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BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (Nâ =â 11 246), colorectal (Nâ =â 15 425), hepatocellular (Nâ =â 433), pancreatic (Nâ =â 5488), and urothelial (Nâ =â 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.
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BACKGROUND: To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFRâ <â 60 mL/minute per 1.73 m2. RESULTS: Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (Pâ =â .052). The concordance between calculated eGFR formulas was rated substantial (Cohen's kappa (k): 0.66-0.95). Among the subgroup (nâ =â 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60 mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59 mL/minute exhibited a measured CrCIâ ≥â 60 mL/minute. CONCLUSIONS: Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59 mL/minute.
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PURPOSE OF REVIEW: This review will explore various strategies to rendering MSS mCRCs susceptible to ICI. Moreover, we will provide an overview of potential biomarkers that may aid to better patient selection, and discuss ongoing efforts in this area of research. RECENT FINDINGS: Colorectal cancer (CRC) ranks among the top three most common cancers worldwide. While significant advances in treatment strategies have improved the prognosis for patients in the early stages of the disease, treatment options for metastatic CRC (mCRC) remain limited. Although immune checkpoint inhibitors (ICI) have revolutionized the treatment of several malignancies, its efficacy in mCRC is largely confined to patients exhibiting a high microsatellite instability status (MSI-H). However, the vast majority of mCRC patients do not exhibit a MSI-H, but are microsatellite stable (MSS). In these patients ICIs are largely ineffective. So far, ICIs do not play a crucial role in patients with MSS mCRC, despite the promising data for inducing long-term remissions in other tumour entities. For this reason, novel treatment strategies are needed to overcome the primary resistance upon ICI in patients with MSS.
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Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Inestabilidad de Microsatélites , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Metástasis de la Neoplasia , Biomarcadores de Tumor/genéticaRESUMEN
Anemia of inflammation (AI) is frequently present in subjects with inflammatory disorders, primarily caused by inflammation-driven iron retention in macrophages. So far, only limited data on qualitative and quantitative estimates of tissue iron retention in AI patients exist. We performed a prospective cohort study analyzing splenic, hepatic, pancreatic, and cardiac iron content with MRI-based R2*-relaxometry in AI patients, including subjects with concomitant true iron deficiency (AI+IDA) hospitalized between 05/2020-01/2022. Control groups were individuals without inflammation. Spleen R2* values in AI patients with ferritin ≤200 µg/L (AI+IDA) were comparable with those found in controls. In AI patients with ferritin >200 µg/L, spleen (47.6 s-1 vs. 19.3 s-1 , p < .001) and pancreatic R2* values (32.5 s-1 vs. 24.9 s-1 , p = .011) were significantly higher compared with controls, while liver and heart R2*-values did not differ. Higher spleen R2* values were associated with higher ferritin, hepcidin, CRP, and IL-6 concentrations. Spleen R2* values normalized in AI patients after recovery (23.6 s-1 vs. 47.6 s-1 , p = .008), while no changes were found in patients with baseline AI+IDA. This is the first study investigating tissue iron distribution in patients with inflammatory anemia and AI with concomitant true iron deficiency. The results support the findings in animal models demonstrating iron retention in macrophages, which are primarily accumulating in the spleen under inflammatory conditions. MRI-related iron measurement may help to better characterize actual iron needs and to define better biomarker thresholds in the diagnosis of true ID in patients with AI. It may qualify as a useful diagnostic method to estimate the need for iron supplementation and to guide therapy.
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Anemia Ferropénica , Anemia , Deficiencias de Hierro , Animales , Hierro/metabolismo , Proyectos Piloto , Estudios Prospectivos , Anemia/etiología , Anemia Ferropénica/complicaciones , Hepcidinas , Ferritinas , InflamaciónRESUMEN
We would like to change the authors' names and affiliations on Page 1 of paper [...].
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BACKGROUND: Tumor profiling is increasingly used in advanced cancer patients to define treatment options, especially in refractory cases where no standard treatment is available. Caris Molecular Intelligence (CMI) is a multiplatform tumor profiling service that is comprehensive of next-generation sequencing (NGS) of DNA and RNA, immunohistochemistry (IHC) and in situ hybridisation (FISH). The aim of this study is to compare costs of CMI-guided treatment with prior or planned treatment options in correlation with outcome results. METHODS: Retrospective data from five clinical trials were collected to define the treatment decision prior to the receipt of the CMI report (n = 137 patients). A systematic review of treatment data from 11 clinical studies of CMI (n = 385 patients) allowed a comparison of planned vs actual (n = 137) and prior vs actual (n = 229) treatment costs. RESULTS: Treatment plan was changed in 88% of CMI-profiled cases. The actual CMI guided treatment cost per cycle was £995 in 385 treated patients. Planned treatment costs were comparable to actual treatment costs (£979 vs £945; p = 0.7123) and prior treatment costs were not significantly different to profiling-guided treatments (£892 vs £850; p = 0.631). CONCLUSIONS: Caris Molecular Intelligence guided treatment cost per cycle was in the range of prior or planned treatment cost/cycle. Due to beneficial overall survival the additional cost of performing CMI's multiplatform testing to the treatment costs seems to be cost-effective.
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Cancer patients frequently use complementary medicine. Curcumin (CUR) and its derivates (from the extract of Curcuma longa L.) represent some of the most frequently used ones, having a long history in traditional Asian medicine. CUR was demonstrated, both in vitro and in vivo, to have significant anti-inflammatory effects, thus potentially counteracting cancer-promoting inflammation, which is a hallmark of cancer. CUR modulate a plethora of signaling pathways in cancer cells, comprising the NF-κB (nuclear factor k-light-chain-enhancer of activated B cells), the JAK/STAT (Janus-Kinase/Signal Transducers and Activators of Transcription), and the TGF-ß (transforming growth factor-ß) pathways. Furthermore, CUR confers properties of electron receptors, which destabilize radical oxygen species (ROS), explaining its antioxidant and anti-apopototic effects. Although CUR has a low bioavailability, its role in advanced cancer treatment and supportive care was addressed in numerous clinical trials. After promising results in phase Iâ»II trials, multiple phase III trials in different indications are currently under way to test for direct anti-cancer effects. In addition, CUR exerts beneficial effects on cancer treatment-related neurotoxcity, cardiotoxicity, nephrotoxicity, hemato-toxicity, and others. More efficient galenic formulations are tested to optimze CUR's usability in cancer treatment. This review should provide a comprehensive overview of basic science, and pre-clinical and clinical data on CUR in the field of oncology.
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Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Curcumina/química , Curcumina/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/química , Antioxidantes/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estudios Clínicos como Asunto , Curcumina/uso terapéutico , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Metabolismo Energético/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non-responders (33.3%, n = 3/9; P = .028), resulting in a better progression-free survival during immunotherapy (IDO-1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log-rank test). In addition, IDO-1 was positively correlated with CD8+ T cell expression (rs = .691, P = .006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non-responders: 83.3% vs 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1 < 1% in 66.7% of both responders and non-responders). In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC.
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Carcinoma de Células Renales/terapia , Células Endoteliales/enzimología , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Neoplasias Renales/terapia , Anciano , Antígeno B7-H1/análisis , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Femenino , Humanos , Inmunoterapia , Neoplasias Renales/enzimología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana EdadRESUMEN
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author's own experiences/views.
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Antineoplásicos/uso terapéutico , Perfilación de la Expresión Génica , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Biomarcadores de Tumor/metabolismo , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Resultado del TratamientoRESUMEN
Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials. Furthermore, a potential benefit of new agents targeting DLL3, Aurora A kinase and PARP-inhibitor was reported. In this review we summarize new developments and critically highlight the most important and promising data in the relapsed small cell lung cancer disease.
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Terapia Molecular Dirigida/tendencias , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Aurora Quinasa A/antagonistas & inhibidores , Progresión de la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM(MF) (full-length) and EpCAM(MT) (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Using immunohistochemistry, we analyzed the expression of EpCAM(MF) and EpCAM(MT) variants in 640 patients with colorectal cancer and determined their correlations with other prognostic factors and clinical outcome. A statistically significant association was observed for EpCAM(MT) with advanced tumor stage (p < 0.001), histological grade (p = 0.01), vascular (p < 0.001) and marginal (p = 0.002) invasion. Survival analysis demonstrated reduced overall survival (p < 0.004) in patients with tumors expressing the EpCAM(MT) phenotype when compared to patients with tumors expressing the EpCAM(MF) variant. In conclusion, this study for the first time indicates that expression of EpCAM(MT) is associated with a more aggressive phenotype and predicts poor survival in patients with colorectal cancer.
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Biomarcadores de Tumor , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Molécula de Adhesión Celular Epitelial/metabolismo , Fenotipo , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Molécula de Adhesión Celular Epitelial/genética , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de Matrices TisularesRESUMEN
BACKGROUND: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. METHODS: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF-ß1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. RESULTS: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-ß1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. CONCLUSION: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization.
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Neoplasias Óseas/secundario , Transición Epitelial-Mesenquimal/fisiología , Tumores Neuroendocrinos/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Estudios de Cohortes , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , PubMed/estadística & datos numéricos , Receptores CXCR4/metabolismo , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Factor de Crecimiento Transformador beta1/metabolismo , Adulto JovenRESUMEN
BACKGROUND: EpCAM is highly expressed on membrane of epithelial tumor cells and has been detected as soluble/secreted (sEpCAM) in serum of cancer patients. In this study we established an ELISA for in vitro diagnostics to measure sEpCAM concentrations in ascites. Moreover, we evaluated the influence of sEpCAM levels on catumaxomab (antibody)--dependent cellular cytotoxicity (ADCC). METHODS: Ascites specimens from cancer patients with positive (C+, n = 49) and negative (C-, n = 22) cytology and ascites of patients with liver cirrhosis (LC, n = 31) were collected. All cell-free plasma samples were analyzed for sEpCAM levels with a sandwich ELISA system established and validated by a human recombinant EpCAM standard for measurements in ascites as biological matrix. In addition, we evaluated effects of different sEpCAM concentrations on catumaxomab-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood mononuclear cells (PBMNCs) and human tumor cells. RESULTS: Our ELISA showed a high specificity for secreted EpCAM as determined by control HEK293FT cell lines stably expressing intracellular (EpICD), extracellular (EpEX) and the full-length protein (EpCAM) as fusion proteins. The lower limit of quantification was 200 pg/mL and the linear quantification range up to 5,000 pg/mL in ascites as biological matrix. Significant levels of sEpCAM were found in 39% of C+, 14% of C- and 13% of LC ascites samples. Higher concentrations of sEpCAM were detectable in C+ (mean: 1,015 pg/mL) than in C- (mean: 449 pg/mL; p = 0.04) or LC (mean: 326 pg/mL; p = 0.01). Soluble EpCAM concentration of 1 ng/mL significantly inhibited ADCC of PBMNCs on EpCAM overexpressing target cells. CONCLUSION: Elevated concentrations of sEpCAM can be found in a subgroup of C+ and also in a small group of C- patients. We consider that sEpCAM levels in different tumor entities and individual patients should be evaluated prior to applying anti-EpCAM antibody-based cancer therapies, since sEpCAM neutralizes catumaxomab activity, making therapy less efficient.
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Anticuerpos Biespecíficos/farmacología , Antígenos de Neoplasias/metabolismo , Ascitis/metabolismo , Ascitis/patología , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica , Molécula de Adhesión Celular Epitelial , Células HEK293 , Humanos , Cirrosis Hepática/patología , Neoplasias/patología , Estudios RetrospectivosRESUMEN
AIMS: Epithelial cell adhesion molecule (EpCAM) is a widely used immunohistochemical marker for epithelial human malignancies. Antibodies to target EpCAM are usually directed against its ectodomain (EpEX), but do not detect the intracellular domain (EpICD). The aim of this study was to compare membranous EpEX versus EpICD expression by immunohistochemistry. METHODS AND RESULTS: Concurrent EpEX and EpICD expression was investigated retrospectively in cancerous and matched non-neoplastic tissue samples from patients with pancreatic adenocarcinoma. In total, 317 paired samples of pancreatic tissue from 88 patients were analysed and correlated with clinicopathological parameters. In non-cancerous tissue, a high concordance of membranous EpEX and EpICD expression was observed and defined as the expression of the full-length EpCAM (EpEX(+)/EpICD(+) phenotype, EpCAM(MF)), which was highly predominant. In contrast, while most tumour samples were EpEX positive, loss of membranous EpICD expression (EpEX(+)/EpICD(-) phenotype, EpCAM(MT)) was observed in one-third of cases, and these patients had a significantly shortened disease-free and overall survival. CONCLUSIONS: This study demonstrates for the first time that loss of membranous EpICD expression is a frequent event and predicts poor prognosis in patients with pancreatic cancer. Additional studies evaluating the predictive and prognostic value of the expression of different membranous EpCAM variants are warranted in epithelial cancers.
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Adenocarcinoma/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/patología , Anciano , Especificidad de Anticuerpos , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/química , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Moléculas de Adhesión Celular/inmunología , Molécula de Adhesión Celular Epitelial , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Pronóstico , Estructura Terciaria de Proteína , Estudios Retrospectivos , Análisis de Matrices TisularesRESUMEN
Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.
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Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.
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Antígeno B7-H1 , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico , Mutación , Neoplasias , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Pronóstico , Biomarcadores de Tumor/genética , Inestabilidad de Microsatélites , Femenino , Repeticiones de Microsatélite , MasculinoRESUMEN
Although histological and molecular classifications have been extensively studied for gastric cancer (GC), targeted therapies for GC remain limited. CDH1 mutations (MT) are characteristic of genomically stable GC and are associated with poor prognosis, but lack effective or targeted therapies. Here, we showed the overall mutation frequency of CDH1 was 9.7% (155 of 1596). CDH1-MT GC showed significantly lower rates of PD-L1 positivity (CPS score ≥1) than CDH1-wildtype (WT) GC (56.7% vs. 73.3%, p < 0.05). Compared to CDH1-WT GC, mutations of ARID1A, WRN, POT1, CDK12, and FANCC were significantly higher, while TP53 and APC were significantly lower in CDH1-MT GC (p < 0.05); The rates of KRAS and HER2 amplifications were significantly lower, while CRKL and IGF1R amplifications were significantly higher in CDH1-MT GC, compared to CDH1-WT GC (p < 0.05). Frequently altered genes in CDH1-MT GC were especially enriched in DNA damage repair and cell cycle checkpoint pathways. Inhibition of E-cadherin sensitized GC cell lines to PARP and Wee1 inhibitors by disrupting DNA damage repair pathway and cell cycle checkpoint. This is the largest study to investigate the distinct genomic landscape of CDH1-MT GC. Our data indicated GC patients with CDH1 mutations could potentially benefit from agents targeting PARP and Wee1.
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PURPOSE: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations. EXPERIMENTAL DESIGN: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). RESULTS: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. CONCLUSIONS: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.
Asunto(s)
Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales , Inhibidores de Puntos de Control Inmunológico , Mutación , Humanos , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Anciano , Masculino , Persona de Mediana Edad , Neoplasias Endometriales/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Biomarcadores de Tumor/genética , Adulto , Anciano de 80 o más Años , Pronóstico , Proteínas de Unión al ADN/genéticaRESUMEN
PURPOSE: Open-access publishing expanded opportunities to give visibility to research results but was accompanied by the proliferation of predatory journals (PJos) that offer expedited publishing but potentially compromise the integrity of research and peer review. To our knowledge, to date, there is no comprehensive global study on the impact of PJos in the field of oncology. MATERIALS AND METHODS: A 29 question-based cross-sectional survey was developed to explore knowledge and practices of predatory publishing and analyzed using descriptive statistics and binary logistic regression. RESULTS: Four hundred and twenty-six complete responses to the survey were reported. Almost half of the responders reported feeling pressure to publish from supervisors, institutions, and funding and regulatory agencies. The majority of authors were contacted by PJos through email solicitations (67.8%), with fewer using social networks (31%). In total, 13.4% of the responders confirmed past publications on PJo, convinced by fast editorial decision time, low article-processing charges, limited peer review, and for the promise of academic boost in short time. Over half of the participants were not aware of PJo detection tools. We developed a multivariable model to understand the determinants to publish in PJos, showing a significant correlation of practicing oncology in low- and middle-income countries (LMICs) and predatory publishing (odds ratio [OR], 2.02 [95% CI, 1.01 to 4.03]; P = .04). Having previous experience in academic publishing was not protective (OR, 3.81 [95% CI, 1.06 to 13.62]; P = .03). Suggestions for interventions included educational workshops, increasing awareness through social networks, enhanced research funding in LMICs, surveillance by supervisors, and implementation of institutional actions against responsible parties. CONCLUSION: The prevalence of predatory publishing poses an alarming problem in the field of oncology, globally. Our survey identified actionable risk factors that may contribute to vulnerability to PJos and inform guidance to enhance research capacity broadly.