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1.
Dig Dis Sci ; 67(2): 516-523, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33713247

RESUMEN

BACKGROUND: Progression of Barrett esophagus (BE) to esophageal adenocarcinoma occurs among a minority of BE patients. To date, BE behavior cannot be predicted on the basis of histologic features. AIMS: We compared BE samples that did not develop dysplasia or carcinoma upon follow-up of ≥ 7 years (BE nonprogressed [BEN]) with BE samples that developed carcinoma upon follow-up of 3 to 4 years (BE progressed [BEP]). METHODS: The NanoString nCounter miRNA assay was used to profile 24 biopsy samples of BE, including 13 BENs and 11 BEPs. Fifteen samples were randomly selected for miRNA prediction model training; nine were randomly selected for miRNA validation. RESULTS: Unpaired t tests with Welch's correction were performed on 800 measured miRNAs to identify the most differentially expressed miRNAs for cases of BEN and BEP. The top 12 miRNAs (P < .003) were selected for principal component analyses: miR-1278, miR-1301, miR-1304-5p, miR-517b-3p, miR-584-5p, miR-599, miR-103a-3p, miR-1197, miR-1256, miR-509-3-5p, miR-544b, miR-802. The 12-miRNA signature was first self-validated on the training dataset, resulting in 7 out of the 7 BEP samples being classified as BEP (100% sensitivity) and 7 out of the 8 BEN samples being classified as BEN (87.5% specificity). Upon validation, 4 out of the 4 BEP samples were classified as BEP (100% sensitivity) and 4 out of the 5 BEN samples were classified as BEN (80% specificity). Twenty-four samples were evaluated, and 22 cases were correctly classified. Overall accuracy was 91.67%. CONCLUSION: Using miRNA profiling, we have identified a 12-miRNA signature able to reliably differentiate cases of BEN from BEP.


Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Neoplasias Esofágicas/genética , MicroARNs/genética , Transcriptoma , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Esófago de Barrett/patología , Progresión de la Enfermedad , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico
2.
Dig Dis Sci ; 65(7): 1992-1998, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31691172

RESUMEN

BACKGROUND: CDX-2 is a nuclear homeobox transcription factor not normally expressed in esophageal and gastric epithelia, reported to highlight intestinal metaplasia (IM) in the esophagus. Pathological absence of goblet cells at initial screening via hematoxylin and eosin (HE) and alcian blue (AB) staining results in patient exclusion from surveillance programs. AIMS: This study aimed to determine whether non-goblet cell IM, as defined by CDX-2 positivity, can be considered to be a precursor to Barrett's esophagus (BE). METHODS: This study received IRB approval (17,284). Patients with gastroesophageal reflux disease (n = 181) who underwent upper-gastrointestinal endoscopy with biopsies of the distal esophagus to rule out BE using HE/AB staining and CDX-2 immunostaining were followed for 3 years. Initial and follow-up staining results were evaluated for age/sex. RESULTS: Differences between development of goblet cell IM in CDX-2-negative and CDX-2-positive groups were evaluated. A Kaplan-Meier curve showed that, out of the 134 patients initially positive for CDX-2, 25 (18.7%) had developed goblet cell IM after 2 years and 106 (79.1%) after 3 years. Conversely, of the 47 patients initially negative for CDX-2, 8 (17.9%) developed goblet cell IM after 24 months and only 11 (23.8%) after 40 to 45 months (P = .049; age-adjusted Cox proportional hazard regression model). CONCLUSION: In cases that are initially AB negative and CDX-2 positive, CDX-2 was demonstrated to have a potential prognostic utility for early detection of progression to BE. CDX-2 expression is significantly predictive for risk of goblet cell IM development 40 to 45 months after initial biopsy.


Asunto(s)
Esófago de Barrett/metabolismo , Factor de Transcripción CDX2/metabolismo , Esófago/metabolismo , Células Caliciformes/patología , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/patología , Biopsia , Progresión de la Enfermedad , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Esofagoscopía , Esófago/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos
3.
J Natl Compr Canc Netw ; 16(7): 797-800, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-30006421

RESUMEN

Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , Sarcoma de Kaposi/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/inmunología , Biopsia , Resistencia a Antineoplásicos/inmunología , Herpesvirus Humano 8/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/virología , Resultado del Tratamiento
4.
Oncology (Williston Park) ; 31(2): 110-21, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28205191

RESUMEN

The nonradiologic medical management of solid tumors has evolved from the use of traditional cytotoxic agents to modern targeted therapies, monoclonal antibodies, and immunotherapies. Advances in the understanding of cancer biology and therapeutic strategies have resulted in increasing numbers of new drug applications and approvals. Consequently, practicing oncologists need to learn how the newly available agents function and what toxicities to watch for, as well as ways to optimize the use of both new drugs and previously approved drugs with new indications. In 2016, the US Food and Drug Administration approved three novel drugs for the treatment of solid malignancies-olaratumab in selected patients with soft-tissue sarcoma, atezolizumab for the treatment of bladder cancer, and rucaparib for the treatment of ovarian cancer; also in 2016, the use of previously approved anticancer agents (including atezolizumab) was expanded into 11 new patient populations. The diversity of options for patients is evident in the broad range of the 2016 approvals, which include immune checkpoint inhibitors, targeted therapies, monoclonal antibodies, and traditional cytotoxic agents. This article focuses on the new agents and indications that emerged in 2016 for solid tumor treatment. We review the drug indications, mechanisms of action, pivotal trial data, pertinent toxicities, use in special populations, and the appropriate clinical contexts for treatment planning.


Asunto(s)
Antineoplásicos/uso terapéutico , Aprobación de Drogas , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Humanos , Inmunoterapia
5.
Oncology (Williston Park) ; 31(2): 138-46, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28205194

RESUMEN

The recent past has brought pharmacotherapeutic advances that benefit patients with hematologic malignancies. In 2016, two novel hematology drugs were approved and four previously approved hematology drugs were granted expanded use for the treatment of appropriate patient populations by the US Food and Drug Administration. These new approvals and indications represent significant steps forward in patient management: they include the first-in-class B-cell lymphoma 2 inhibitor, venetoclax, the newest targeted therapy available for the treatment of hematologic malignancies; and nivolumab, the first immune checkpoint inhibitor to be approved for treatment of a hematologic malignancy. Other advances include defibrotide as the first drug approved for the treatment of veno-occlusive disease with evidence of multiorgan dysfunction, and the expansion of indications for the two anti-CD20 monoclonal antibodies ofatumumab and obinutuzumab, as well as the anti-CD38 monoclonal antibody daratumumab. This article reviews each of these drugs and their indications, mechanisms of action, accompanying pivotal trial data, pertinent toxicities, use in special populations, and appropriate clinical context.


Asunto(s)
Antineoplásicos/uso terapéutico , Aprobación de Drogas , Neoplasias Hematológicas/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico
6.
Head Neck Pathol ; 18(1): 11, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38393464

RESUMEN

BACKGROUND: Metastatic carcinoma of unknown primary origin to the head and neck lymph nodes (HNCUP) engenders unique diagnostic considerations. In many cases, the detection of a high-risk human papillomavirus (HR-HPV) unearths an occult oropharyngeal squamous cell carcinoma (SCC). In metastatic HR-HPV-independent carcinomas, other primary sites should be considered, including cutaneous malignancies that can mimic HR-HPV-associated SCC. In this context, ultraviolet (UV) signature mutations, defined as ≥ 60% C→T substitutions with ≥ 5% CC→TT substitutions at dipyrimidine sites, identified in tumors arising on sun exposed areas, are an attractive and underused tool in the setting of metastatic HNCUP. METHODS: A retrospective review of institutional records focused on cases of HR-HPV negative HNCUP was conducted. All cases were subjected to next generation sequencing analysis to assess UV signature mutations. RESULTS: We identified 14 HR-HPV negative metastatic HNCUP to either the cervical or parotid gland lymph nodes, of which, 11 (11/14, 79%) had UV signature mutations, including 4 (4/10, 40%) p16 positive cases. All UV signature mutation positive cases had at least one significant TP53 mutation and greater than 20 unique gene mutations. CONCLUSION: The management of metastatic cutaneous carcinomas significantly differs from other HNCUP especially metastatic HR-HPV-associated SCC; therefore, the observation of a high percentage of C→T with CC →TT substitutions should be routinely incorporated in next generation sequencing reports of HNCUP. UV mutational signatures testing is a robust diagnostic tool that can be utilized in daily clinical practice.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Primarias Desconocidas , Infecciones por Papillomavirus , Neoplasias Cutáneas , Humanos , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/patología , Infecciones por Papillomavirus/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Mutación , Papillomaviridae/genética
7.
Front Genet ; 15: 1377158, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38566816

RESUMEN

Introduction: Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in RET. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. RET SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC. Methods: The prevalence of RET SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare RET SSV frequency in cancers with/without a diagnosis of MTC. Results: All 25 MTCs had at least one of the two most common RET SSVs versus 0.3% of 3,599 cancers with other diagnoses (p < 0.00001). The 11 cancers with non-MTC diagnoses that had the common RET SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common RET SSVs, including 4 with no identified mutational driver. Discussion: The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC.

8.
Cancer Genomics Proteomics ; 20(2): 154-164, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36870693

RESUMEN

BACKGROUND/AIM: Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. PATIENTS AND METHODS: Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. RESULTS: There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. CONCLUSION: The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.


Asunto(s)
MicroARNs , Tumores Neuroectodérmicos Primitivos , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Reproducibilidad de los Resultados
9.
Cancer Genomics Proteomics ; 20(6): 522-530, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37889062

RESUMEN

BACKGROUND/AIM: P21 is a cyclin-dependent kinase inhibitor regulating the cell cycle as a tumor suppressor. Using a p21 immunohistochemistry (IHC) assay, we compared tumor p21 levels with conventional clinico-pathological criteria in primary pancreatic endocrine tumor subsets with and without liver metastases. MATERIALS AND METHODS: Sections from tissue microarray (TMA) including 13 archival metastatic primary and 18 non-metastatic primary pancreatic endocrine carcinomas/tumors (MP-PECAs/NMP-PETs) were stained with a monoclonal anti-p21WAFI,CIP primary antibody. Tumor p21 IHCs were scored as the sum of intensity (0-3) and proportion scores (0-5) (Total Allred score: 0-8), and as p21% labelling index in the tumor. ROC curve analysis was used for most optimal p21 score cut-off (4 or >) and Fisher's exact test was used to compare the association among tumor p21 scores, conventional prognostic criteria, and liver metastases. RESULTS: For PET/PECA patients, mean ages were 55.6 years (27-73) and 49.3 years (28-71), M/F ratios were 7/11 and 7/6. Mean p21 labelling index (%) for MP- PECAs was 24% (range=3-63%) vs. 9% for NMP-PETs (range=1-25%) (p=0.022). The mean p21 index in MP-PECAs was significantly higher (24%) as compared to PIs (7%) (p=0.0047). Using a p21 Allred score of ≥4, high p21 IHC score had strong association with the presence of liver metastases (p-value <0.001). High tumor p21 IHC score had a 93% sensitivity, 68% specificity, 78% predictive accuracy, 66% positive, and 94% negative predictive values. CONCLUSION: In patients with primary PETs, p21 IHC is superior to conventional criteria in predicting presence or absence of liver metastases.


Asunto(s)
Neoplasias Hepáticas , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Adulto , Persona de Mediana Edad , Anciano , Neoplasias Pancreáticas/patología , Neoplasias Hepáticas/metabolismo , Pronóstico , Tumores Neuroendocrinos/patología , Valor Predictivo de las Pruebas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Biomarcadores de Tumor/metabolismo , Proteína p53 Supresora de Tumor
10.
NPJ Precis Oncol ; 7(1): 68, 2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37464050

RESUMEN

Preclinical genetically engineered mouse models (GEMMs) of lung adenocarcinoma are invaluable for investigating molecular drivers of tumor formation, progression, and therapeutic resistance. However, histological analysis of these GEMMs requires significant time and training to ensure accuracy and consistency. To achieve a more objective and standardized analysis, we used machine learning to create GLASS-AI, a histological image analysis tool that the broader cancer research community can utilize to grade, segment, and analyze tumors in preclinical models of lung adenocarcinoma. GLASS-AI demonstrates strong agreement with expert human raters while uncovering a significant degree of unreported intratumor heterogeneity. Integrating immunohistochemical staining with high-resolution grade analysis by GLASS-AI identified dysregulation of Mapk/Erk signaling in high-grade lung adenocarcinomas and locally advanced tumor regions. Our work demonstrates the benefit of employing GLASS-AI in preclinical lung adenocarcinoma models and the power of integrating machine learning and molecular biology techniques for studying the molecular pathways that underlie cancer progression.

11.
Artículo en Inglés | MEDLINE | ID: mdl-34751163

RESUMEN

This overview of the molecular pathology of lung cancer includes a review of the most salient molecular alterations of the genome, transcriptome, and the epigenome. The insights provided by the growing use of next-generation sequencing (NGS) in lung cancer will be discussed, and interrelated concepts such as intertumor heterogeneity, intratumor heterogeneity, tumor mutational burden, and the advent of liquid biopsy will be explored. Moreover, this work describes how the evolving field of molecular pathology refines the understanding of different histologic phenotypes of non-small-cell lung cancer (NSCLC) and the underlying biology of small-cell lung cancer. This review will provide an appreciation for how ongoing scientific findings and technologic advances in molecular pathology are crucial for development of biomarkers, therapeutic agents, clinical trials, and ultimately improved patient care.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Biopsia Líquida , Neoplasias Pulmonares/genética , Mutación , Patología Molecular
12.
Anticancer Res ; 42(3): 1381-1396, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35220231

RESUMEN

BACKGROUND/AIM: Cancer of unknown primary (CUP), representing 3-5% of all newly diagnosed cancers in the United States, is a presumptive, non-definitive diagnosis rendered when a primary tumor site cannot be identified after exhaustive diagnostic evaluation, including cases of neuroendocrine neoplasms (NENs). CUPs are characterized by findings that are challenging to reconcile, including inconclusive immunohistochemical (IHC) stains, an undifferentiated morphologic phenotype, history of multiple cancers, a clinical presentation that is discordant from histologic findings, an atypical distribution of metastases, or lack of expected response to treatment. For a significant subset of NENs (10%), traditional diagnostic evaluation is unable to determine a primary tumor site using histomorphology and IHC stains. Gene expression profiling (GEP) of either mRNA or microRNA is the technique utilized in the three commercially available platforms that provide a prediction of tumor type in cases of diagnostic uncertainty of CUPs, including those with neuroendocrine differentiation. Case Series Report: Here we present four cases of NENs, where the diagnosis based upon histomorphological and IHC features presented a unique challenge that ultimately benefited from the integration of molecular tumor classification using the validated assay. CancerTYPE ID by Biotheranostics is based on a quantitative RT-PCR assay that uses a computational algorithm to measure the collective expression of 92 genes (87 cancer-related genes and 5 control genes). This case series reports five appropriate clinical scenarios that highlight the utility of a GEP-based assay to effectively provide a molecular tumor classification to identify NEN subtypes and tumor primary site of origin. CONCLUSION: These cases demonstrated that the CancerTYPE ID test was able to resolve challenging diagnoses for primary and metastatic NENs. These cases emphasize the clinical need of utilizing a GEP-based assay for determining the anatomic site of origin and NEN subtyping, both essential for the appropriate clinical management of NENs.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Gastrointestinales/genética , Perfilación de la Expresión Génica , Neoplasias Primarias Desconocidas/genética , Tumores Neuroendocrinos/genética , Reacción en Cadena de la Polimerasa , Transcriptoma , Anciano , Anciano de 80 o más Años , Algoritmos , Biomarcadores de Tumor/análisis , Femenino , Neoplasias Gastrointestinales/química , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/terapia , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/química , Neoplasias Primarias Desconocidas/patología , Neoplasias Primarias Desconocidas/terapia , Tumores Neuroendocrinos/química , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos
13.
Cancer Genomics Proteomics ; 19(2): 145-150, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35181584

RESUMEN

BACKGROUND/AIM: Cancers with a microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status respond to immune checkpoint inhibition (ICI). Regardless of the tumor type, MSI-H/dMMR status is a reliable biomarker for ICI responsiveness. This study aimed at determining the MSI-H status in precursor lesions to esophageal adenocarcinoma (EAC) such as Barrett's esophagus (BE) and BE with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). PATIENTS AND METHODS: We performed immunohistochemical staining (IHC) for PMS2, MSH6, PD1, and PD-L1. RESULTS: All cases of BE (50), LGD (48), and HGD (50) had intact PMS2 and MSH6 nuclear expression; were negative for PD1; and had a PD-L1 combined positive score (CPS) score <1. One EAC case (2%) was negative for PMS2 nuclear expression. One HGD case (2%) and two EAC cases (4%) were PD1 positive (CPS score <1 applied to PD1). One EAC case (2%) had a CPS score >1, and one EAC case (2%) was MSI-H. MSI-H tumors usually show PD-L1 expression, although the MSI-H EAC in this study had a PD-L1 CPS score of <1. CONCLUSION: Further studies investigating EAC and its precursor lesions for PD1, PD-L1, and dMMR status may be informative regarding the immunogenicity of the evolution of EAC.


Asunto(s)
Adenocarcinoma , Antígeno B7-H1 , Esófago de Barrett , Neoplasias Esofágicas , Receptor de Muerte Celular Programada 1 , Adenocarcinoma/genética , Adenocarcinoma/patología , Antígeno B7-H1/genética , Esófago de Barrett/genética , Esófago de Barrett/patología , Reparación de la Incompatibilidad de ADN , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Humanos , Receptor de Muerte Celular Programada 1/genética
14.
Mol Cancer Res ; 20(4): 542-555, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35022314

RESUMEN

To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely. IMPLICATIONS: Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.


Asunto(s)
Neoplasias Pulmonares , Proteómica , Línea Celular Tumoral , Movimiento Celular , Resistencia a Antineoplásicos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteómica/métodos , Transducción de Señal
15.
Cancer Diagn Progn ; 1(4): 285-288, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35403148

RESUMEN

Background: Pancreatic-type mixed acinar-neuroendocrine carcinoma (PMANEC) in the stomach is very rare. We report a case of PMANEC that was initially misdiagnosed as a gastric neuroendocrine tumor. Case Report: A 63-year-old female was found to have a gastric mass by histology and immunohistochemistry. The tumor had a heterogenous histology, with areas resembling pancreatic acinar cell carcinoma and other areas exhibiting neuroendocrine features. Only the neuroendocrine component was present in the initial biopsy, resulting in the erroneous diagnosis of gastric neuroendocrine tumor. Evaluation of the final resected tumor revealed cells expressing pancreatic exocrine markers, including trypsin and chymotrypsin and BCL10 immune signaling adaptor. Large areas of the tumor (>30%) were also positive for chromogranin A and synaptophysin. The final diagnosis was PMANEC. Conclusion: This type of gastric cancer is rare and may cause diagnostic difficulty, especially if only the neuroendocrine component of the tumor is sampled in a biopsy.

16.
JNCI Cancer Spectr ; 5(4)2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34409252

RESUMEN

Background: Immunotherapy yields survival benefit for some advanced stage non-small cell lung cancer (NSCLC) patients. Because highly predictive biomarkers of immunotherapy response are an unmet clinical need, we used pretreatment radiomics and clinical data to train and validate a parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Methods: Three cohorts of NSCLC patients treated with immunotherapy were analyzed: training (n = 180), validation 1 (n = 90), and validation 2 (n = 62). The most informative clinical and radiomic features were subjected to decision tree analysis, which stratified patients into risk groups of low, moderate, high, and very high risk of death after initiation of immunotherapy. All statistical tests were 2-sided. Results: The very high-risk group was associated with extremely poor overall survival (OS) in validation cohorts 1 (hazard ratio [HR] = 5.35, 95% confidence interval [CI] = 2.14 to 13.36; 1-year OS = 11.1%, 95% CI = 1.9% to 29.8%; 3-year OS = 0%) and 2 (HR = 13.81, 95% CI = 2.58 to 73.93; 1-year OS = 47.6%, 95% CI = 18.2% to 72.4%; 3-year OS = 0%) when compared with the low-risk group (HR = 1.00) in validation cohorts 1 (1-year OS = 85.0%, 95% CI = 60.4% to 94.9%; 3-year OS = 38.9%, 95% CI = 17.1% to 60.3%) and 2 (1-year OS = 80.2%, 95% CI = 40.3% to 94.8%; 3-year OS = 40.1%, 95% CI = 1.3% to 83.5%). The most informative radiomic feature, gray-level co-occurrence matrix (GLCM) inverse difference, was positively associated with hypoxia-related carbonic anhydrase 9 using gene-expression profiling and immunohistochemistry. Conclusion: Utilizing standard-of-care imaging and clinical data, we identified and validated a novel parsimonious model associated with survival outcomes among NSCLC patients treated with immunotherapy. Based on this model, clinicians can identify patients who are unlikely to respond to immunotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/terapia , Hipoxia Tumoral , Anciano , Antígenos de Neoplasias/genética , Anhidrasa Carbónica IX/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Estudios de Cohortes , Intervalos de Confianza , Árboles de Decisión , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
17.
Int J Radiat Oncol Biol Phys ; 109(2): 425-435, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002543

RESUMEN

PURPOSE: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer. METHODS AND MATERIALS: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year. RESULTS: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02). CONCLUSIONS: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.


Asunto(s)
Ipilimumab/uso terapéutico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Nivolumab/uso terapéutico , Platino (Metal)/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Estudios Prospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Tórax/efectos de la radiación
18.
Nat Med ; 27(8): 1410-1418, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34385708

RESUMEN

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion and interleukin-2, followed by maintenance nivolumab. The end point of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval, 3-29%). Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Resistencia a Antineoplásicos , Neoplasias Pulmonares/terapia , Linfocitos Infiltrantes de Tumor , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia
19.
Methods Mol Biol ; 2194: 187-221, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32926368

RESUMEN

Highly collaborative scientists are often called on to extend their expertise to different types of projects and to expand the scope and scale of projects well beyond their previous experience. For a large-scale project involving "big data" to be successful, several different aspects of the research plan need to be developed and tested, which include but are not limited to the experimental design, sample collection, sample preparation, metadata recording, technical capability, data acquisition, approaches for data analysis, methods for integration of different data types, recruitment of additional expertise as needed to guide the project, and strategies for clear communication throughout the project. To capture this process, we describe an example project in proteogenomics that built on our collective expertise and experience. Key steps included definition of hypotheses, identification of an appropriate clinical cohort, pilot projects to assess feasibility, refinement of experimental designs, and extensive discussions involving the research team throughout the process. The goal of this chapter is to provide the reader with a set of guidelines to support development of other large-scale multiomics projects.


Asunto(s)
Bioestadística/métodos , Investigación Interdisciplinaria/métodos , Proteogenómica/métodos , Macrodatos , Estudios de Cohortes , Expresión Génica , Genómica/métodos , Humanos , Proyectos Piloto , Proteómica/métodos , Proyectos de Investigación
20.
Clin Colorectal Cancer ; 19(2): 123-131, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32171644

RESUMEN

BACKGROUND: Patients with deficient microsatellite mismatch repair (dMMR) colorectal cancer (CRC) may respond to immune checkpoint inhibition (ICI), whereas patients with microsatellite-stable (MSS) CRC have not demonstrated response. However, a proportion of MSS tumors display histomorphologic features characteristic of dMMR tumors consistent with an increased antigenicity. Therefore, a subset of patients with CRC not currently receiving ICI treatment may derive benefit from ICI therapy. We review tumors in which the histologic features suggestive of dMMR were in disagreement with the DNA mismatch repair proteins obtained by immunohistochemistry (IHC). Possible causes of such disagreement are discussed. MATERIALS AND METHODS: Three patients with CRC suggestive of histomorphologic immunogenicity underwent evaluation by IHC staining for mismatch repair (MMR) status, next-generation sequencing assays, and/or polymerase chain reaction. RESULTS: Findings compatible with an immunogenic response were similarly observed in all patients. Case 1 highlighted the limiting factors inherent to IHC staining for MMR status: a biopsy initially interpreted as MSS was subsequently interpreted as being dMMR. Case 2 examined the challenges in reconciling histologic characteristics traditionally associated with dMMR CRCs but ultimately determined to be MSS. Case 3 examined the microsatellite instability of CRC resulting from MLH1-methylation and/or MSH6 mutation. CONCLUSIONS: We demonstrated the challenges in establishing MMR status when confronted with conflicting results from histology, IHC, polymerase chain reaction, and next-generation sequencing. Given that dMMR status has been shown to be a biomarker for ICI responsiveness, the importance of accurate identification is critical.


Asunto(s)
Biomarcadores de Tumor/genética , Colectomía , Neoplasias Colorrectales/diagnóstico , Reparación de la Incompatibilidad de ADN , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Selección de Paciente
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