromo P-450 CYP2D6 , Dextrometorfano/farmacologia , Quinazolinonas/farmacologia , Adulto , Estudos Cross-Over , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/efeitos adversos , Dextrometorfano/farmacocinética , Interações Medicamentosas , Humanos , Masculino , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinéticaRESUMO
PURPOSE: The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine) induces DNA demethylation and re-expression of epigenetically silenced genes, and increases carboplatin sensitivity of tumor xenograft models. We designed a clinical study to determine the feasibility of delivering a dose of decitabine, combined with carboplatin, that would be capable of producing equivalent biologic effects in patients with solid tumors. PATIENTS AND METHODS: In a two-stage design, 33 patients received escalating doses of decitabine administered as a 6-hour infusion on day 1 followed by carboplatin, area under the concentration-time curve (AUC) 5 (cohort 1) and AUC 6 (cohort 2), on day 8 of a 28-day cycle. Pharmacodynamic analyses included 5-methyl-2'-deoxycytidine levels, MAGE1A CpG island methylation, and fetal hemoglobin (HbF) expression. RESULTS: The major toxicity was myelosuppression. Dose limiting toxicities, prolonged grade 4 neutropenia (one patient), and sepsis and grade 3 anorexia/fatigue (one patient), were seen in two of four patients treated with decitabine 135 mg/m2 and carboplatin AUC 5. Dose limiting toxicity comprising neutropenic sepsis (one patient) and grade 3 fatigue (one patient) was seen in two of 10 patients treated at decitabine 90 mg/m2 and carboplatin AUC 6. Decitabine induced dose-dependent, reversible demethylation in peripheral-blood cells (PBCs) maximally at day 10. Furthermore, decitabine 90 mg/m2 induced demethylation of the MAGE1A CpG island in PBCs, buccal cells, and tumor biopsies, as well as elevation of HbF expression. CONCLUSION: Decitabine can be combined safely with carboplatin at a dose and schedule that causes epigenetic changes equivalent to or greater than that observed in mice with carboplatin-sensitized xenografts. The recommended dose/schedule for phase II trials is decitabine 90 mg/m2 (day 1) followed by carboplatin AUC 6 (day 8) every 28 days.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/análogos & derivados , Carboplatina/farmacologia , Metilases de Modificação do DNA/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Adulto , Idoso , Área Sob a Curva , Azacitidina/administração & dosagem , Azacitidina/farmacologia , Carboplatina/administração & dosagem , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Decitabina , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To examine DNA methylation in mouse hemopoiesis before and after in vivo exposure to a leukemogenic dose of x-rays, and address whether methylation levels are associated with the relative radiosensitivity of tissues in vivo. METHODS: The methylation status of control CBA/H and C57BL/6 mouse tissues before and after exposure to 3-Gy x-rays, and myeloid and lymphoid leukemias and lymphomas, was assessed by the direct analysis of the 5-methylcytosine (5-(Me)C) content of DNA, and by Southern blot analysis of genomic repeat sequences. RESULTS: The DNA 5-(Me)C content of bone marrow is 15% lower than spleen. Together with the analyses of stem (myeloid) and progenitor (lymphoid) leukemias and lymphomas, we found a trend of increasing methylation during hemopoietic differentiation. Exposure to x-rays induced greater cell death in the hypomethylated bone marrow (>80%) than spleen (50%) in vivo, supporting the observed correlation found between methylation status and radiosensitivity of other high-turnover hierarchical tissues. Furthermore, there was an 8% DNA 5-(Me)C content decrease in bone marrow after in vivo exposure to 3-Gy x-rays, but this was genotype dependent, being observed in AML-susceptible (CBA/H) but not AML-resistant (C57BL/6) inbred mice. CONCLUSION: Together these data suggest that methylation status may be related to the relative radiosensitivity of high-turnover hierarchical tissues such as bone marrow and that radiation-induced DNA hypomethylation has a role in radiation leukemogenesis.
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Metilação de DNA/efeitos da radiação , DNA/efeitos da radiação , Células-Tronco Hematopoéticas/efeitos da radiação , Leucemia Induzida por Radiação/genética , 5-Metilcitosina/análise , Animais , Southern Blotting , Células da Medula Óssea/efeitos da radiação , Morte Celular/efeitos da radiação , Diferenciação Celular/efeitos da radiação , DNA/química , Relação Dose-Resposta à Radiação , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Especificidade da Espécie , Baço/citologia , Baço/efeitos da radiação , Raios XRESUMO
MSH2 and MLH1 have a central role in correcting mismatches in DNA occurring during DNA replication and have been implicated in the engagement of apoptosis induced by a number of cytotoxic anticancer agents. The function of MLH1 is not clearly defined, although it is required for mismatch repair (MMR) and engagement of apoptosis after certain types of DNA damage. In order to identify other partners of MLH1 that may be involved in signalling MMR or apoptosis, we used human MLH1 in yeast two-hybrid screens of normal human breast and ovarian cDNA libraries. As well as known partners of MLH1 such as PMS1, MLH3 and MBD4, we identified the carboxy terminus of the human c-MYC proto-oncogene as an interacting sequence. We demonstrate, both in vitro by yeast two-hybrid and GST-fusion pull-down experiments, as well as in vivo by coimmunoprecipitation from human tumour cell extracts, that MLH1 interacts with the c-MYC protein. We further demonstrate that the heterodimeric partner of c-MYC, MAX, interacts with a different MMR protein, MSH2, both in vitro and in vivo. Using an inducible c-MYC-ER fusion gene, we show that elevated c-MYC expression leads to an increased HGPRT mutation rate of Rat1 cells and an increase in the number of frameshift mutants at the HGPRT locus. The effect on HGPRT mutation rate is small (2-3-fold), but is consistent with deregulated c-MYC expression partially inhibiting MMR activity.