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1.
PLoS One ; 19(2): e0295209, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38329946

RESUMO

BACKGROUND: Lymph node status and lymph node count (LNC) are predictors of colorectal cancer outcome. Under-sampling of lymph nodes may lead to clinically relevant stage migration. METHODS: Colorectal cancer (CRC) cases with a synoptic report, accessioned 2012-2020 at a regional laboratory, were extracted and retrospectively studied. LNC, positive lymph node count (PLNC), tumour deposits present (TDpos), and 'y' (staging) prefix (YS) were retrieved and tabulated by pathologist using custom software. Statistical analyses were done with R. DATA AND RESULTS: The cohort had 2,543 CRC resections. Seventeen pathologists interpreted >50 cases (range: 56-356) each and collectively saw 2,074. After cases with unavailable data were purged, 2,028 cases remained with 43,996 lymph nodes, of which 2,637/43,996 were positive. 368 cases had a 'y' prefix, and 379 had TDpos. The 17 pathologists' median LNC/case was 19.0 (range: 14.0-24.0), and the mean PLNC per case was 1.4 (range: 1.0-2.0). Kruskal-Wallis rank sum tests showed there were differences in LNC (p<0.001) among pathologists; however, PLNC did not show this association (p = 0.2917). T-tests showed that mean LNC (p<0.001) and PLNC (p<0.035) differed between YS. 138 of 2,028 cases had less than the 12 LNC target. Logistic regression revealed a strong association between meeting the LNC target and pathologist (p<0.001) but TDpos was non-predictive (p = 0.4736). CONCLUSIONS: Positive lymph node call rate has a good consistency in the laboratory; however, lymph node count varies significantly between pathologists. Standardized counting criteria are needed to improve uniformity and could be aided by synoptic reporting data.


Assuntos
Neoplasias Colorretais , Excisão de Linfonodo , Humanos , Estudos Retrospectivos , Linfonodos/cirurgia , Linfonodos/patologia , Manejo de Espécimes , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Estadiamento de Neoplasias
2.
Front Microbiol ; 15: 1325558, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38328418

RESUMO

Introduction: Tumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs). Methods: To reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1. Results: Intratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only. Discussion: These data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses.

3.
J Exp Clin Cancer Res ; 42(1): 2, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36588164

RESUMO

BACKGROUND: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. METHODS: PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9-/- mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. RESULTS: PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9-/- mice. CONCLUSIONS: Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.


Assuntos
Melanoma Experimental , Melanoma , Humanos , Camundongos , Animais , Pró-Proteína Convertase 9/genética , Proteína Ligante Fas , Camundongos Endogâmicos C57BL , Melanoma/genética , Melanoma Experimental/genética , Melanoma Experimental/patologia , Moléculas de Adesão Celular , Fatores de Troca do Nucleotídeo Guanina , Proteínas Ativadoras de GTPase
4.
Cureus ; 14(8): e27714, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36081978

RESUMO

Background Ineffective communication between healthcare providers is a known risk factor for adverse events. Objective The aim of this study was to retrospectively assess the communication with pathology via an analysis of the information provided on the pathology requisitions over ten years. Methods All in-house surgical specimens and all non-gynecologic cytopathology specimens accessioned from 2011 to 2020 were retrieved at a regional laboratory. Cases with any clinical information were deemed to have a clinical history present (CHP). CHP was tabulated by submitting physicians/surgeons (SPS), hospital site, year, and tissue group. Results The study period contained 554,817 relevant pathology reports, of which 553,966 could be extracted. The overall CHP rate was 74% and varied from 76% to 67% over the study period. SPSes submitting ≥200 cases (n=314) had a mean/median/standard deviation/max/min CHP rate of 81%/92%/23%/100%/5%. The CHP varied between four hospital sites, from 53% to 97%. CHP varied from 61% to 99% by tissue group. Conclusions CHP is associated with several factors and appears to depend on the hospital culture, specialty, and individual physician/surgeon. The pathology requisition is a way to measure and track the communication that is clinically relevant. Improving communication with pathologists/the pathology department will likely require process changes and mandates. Hospital and laboratory accreditation bodies should consider effective communication with pathology a marker of quality and an accreditation issue.

5.
Cancers (Basel) ; 14(11)2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35681785

RESUMO

Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and fatality at AUC of 0.91, 0.88, 0.85, and 0.87, respectively. Among their 33 component genes, 31 are novel. They could be differentially expressed in ACCs from normal tissues, tumors with different severity (stages and lymph node metastasis), ACCs with TP53 mutations, and tumors with differentially expressed immune checkpoints (CTLA4, PD1, TGFBR1, and others). All panels correlate with reductions of ACC-associated CD8+ and/or NK cells. Furthermore, we provide the first evidence for the association of mesenchymal stem cells (MSCs) with ACC relapse (p = 2 × 10-6) and prognosis (p = 2 × 10-8). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B correlate with MSC (spearman r ≥ 0.53, p ≤ 1.38 × 10-5). Sig27var25 and SigIQvar8 were derived from a prostate cancer (PC) and clear cell renal cell carcinoma (ccRCC) multigene signature, respectively; SigCmbnvar5 and SigCmbn_B are combinations of both panels, revealing close relationships of ACC with PC and ccRCC. The origin of these four panels from PC and ccRCC favors their prognostic potential towards ACC.

6.
PLoS One ; 17(3): e0265905, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35333879

RESUMO

OBJECTIVE: Assess the work environment of salaried pathologists via (1) the national workload system (L4E), (2) work distribution among/in three hospital groups, and (3) the frequency of significant absences or departures (SADs). METHODS: Automated analysis of pathology reports from a regional laboratory (accessioned 2011-2019) using validated computer code. RESULTS: The study set contained 574,099 pathology reports, reported by 63 pathologists. The average yearly L4E workload units/full-time equivalent for three hospital groups were 8,101.6, 6,906.5 and 4,215.8. The average Gini coefficient for full-time pathologists in the three hospital groups were respectively 0.05, 0.16 and 0.23. The average yearly SADs rates were respectively 13%, 16% and 9%. The group with the highest SADs rate had the intermediate Gini coefficient and intermediate workload. CONCLUSIONS: High individual workload and work maldistribution appear to be associated with SADs. Individual workload maximums and greater transparency may be essential for limiting staff turnover, maintaining high morale, and efficient laboratory function with a high quality of care.


Assuntos
Laboratórios Hospitalares , Humanos , Patologistas , Reorganização de Recursos Humanos , Carga de Trabalho
7.
Biomedicines ; 10(2)2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35203573

RESUMO

Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.

8.
Cancers (Basel) ; 13(24)2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34945007

RESUMO

Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care for metastatic PC (mPC) remains androgen deprivation therapy (ADT). Resistance commonly occurs in the form of castration resistant PC (CRPC). Despite decades of research efforts, CRPC remains lethal. Understanding of mechanisms underpinning metastatic progression represents the overarching challenge in PC research. This progression is regulated by complex mechanisms, including those regulating PC cell proliferation, epithelial-mesenchymal transition (EMT), and androgen receptor (AR) signaling. Among this PC metastatic network lies an intriguing suppressor of PC metastasis: the Raf kinase inhibitory protein (RKIP). Clinically, the RKIP protein is downregulated in PC, and showed further reduction in mPC. In xenograft mouse models for PC, RKIP inhibits metastasis. In vitro, RKIP reduces PC cell invasion and sensitizes PC cells to therapeutic treatments. Mechanistically, RKIP suppresses Raf-MEK-ERK activation and EMT, and modulates extracellular matrix. In return, Snail, NFκB, and the polycomb protein EZH2 contribute to inhibition of RKIP expression. In this review, we will thoroughly analyze RKIP's tumor suppression actions in PC.

9.
iScience ; 24(11): 103219, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34632328

RESUMO

The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Worldwide efforts are being made to develop vaccines to mitigate this pandemic. We engineered two recombinant Newcastle disease virus (NDV) vectors expressing either the full-length SARS-CoV-2 spike protein (NDV-FLS) or a version with a 19 amino acid deletion at the carboxy terminus (NDV-Δ19S). Hamsters receiving two doses (prime-boost) of NDV-FLS developed a robust SARS-CoV-2-neutralizing antibody response, with elimination of infectious virus in the lungs and minimal lung pathology at five days post-challenge. Single-dose vaccination with NDV-FLS significantly reduced SARS-CoV-2 replication in the lungs but only mildly decreased lung inflammation. NDV-Δ19S-treated hamsters had a moderate decrease in SARS-CoV-2 titers in lungs and presented with severe microscopic lesions, suggesting that truncation of the spike protein was a less effective strategy. In summary, NDV-vectored vaccines represent a viable option for protection against COVID-19.

10.
Sci Rep ; 11(1): 16942, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417490

RESUMO

This work sought to quantify pathologists' diagnostic bias over time in their evaluation of colorectal polyps to assess how this may impact the utility of statistical process control (SPC). All colorectal polyp specimens(CRPS) for 2011-2017 in a region were categorized using a validated free text string matching algorithm. Pathologist diagnostic rates (PDRs) for high grade dysplasia (HGD), tubular adenoma (TA_ad), villous morphology (TVA + VA), sessile serrated adenoma (SSA) and hyperplastic polyp (HP), were assessed (1) for each pathologist in yearly intervals with control charts (CCs), and (2) with a generalized linear model (GLM). The study included 64,115 CRPS. Fifteen pathologists each interpreted > 150 CRPS/year in all years and together diagnosed 38,813. The number of pathologists (of 15) with zero or one (p < 0.05) outlier in seven years, compared to their overall PDR, was 13, 9, 9, 5 and 9 for HGD, TVA + VA, TA_ad, HP and SSA respectively. The GLM confirmed, for the subset where pathologists/endoscopists saw > 600 CRPS each(total 52,760 CRPS), that pathologist, endoscopist, anatomical location and year were all strongly correlated (all p < 0.0001) with the diagnosis. The moderate PDR stability over time supports the hypothesis that diagnostic rates are amendable to calibration via SPC and outcome data.


Assuntos
Pólipos do Colo/diagnóstico , Pólipos do Colo/patologia , Estatística como Assunto , Estudos de Coortes , Humanos , Modelos Lineares , Patologistas
11.
PLoS One ; 16(6): e0253876, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34185808

RESUMO

OBJECTIVE: Quantify changes in workload in relation to the anatomic pathologist workforce. METHODS: In house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy. RESULTS: The study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x. CONCLUSIONS: Work by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce.


Assuntos
Citodiagnóstico , Laboratórios Hospitalares/normas , Neoplasias/diagnóstico , Patologia Clínica/normas , Biópsia , Humanos , Neoplasias/patologia , Patologia Cirúrgica , Médicos , Recursos Humanos/normas , Carga de Trabalho/normas
12.
Mol Ther Oncolytics ; 20: 306-324, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33614913

RESUMO

The avian paramyxovirus, Newcastle disease virus (NDV), is a promising oncolytic agent that has been shown to be safe and effective in a variety of pre-clinical cancer models and human clinical trials. NDV preferentially replicates in tumor cells due to signaling defects in apoptotic and antiviral pathways acquired during the transformation process and is a potent immunostimulatory agent. However, when used as a monotherapy NDV lacks the ability to consistently generate durable remissions. Here we investigate the use of viral sensitizer-mediated combination therapy to enhance the anti-neoplastic efficacy of NDV. Intratumoral injection of vanadyl sulfate, a pan-inhibitor of protein tyrosine phosphatases, in combination with NDV significantly increased the number and activation status of natural killer (NK) cells in the tumor microenvironment, concomitant with increased expression of interferon-ß, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1, leading to rapid tumor regression and long-term cures in mice bearing syngeneic B16-F10 melanomas. The anti-tumor efficacy of this combination therapy was abrogated when NK cells were depleted and when interferon-ß expression was transiently suppressed. Tumor-specific CD8+ T cell responses were not detected, nor were mice whose tumors regressed protected from re-challenge. This suggested efficacy of the combination therapy predominantly relied on the innate immune system. Importantly, efficacy was not limited to melanoma; it was also demonstrated in a murine prostate cancer model. Taken together, these results suggest that combining NDV with vanadyl sulfate potentiates an innate immune response that can potentiate rapid clearance of tumors, with type I interferon signaling and NK cells being important mechanisms of action.

13.
Cancers (Basel) ; 13(3)2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498739

RESUMO

IQGAP1 expression was analyzed in: (1) primary prostate cancer, (2) xenografts produced from LNCaP, DU145, and PC3 cells, 3) tumor of PTEN-/- and TRAMP mice, and (3) castration resistant PC (CRPC) produced by LNCaP xenografts and PTEN-/- mice. IQGAP1 downregulations occurred in CRPC and advanced PCs. The downregulations were associated with rapid PC recurrence in the TCGA PanCancer (n = 492, p = 0.01) and MSKCC (n = 140, p = 4 × 10-6) cohorts. Differentially expressed genes (n = 598) relative to IQGAP1 downregulation were identified with enrichment in chemotaxis, cytokine signaling, and others along with reductions in immune responses. A novel 27-gene signature (Sig27gene) was constructed from these DEGs through random division of the TCGA cohort into a Training and Testing population. The panel was validated using an independent MSKCC cohort. Sig27gene robustly predicts PC recurrence at (hazard ratio) HR 2.72 and p < 2 × 10-16 in two independent PC cohorts. The prediction remains significant after adjusting for multiple clinical features. The novel and robust nature of Sig27gene underlie its great translational potential as a prognostic biomarker to predict PC relapse risk in patients with primary PC.

14.
Qual Manag Health Care ; 30(3): 176-183, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33405466

RESUMO

BACKGROUND: Prior work suggests high interrater variability in the pathologist diagnostic rate (PDR) of the precancerous polyp sessile serrated adenoma (SSA). OBJECTIVES: To improve the diagnostic consistency in the pathological evaluation of colorectal polyp specimens with diagnostic rate awareness, using funnel plots (FPs)/control charts (CCs), and a focused group case review. METHODS: All colorectal polyp specimen (CRPS) reports September 2015 to August 2017 were analyzed at one institution. PDRs were extracted using a hierarchical free-text string matching algorithm and visualized using FPs, showing pathologist specimen volume versus PDR, and CCs, showing pathologist versus normed PDR. The FPs/CCs were centered on the group median diagnostic rate (GMDR). Pathologists were shown their baseline SSA diagnostic rate in relation to the practice, and in January 2017, there was a focused group case review/open discussion of approximately 40 sequential cases signed as SSA with a gastrointestinal pathology expert. RESULTS: Nine pathologists interpreted more than 250 CRPSs per year. FPs/CCs for the first and second years showed 6/4 and 3/1 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for SSA and 0/0 and 0/0 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for tubular adenoma (TA). An in silico kappa (ISK) for SSA improved from 0.52 to 0.62. CONCLUSION: Diagnostic rate awareness facilitated by FPs/CCs coupled with focused expert-led reviews may help calibrate PDR. Variation in SSA PDRs still remains high in relation to TA. ISK represents an intuitive, useful metric and Next Generation Quality/Statistical Process Control a promising approach for objectively increasing diagnostic consistency.


Assuntos
Adenoma , Pólipos do Colo , Neoplasias Colorretais , Lesões Pré-Cancerosas , Adenoma/diagnóstico , Pólipos do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Humanos , Lesões Pré-Cancerosas/diagnóstico
15.
PLoS One ; 15(12): e0242656, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370310

RESUMO

OBJECTIVE: Assess interpretative variation in Nottingham grading using control charts (CCs) and in silico kappa (ISK). METHODS: In house invasive breast cancer cases (2011-2019) at two institutions with a synoptic report were extracted. Pathologist interpretative rates (PIRs) were calculated and normed for Nottingham grade (G) and its components (tubular score (TS), nuclear score (NS), mitotic score (MS)) for pathologists interpreting >35 cases. ISKs were calculated using the ordered mutually exclusive category assumption (OMECA) and maximal categorical overlap assumption (MCOA). RESULTS: The study period included 1,994 resections. Ten pathologists each assessed 38-441 cases and together saw 1,636; these were further analyzed. The PIR medians (normed ranges) were: G1:24%(18-27%), G2:53%(43-56%) and G3:26%(19-33%). The MCOA ISK and the number of statistical outliers (p< 0.05/p< 0.001) to the group median interpretive rate (GMIR) for the ten pathologists was G1: 0.82(2/0 of 10), G2: 0.76(1/1), G3: 0.71(3/1), TS1: 0.79(1/0), TS2: 0.63(5/1), TS3: 0.66(5/1), NS1: 0.37(5/4), NS2: 0.60(4/3), NS3: 0.59(4/4), MS1: 0.78(3/1), MS2: 0.78(3/1), MS3: 0.77(2/0). The OMECA ISK was 0.62, 0.49, 0.69 and 0.71 for TS, NS, MS and G. CONCLUSIONS: The nuclear score has the most outliers. NS1 appears to be inconsistently used. ISK mirrors trends in conventional kappa studies. CCs and ISK allow insight into interpretive variation and may be essential for the next generation in quality.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Mastectomia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Simulação por Computador , Feminino , Humanos , Gradação de Tumores , Variações Dependentes do Observador , Reprodutibilidade dos Testes
16.
Cancers (Basel) ; 12(11)2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33266355

RESUMO

We observed associations of IQGAP1 downregulation with poor overall survival (OS) in clear cell renal cell carcinoma (ccRCC). Differentially expressed genes (DEGs, n = 611) were derived from ccRCCs with (n = 111) and without IQGAP1 (n = 397) reduction using the TCGA PanCancer Atlas ccRCC dataset. These DEGs exhibit downregulations of immune response and upregulations of DNA damage repair pathways. Through randomization of the TCGA dataset into a training and testing subpopulation, a 9-gene panel (SigIQGAP1NW) was derived; it predicts poor OS in training, testing, and the full population at a hazard ratio (HR) 2.718, p < 2 × 10-16, p = 1.08 × 10-5, and p < 2 × 10-16, respectively. SigIQGAP1NW independently associates with poor OS (HR 1.80, p = 2.85 × 10-6) after adjusting for a set of clinical features, and it discriminates ccRCC mortality at time-dependent AUC values of 70% at 13.8 months, 69%/31M, 69%/49M, and 75.3%/71M. All nine component genes of SigIQGAP1NW are novel to ccRCC. The inclusion of RECQL4 (a DNA helicase) in SigIQGAP1NW agrees with IQGAP1 DEGs enhancing DNA repair. THSD7A affects kidney function; its presence in SigIQGAP1NW is consistent with our observed THSD7A downregulation in ccRCC (n = 523) compared to non-tumor kidney tissues (n = 100). Collectively, we report a novel multigene panel that robustly predicts poor OS in ccRCC.

17.
Cytokine Growth Factor Rev ; 56: 69-82, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32893095

RESUMO

In the past two decades there have been substantial advances in understanding the anti-cancer mechanisms of oncolytic viruses (OVs). OVs can mediate their effects directly, by preferentially infecting and killing tumour cells. Additionally, OVs can indirectly generate anti-tumour immune responses. These differing mechanisms have led to a paradoxical divergence in strategies employed to further increase the potency of oncolytic virotherapies. On one hand, the tumour neovasculature is seen as a vital lifeline to the survival of the tumour, leading some to use OVs to target the tumour vasculature in hopes to starve cancers. Therapeutics causing vascular collapse can potentiate tumour hypoxia, nutrient restriction and pro-inflammatory cytokine release, which has shown promise in oncological studies. On the other hand, the same vasculature plays an important role for the dissemination of OVs, trafficking of effector cells and other therapeutics, which has prompted researchers to find ways of normalizing the vasculature to enhance infiltration of leukocytes and delivery of therapeutic agents. This article describes the recent developments of therapies aimed to shut down versus normalize tumour vasculature in order to inform researchers striving to optimize OV-based therapies.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Imunoterapia , Neoplasias/terapia
18.
Genes (Basel) ; 11(8)2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32752094

RESUMO

Even with recent progress, cancer remains the second leading cause of death, outlining a need to widen the current understanding on oncogenic factors. Accumulating evidence from recent years suggest Contactin 1 (CNTN1)'s possession of multiple oncogenic activities in a variety of cancer types. CNTN1 is a cell adhesion molecule that is dysregulated in many human carcinomas and plays important roles in cancer progression and metastases. Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis. Mechanistically, CNTN1 functions in various signaling pathways frequently altered in cancer, such as the vascular endothelial growth factor C (VEGFC)-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Notch signaling pathway and epithelial-mesenchymal transition (EMT) process. These oncogenic events are resulted via interactions between tumor and stroma, which can be contributed by CNTN1, an adhesion protein. CNTN1 expression in breast cancer correlates with the expression of genes functioning in cancer-stroma interactions and skeletal system development. Evidence supports that CNTN1 promotes cancer-stromal interaction, resulting in activation of a complex network required for cancer progression and metastasis (bone metastasis for breast cancer). CNTN1 inhibitions has been proven to be effective in experimental models to reduce oncogenesis. In this paper, we will review CNTN1's alterations in cancer, its main biochemical mechanisms and interactions with its relevant cancer pathways.


Assuntos
Carcinogênese/metabolismo , Contactina 1/metabolismo , Proteínas Oncogênicas/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Contactina 1/genética , Humanos , Neurogênese , Proteínas Oncogênicas/genética , Transdução de Sinais
19.
BMC Biotechnol ; 20(1): 32, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552807

RESUMO

BACKGROUND: Oncolytic viruses are playing an increasingly important role in cancer immunotherapy applications. Given the preclinical and clinical efficacy of these virus-based therapeutics, there is a need for fast, simple, and inexpensive downstream processing methodologies to purify biologically active viral agents that meet the increasingly higher safety standards stipulated by regulatory authorities like the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. However, the production of virus materials for clinical dosing of oncolytic virotherapies is currently limited-in quantity, quality, and timeliness-by current purification technologies. Adsorption of virus particles to solid phases provides a convenient and practical choice for large-scale fractionation and recovery of viruses from cell and media contaminants. Indeed, chromatography has been deemed the most promising technology for large-scale purification of viruses for biomedical applications. The implementation of new chromatography media has improved process performance, but low yields and long processing times required to reach the desired purity are still limiting. RESULTS: Here we report the development of an interference chromatography-based process for purifying high titer, clinical grade oncolytic Newcastle disease virus using NatriFlo® HD-Q membrane technology. This novel approach to optimizing chromatographic performance utilizes differences in molecular bonding interactions to achieve high purity in a single ion exchange step. CONCLUSIONS: When used in conjunction with membrane chromatography, this high yield method based on interference chromatography has the potential to deliver efficient, scalable processes to enable viable production of oncolytic virotherapies.


Assuntos
Cromatografia/métodos , Vírus/isolamento & purificação , Adsorção , Animais , Feminino , Fibroblastos , Camundongos Endogâmicos BALB C , Doença de Newcastle/virologia , Terapia Viral Oncolítica/métodos , Vírion
20.
Appl Immunohistochem Mol Morphol ; 28(4): 259-266, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30628979

RESUMO

BACKGROUND: Immunohistochemistry (IHC) use in prostate cores is not routinely determined and its value assessed. METHODS: Pathology reports for cases accessioned 2011 to 2017 at two hospitals were retrieved. IHC orders by pathologist and hospital were extracted with a custom program and tabulated. The diagnostic category (and highest grade cancer if applicable) was obtained by a hierarchical (free text) string matching algorithm. RESULTS: The study period contained 4477 biopsy sets. Categorized by worst pathology (% stained), the cohort was: benign: 1184 cases (42%); prostatic intraepithelial neoplasia: 168 (68%); suspicious: 323 (93%); grade group 1 cancer (WHO1): 900 (78%); grade group two (WHO2): 840 (60%); WHO3 cancer: 451 (54%); WHO4 cancer: 363 (46%); WHO5 cancer: 215 (56%); cancer grade not specified: 33 (52%). The hospital was a predictor; site A(2716 biopsies) and site B(1761) accounted for 10,183 and 14,852 IHC, respectively. The cases with IHC decreased in the last 4 years (site A: 57->45%, site B: 79->73%). Thirty-five pathologists read >20 cases each and together interpreted 4418 (range, 21 to 415; median, 88). In total 24,766 IHCs were done on the 4,418 cases (5.6/case). The mean/median/SD/max/min IHCs/case for the 35 pathologists was 5.6/4.1/3.9/15.2/0.9. High IHC users (1st and 2nd quintile pathologists) called more suspicious for malignancy but not significantly more WHO1 than low IHC users. CONCLUSIONS: IHC use is most frequent at the benign/malignant interface, and dependent on the pathologist and hospital; however, it is independent of WHO1 cancer rate. Diagnostic rate information can inform and define appropriate and rational IHC use. We plan to follow IHC utilization retrospectively in relation to the diagnostic category going forward.


Assuntos
Neoplasias da Próstata , Biópsia com Agulha de Grande Calibre , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
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