RESUMEN
BACKGROUND: The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. METHODS: Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%). RESULTS: A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003). CONCLUSIONS: Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Tumores Neuroendocrinos/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/genética , Proyectos Piloto , PronósticoRESUMEN
Next-generation sequencing of primary and metachronous metastatic cancer lesions may impact patient care. We present a case of relapsed metastatic breast cancer with a dominant pulmonary lesion originally identified as lung adenocarcinoma. A 72-year-old, never-smoker woman with a protracted cough was found to have a large lung mass and regional lymphadenopathy on a chest CT. Lung mass biopsy showed adenocarcinoma with focal TTF-1 (thyroid transcription factor 1) positivity, favoring a lung primary. In addition to stereotactic brain radiation for cerebral metastases, she was started on carboplatin/pemetrexed. As part of the workup, the tumor was analyzed by a 50-gene targeted mutation panel, which detected 3 somatic mutations: ERBB2 (HER2) D769H activating missense mutation, TP53 Y126 inactivating truncating mutation, and SMARCB1 R374Q missense mutation. Of note, the patient had a history of stage IIA triple-negative grade 3 invasive ductal carcinoma of the left breast 1.5 years ago and received neoadjuvant chemotherapy and adjuvant radiation, and underwent a lumpectomy. Further analysis of her primary breast tumor showed a mutational profile identical to that of the lung tumor. Fluorescence in situ hybridization revealed HER2 amplification in the lung tumor, with a HER2/CEP17 ratio of 3.9. The patient was diagnosed with recurrent HER2-positive metastatic breast carcinoma with a coexisting ERBB2 (HER2) activating mutation. Chemotherapy was adjusted to include dual HER2-targeted therapy containing trastuzumab and pertuzumab, resulting in an ongoing partial response. This case demonstrates that a unique genetic mutational profile can clarify whether a tumor represents a metastatic lesion or new malignancy when conventional morphological and immunohistochemical methods are indeterminate, and can directly impact treatment decisions.
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Neoplasias de la Mama/genética , Amplificación de Genes , Mutación , Receptor ErbB-2/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Pruebas Genéticas , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Estadificación de Neoplasias , Neoplasias Primarias Secundarias , Radiografía Torácica , Radiocirugia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVES: To determine the diagnostic accuracy of cytomorphology for subclassifying non-small cell lung cancer into adenocarcinoma (AC) and squamous cell carcinoma (SqC), and the utility of immunocytochemistry (ICC) for poorly differentiated cases. STUDY DESIGN: Preoperative cytologic diagnoses of SqC, AC, or non-small cell carcinoma (NSCC) were compared with surgical resection diagnoses. NSCC cases with adequate cell block material were stained with CK7, CK5/6, TTF-1 and p63 antibodies and subclassified as SqC, AC, or equivocal. RESULTS: 123 of 140 (88%) preoperative cytologic specimens had a malignant diagnosis, including 36 SqC, 72 AC, 6 adenosquamous carcinomas (ASC), and 9 large cell carcinomas (LCC). Accurate cytologic diagnoses were rendered in 18 (50%) SqC and 49 (68%) AC; 26 of 54 cases with a diagnosis of NSCC had adequate cell block material for ICC. TTF-1 and p63 accurately classified 8 of 9 (89%) SqC and 8 of 8 (100%) AC. One SqC, 2 ASC and 3 LCC had equivocal staining, while 1 ASC and 3 LCC stained as AC. CONCLUSIONS: The majority of SqC and AC (56%) can be classified by cytomorphology alone. TTF-1 and p63 ICC on cell blocks can provide accurate subclassification for NSCC in the vast majority of cases.
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Carcinoma de Pulmón de Células no Pequeñas/clasificación , Citodiagnóstico/métodos , Inmunohistoquímica , Neoplasias Pulmonares/clasificación , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Humanos , Neoplasias Pulmonares/diagnóstico , Estudios RetrospectivosRESUMEN
Cytology and cell biology are two separate fields that share a focus on cancer. Cancer is still diagnosed based on morphology, and surprisingly little is known about the molecular basis of the defining structural features. Cytology uses the smallest possible biopsy for diagnosis by reducing morphologic "criteria of malignancy" to the smallest scale. To begin to develop common ground, members of the American Society of Cytopathology Cell Biology Liaison Working Group classify some of the "criteria of malignancy" and review their relation to current cell biology concepts. The criteria of malignancy are extremely varied, apparently reflecting many different pathophysiologies in specific microenvironments. Criteria in Group 1 comprise tissue-level alterations that appear to relate to resistance to anoikis, alterations in cell adhesion molecules, and loss of apical-basal polarity. Criteria in Group 2 reflect genetic instability, including chromosomal and possibly epigenetic instability. Criteria in Groups 3 are subcellular structural changes involving cytoplasmic components, nuclear lamina, chromatin and nucleoli that cannot be accounted for by genetic instability. Some distinct criteria in Group 3 are known to be induced by cancer genes, but their precise structural basis remains obscure. The criteria of malignancy are not closely related to the histogenetic classification of cancers, and they appear to provide an alternative, biologically relevant framework for establishing common ground between cytologists and cell biologists. To understand the criteria of malignancy at a molecular level would improve diagnosis, and likely point to novel cell physiologies that are not encompassed by current cell biology concepts.
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Neoplasias/patología , Polaridad Celular , Humanos , Modelos Biológicos , Neoplasias/genéticaRESUMEN
The cytologic evaluation of serous effusions may be challenging for a number of reasons. Distinction of benign, reactive conditions from malignancy represents the main focus when examining these specimens. The morphologic diagnosis of malignancy may be difficult due to the relative paucity of abnormal cells. In other situations, cellularity is not an issue, but the ability to confidently identify a second, foreign (i.e., tumor) population within a background mesothelial cells on the basis of cytomorphologic features alone may pose problems. Cases with definitive morphologic evidence of malignancy may require additional studies in order to determine the tumor subtype and, in the case of carcinoma, the primary site of origin. Cases in which a definitive and precise diagnosis of malignancy is made may be optimal candidates for further molecular testing in order to gain prognostic information and guide personal therapeutic decisions. Finally, while an inflammatory or infectious condition can be suggested on the basis of cellular components and associated background elements, the identification of causative agent(s) may be difficult without additional studies. In all of these situations, the use of ancillary studies and techniques is critical; their utility and appropriate application are the subject of this review.
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Líquido Ascítico/patología , Citodiagnóstico/métodos , Mesotelioma/patología , Técnicas de Diagnóstico Molecular/métodos , Derrame Pleural Maligno/patología , Líquido Ascítico/metabolismo , Diagnóstico Diferencial , Humanos , Mesotelioma/genética , Derrame Pleural Maligno/genética , Sensibilidad y EspecificidadRESUMEN
Aberrant DNA methylation of tumor suppressor genes is a frequent epigenetic event that occurs early in tumor progression. Real-time quantitative methylation-specific polymerase chain reaction (QMSP) assays can provide accurate detection and quantitation of methylated alleles that may be potentially useful in diagnosis and risk assessment for cancer. Development of QMSP requires optimization to maximize analytical specificity and sensitivity for the detection of methylated alleles. However, in some cases challenges encountered in primer and probe design can make optimization difficult and limit assay performance. Locked nucleic acids (LNAs) demonstrate increased affinity and specificity for their cognate DNA sequences. In this proof-of-principle study, LNA residues were incorporated into primer and probe design to determine whether LNA-modified oligonucleotides could enhance the analytical performance of QMSP for IGSF4 promoter methylation in human cancer cell lines using either SYBR Green or fluorogenic probe detection methods. Use of LNA primers in QMSP with SYBR Green improved analytical specificity for methylated alleles and eliminated the formation of nonspecific products because of mispriming from unmethylated alleles. QMSP using LNA probe and primers showed an increased amplification efficiency and maximum fluorescent signal. QMSP with LNA oligonucleotides and either detection method could reliably detect five genome equivalents of methylated DNA in 1000- to 10,000-fold excess unmethylated DNA. Thus, LNA oligonucleotides can be used in QMSP optimization to enhance analytical performance.
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Metilación de ADN , Oligonucleótidos/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa/normas , Benzotiazoles , Tampones (Química) , Línea Celular Tumoral , Islas de CpG/genética , Cartilla de ADN/metabolismo , ADN de Neoplasias/metabolismo , Diaminas , Electroforesis en Gel de Agar , Colorantes Fluorescentes/metabolismo , Humanos , Compuestos Orgánicos/metabolismo , Quinolinas , Moldes GenéticosRESUMEN
We examined the histologic outcomes and prevalence of high-risk human papillomavirus (HR-HPV) in women with liquid-based Papanicolaou (Pap) tests interpreted as "low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion" (LSIL-H) compared with the 2001 Bethesda System (TBS 2001) cytologic categories of LSIL, high-grade SIL (HSIL), and atypical squamous cells, cannot exclude HSIL (ASC-H). A computer search identified 426 LSIL, 86 ASC-H, 81 LSIL-H, and 110 HSIL cytologic interpretations during a 1-year period, each with up to 2 years of histologic follow-up. The risk of histologic cervical intraepithelial neoplasia (CIN) 2 or worse (CIN 2+) associated with LSIL-H (32/81 [40%]) was intermediate between LSIL (46/426 [10.8%]) and HSIL (72/110 [65.5%]), but not significantly different from ASC-H (23/86 [27%]). However, LSIL-H was more frequently associated with a definitive histologic diagnosis of any CIN (CIN 1+) than ASC-H (53/81 [65%] vs 35/86 [41%]). Moreover, the prevalence of HR-HPV was significantly greater in patients with LSIL-H than in patients with ASC-H (15/15 [100%] vs 43/73 [59%]). The histologic outcomes and HR-HPV prevalence associated with LSIL-H differ significantly from the established categories of TBS 2001 and provide evidence to support the recognition of LSIL-H as a distinct cytologic category.
Asunto(s)
Alphapapillomavirus/aislamiento & purificación , Displasia del Cuello del Útero/clasificación , Displasia del Cuello del Útero/virología , Femenino , Estudios de Seguimiento , Humanos , Prueba de Papanicolaou , Prevalencia , Factores de Riesgo , Frotis Vaginal/métodosRESUMEN
The human major histocompatibility complex (MHC) class Ib gene, HLA-E, codes for the major ligand of the inhibitory receptor NK-G-2A, which is present on most natural killer (NK) cells and some CD8(+) cytotoxic T lymphocytes. We have previously shown that gamma interferon (IFN-gamma) induction of HLA-E gene transcription is mediated through a distinct IFN-gamma-responsive element, the IFN response region (IRR), in all cell types studied. We have now identified and characterized a cell type-restricted enhancer of IFN-gamma-mediated induction of HLA-E gene transcription, designated the upstream interferon response region (UIRR), which is located immediately upstream of the IRR. The UIRR mediates a three- to eightfold enhancement of IFN-gamma induction of HLA-E transcription in some cell lines but not in others, and it functions only in the presence of an adjacent IRR. The UIRR contains a variant GATA binding site (AGATAC) that is critical to both IFN-gamma responsiveness and to the formation of a specific binding complex containing GATA-1 in K562 cell nuclear extracts. The binding of GATA-1 to this site in response to IFN-gamma was confirmed in vivo in a chromatin immunoprecipitation assay. Forced expression of GATA-1 in nonexpressing U937 cells resulted in a four- to fivefold enhancement of the IFN-gamma response from HLA-E promoter constructs containing a wild-type but not a GATA-1 mutant UIRR sequence and increased the IFN-gamma response of the endogenous HLA-E gene. Knockdown of GATA-1 expression in K562 cells resulted in a approximately 4-fold decrease in the IFN-gamma response of the endogenous HLA-E gene, consistent with loss of the increase in IFN-gamma response of HLA-E promoter-driven constructs containing the UIRR in wild-type K562 cells. Coexpression of wild-type and mutant adenovirus E1a proteins that sequester p300/CBP eliminated IFN-gamma-mediated enhancement through the UIRR, but only partially reduced induction through the IRR, implicating p300/CBP binding to Stat-1alpha at the IRR in the recruitment of GATA-1 to mediate the cooperation between the UIRR and IRR. We propose that the GATA-1 transcription factor represents a cell type-restricted mediator of IFN-gamma induction of the HLA-E gene.
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Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Interferón gamma/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Secuencia de Bases , Línea Celular , Proteínas de Unión al ADN/genética , Factores de Unión al ADN Específico de las Células Eritroides , Factor de Transcripción GATA1 , Genes Reporteros , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Datos de Secuencia Molecular , Unión Proteica , Elementos de Respuesta , Factores de Transcripción/genética , Transfección , Antígenos HLA-ERESUMEN
PURPOSE: Anal intraepithelial neoplasia is associated with human papillomavirus infection and may progress to invasive squamous cell carcinoma (SCC), which is increasing in immunocompromised patients. We hypothesize that anal intraepithelial neoplasia is associated with abnormal DNA methylation and that detection of these events may be used to improve screening programs. EXPERIMENTAL DESIGN: Seventy-six patients were identified who underwent anal cytology screening and subsequent biopsy at our institution between 1999 and 2004. The specimens from these patients included 184 anal biopsies [normal, n = 57; low-grade squamous intraepithelial lesion (LSIL), n = 74; high-grade squamous intraepithelial lesion (HSIL), n = 41; and invasive SCC, n = 12] and 37 residual liquid-based anal cytology specimens (normal, n = 11; LSIL, n = 12; HSIL, n = 14). The methylation status of the following genes was determined for each biopsy and cytology sample using real-time methylation-specific PCR: HIC1, RASSF1, RARB, CDKN2A, p14, TP73, APC, MLH1, MGMT, DAPK1, and IGSF4. RESULTS: Methylation-specific PCR analysis of biopsy samples revealed that DNA methylation was more common in SCC and HSIL than LSIL and normal mucosa. Specifically, methylation of IGSF4 and DAPK1 was prevalent in SCC (75% and 75% of cases, respectively) and HSIL (59% and 71%, respectively) but was absent in LSIL and normal biopsy samples. Methylation profiles of cytologic samples were similar to those found in the biopsy samples. CONCLUSIONS: Aberrant DNA methylation is a frequent event in anal HSIL and SCC. Methylation of IGSF4 and DAPK1 is specific for HSIL and SCC, and may serve as a useful molecular biomarker.
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Canal Anal/patología , Neoplasias del Ano/patología , Carcinoma de Células Escamosas/patología , Metilación de ADN , Proteínas Adaptadoras Transductoras de Señales , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Canal Anal/metabolismo , Neoplasias del Ano/genética , Biopsia , Carcinoma de Células Escamosas/genética , Proteínas Portadoras , Molécula 1 de Adhesión Celular , Moléculas de Adhesión Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas de Unión al ADN/genética , Humanos , Inmunoglobulinas/genética , Factores de Transcripción de Tipo Kruppel , Proteínas de la Membrana/genética , Homólogo 1 de la Proteína MutL , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , O(6)-Metilguanina-ADN Metiltransferasa/genética , Reacción en Cadena de la Polimerasa/métodos , Proteínas Serina-Treonina Quinasas/genética , Receptores de Ácido Retinoico/genética , Factores de Transcripción/genética , Proteína p14ARF Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
To determine its usefulness as a specific diagnostic marker for follicular carcinomas (FCs) vs other follicular-patterned thyroid lesions and possible application to fine-needle aspiration specimens, we immunohistochemically studied peroxisome proliferator-activated receptor gamma (PPAR gamma) expression in histologic sections (FC, 13 cases; follicular adenoma [FA], 11; follicular variant of papillary carcinoma [FVPC], 9) and surrounding thyroid tissue by using a PPAR gamma monoclonal antibody. Positivity (detected by nuclear staining) was scored as absent, weak, moderate, or strong. When only moderate or strong nuclear staining was considered positive, 9 FCs (69%), 3 FAs (27%), and 2 FVPCs (22%) demonstrated positive nuclear immunoreactivity. The sensitivity and specificity of immunohistochemical detection of PPAR gamma expression in FCs were 69% and 75%, respectively. In nonlesional surrounding tissue, moderate to strong positive staining was seen in focal areas of chronic lymphocytic thyroiditis in 6 of 33 cases (FC, 2; FA, 3; FVPC, 1); diffuse moderate staining was detected in surrounding tissue in the absence of lymphocytic thyroiditis in 4 cases (12%; FC, 3; FA, 1). Staining in the follicular-patterned lesions and surrounding nonlesional thyroid was specific with peptide blocking experiments. PPAR gamma expression is not a specific marker for FCs, and its detection in nonlesional thyroid tissue suggests limited usefulness as a diagnostic marker for follicular-patterned lesions in general.
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Adenocarcinoma Folicular/metabolismo , Adenoma/metabolismo , Carcinoma Papilar/metabolismo , Técnicas para Inmunoenzimas/métodos , Receptores Citoplasmáticos y Nucleares/metabolismo , Neoplasias de la Tiroides/metabolismo , Factores de Transcripción/metabolismo , Adenocarcinoma Folicular/química , Adenocarcinoma Folicular/patología , Adenoma/química , Adenoma/patología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Carcinoma Papilar/química , Carcinoma Papilar/patología , Núcleo Celular/química , Núcleo Celular/metabolismo , Núcleo Celular/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Citoplasmáticos y Nucleares/análisis , Sensibilidad y Especificidad , Neoplasias de la Tiroides/química , Neoplasias de la Tiroides/patología , Factores de Transcripción/análisisRESUMEN
OBJECTIVES/HYPOTHESIS: Lipomas of the retropharyngeal space are rare and do not cause symptoms until they reach a large size. Although retropharyngeal lipoma is an uncommon entity, several reports of it appear in the literature, and the treatment has routinely been surgical excision. Such fatty tumors also carry the rare possibility of being liposarcomas, which further warrants their excision. We present the case of a lipoma of the retropharyngeal space extending from the nasopharynx to the superior mediastinum causing symptoms of obstructive sleep apnea. The patient had multiple medical problems and was on a regimen of anticoagulation therapy; therefore, he opted against surgical treatment. He has used continuous positive airway pressure and has been followed clinically and radiographically for 5 years. Radiographic follow-up of a retropharyngeal lipoma after a needle biopsy confirming its benign nature is a legitimate means of management of this rare condition. STUDY DESIGN: Case report of a 64-year-old man presenting with this rare lesion. METHODS: Computed tomography-guided needle biopsy of the mass was performed to obtain tissue diagnosis. Thereafter, the patient has been followed for 5 years with annual magnetic resonance imaging scans to determine growth or changes of the retropharyngeal mass. RESULTS: Fine-needle aspiration of the mass revealed mature adipose tissue intermixed with fibroconnective tissue, consistent with lipoma. Based on this result, we opted to follow this patient with serial magnetic resonance imaging scans, which have shown no change in size. There has also been no change in the patient's symptoms. CONCLUSIONS: Large lipomas warrant excision, especially when their location produces pressure symptoms. However, when surgical morbidity is high, fine-needle aspiration biopsy and serial magnetic resonance imaging scans are a safe alternative.
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Lipoma/complicaciones , Neoplasias Faríngeas/complicaciones , Apnea Obstructiva del Sueño/etiología , Biopsia con Aguja , Humanos , Lipoma/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Faríngeas/patología , Tomografía Computarizada por Rayos XRESUMEN
Recombinant protein production in plants such as corn is a promising means to generate high product yields at low comparable production cost. The anti-EGFR monoclonal antibody C225, cetuximab, is a well-characterized receptor antagonist antibody recently approved for the treatment of refractory colorectal cancer. We initiated a study to test and compare the functional activity of glycosylated and aglycosylated C225 produced in stable transgenic corn seed. Both corn antibodies were shown to be functionally indistinguishable from mammalian-derived C225 in demonstrating high-affinity binding to the EGF receptor, blocking of ligand-dependent signaling, and inhibiting cell proliferation. In addition, consistent with cetuximab, both corn antibodies possessed strong anti-tumor activity in vivo. Acute dose primate pharmacokinetic studies, however, revealed a marked increase in clearance for the glycosylated corn antibody, while the aglycosylated antibody possessed in vivo kinetics similar to cetuximab. This experimentation established that corn-derived receptor blocking monoclonal antibodies possess comparable efficacy to mammalian cell culture-derived antibody, and offer a cost effective alternative to large-scale mammalian cell culture production.
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Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Zea mays/genética , Zea mays/inmunología , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Citotoxicidad Celular Dependiente de Anticuerpos , Antineoplásicos/farmacocinética , Cetuximab , Femenino , Humanos , Técnicas In Vitro , Cinética , Macaca fascicularis , Masculino , Ratones , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Plantas Modificadas Genéticamente , Unión Proteica , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/farmacología , Trasplante HeterólogoRESUMEN
Micropapillary carcinoma of the bladder is an extremely aggressive variant of urothelial carcinoma. Radical cystectomy is the standard treatment for all patients, including those with nonmuscle-invasive disease. We present a patient diagnosed with clinical Stage T1 micropapillary carcinoma of the bladder who was found to have a 2-cm metastasis to the head of the pancreas. To our knowledge, this case represents the first report of a solitary metastatic urothelial carcinoma to the pancreas.
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Carcinoma de Células Transicionales/secundario , Neoplasias Pancreáticas/secundario , Neoplasias de la Vejiga Urinaria/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/patología , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/cirugía , Carcinoma de Células Transicionales/ultraestructura , Terapia Combinada , Femenino , Hematuria/etiología , Humanos , Metástasis Linfática/ultraestructura , Estadificación de Neoplasias , Quiste Pancreático/etiología , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/ultraestructura , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Activating mutations in the epidermal growth factor receptor (EGFR) gene are extremely rare in small-cell lung cancer (SCLC). Here, we present a case of an EGFR-mutant gefitinib-responsive non-small-cell lung cancer (NSCLC) of adenocarcinoma histology occurring in a never-smoker followed by subsequent diagnosis of metastatic SCLC carrying an EGFR mutation. Although gefitinib therapy of the primary NSCLC resulted in disease control for over 3 years, the patient subsequently developed metastatic SCLC to the liver. Epidermal growth factor receptor mutation analysis revealed that the exon 21 L858R activating mutation was present in both the original lung adenocarcinoma and the metastatic SCLC. We hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the pathogenesis of SCLC in never-smokers, and the role of selection for an EGFR-mutant SCLC subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Quinazolinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/secundario , Receptores ErbB/antagonistas & inhibidores , Femenino , Gefitinib , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , MutaciónRESUMEN
BACKGROUND: Aberrant promoter methylation of selective tumor suppressor genes has been detected in squamous intraepithelial lesions (SIL) and invasive cervical cancer. Identification of methylation profiles of genes that can distinguish high-grade SIL (HSIL) from low-grade SIL (LSIL), and cytologically negative for intraepithelial lesion or malignancy (NILM) residual liquid-based Papanicolaou (Pap) tests may be potentially useful as an ancillary test for cervical cancer screening. METHODS: Using real-time quantitative methylation-specific polymerase chain reaction (PCR) (QMSP), the authors analyzed the frequency and relative level of promoter methylation for DAPK1, IGSF4, SPARC, and TFPI2 in biopsy-confirmed HSIL and LSIL, and NILM residual liquid-based Pap tests. The percentage of methylation (%M) for each gene was calculated using the reference gene, ACTB. The cumulative methylation score for each sample, defined as the sum of %M of all 4 genes, was used to analyze the genes in combination. RESULTS: For each gene analyzed the frequency and relative level of methylation were increased in HSIL compared with combined NILM/LSIL samples. The cumulative methylation scores were significantly higher in HSIL samples (P < .0001). Area under the receiver operating characteristic (ROC) curve (AUC) demonstrated that methylation of each gene could distinguish HSIL from NILM/LSIL samples (AUC range, 0.6-0.67; P < or = .0028). The combination of 4 genes showed improved test performance (AUC = 0.76; P < .0001). There was no significant difference in cumulative methylation in HSIL cases with histologic outcomes of cervical intraepithelial neoplasia grade 2 (CIN2) versus CIN3. There was no association between the methylation of any gene and the presence of human papillomavirus. CONCLUSIONS: The methylation profile of multiple genes in combination can better distinguish HSIL from combined NILM/LSIL samples. Although aberrant DNA methylation has the potential to function as a molecular biomarker of HSIL in liquid-based Pap tests, additional genes that are selectively methylated in HSIL are needed to improve the clinical performance.
Asunto(s)
Biomarcadores de Tumor/análisis , Metilación de ADN , Prueba de Papanicolaou , Reacción en Cadena de la Polimerasa/métodos , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal/métodos , Adulto , Femenino , Humanos , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Introduction of nonmicroscopic cervical screening techniques creates the potential for liquid-based cytology specimens to be sent for human papillomavirus (HPV) testing, automated screening, or other assays prior to microscopic quality assessment. It was hypothesized that the volumes required to prepare ThinPreps ("sip volumes") represent indicators of specimen quality. METHODS: A stratified random sample of 505 enrollment ThinPreps were assessed in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) to evaluate associations between sip volume and slide cellularity, cellular distribution, and clinical outcomes. Masked assessments included counting cells and qualitative evaluations. RESULTS: Sip volumes were highest among women aged 18-19 or > or =35 years (P = .01), higher during the secretory menstrual phase (P < .0001), and lower among women with a history of Chlamydia infection (P = .04). Low cellularity was associated with Atypical squamous cells-cannot exclude high-grade squamous intra-epithelial lesion (ASC-H) interpretations at the clinical centers (P = .04). Sip volumes were related to cellularity (P < .0001) and cellular distribution (P < .0001). Sip volumes < or =2.0 mL were associated with lower cellularity and both low and high sip volumes yielded less homogeneous cell deposition. However, sip volume was unrelated to the overall performance of cytology and HPV testing. CONCLUSIONS: Extremely low sip volumes are associated with hypocellular ThinPreps, and very low and high sip volumes more often show uneven cellular distribution. Although results of cytology and HPV testing in ALTS were generally unrelated to sip volume, results with other protocols or assays may vary, suggesting that microscopic assessment of specimens with extreme sip volumes prior to nonmicroscopic testing may be useful.
Asunto(s)
Técnicas Citológicas/métodos , Neoplasias de Células Escamosas/diagnóstico , Displasia del Cuello del Útero/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal/métodos , Adolescente , Adulto , Colposcopía , Citodiagnóstico , Femenino , Humanos , Frotis Vaginal/normasRESUMEN
p16(INK4a) is a major tumor-suppressor protein, but its regulation and settings of fuction remain poorly understood. To explore the notion that p16 is induced in vivo in response to replicative stress, we examined p16 expression in tissues from human ulcerative colitis (UC; n = 25) and normal controls (n = 20). p16 was expressed strongly in UC-associated neoplasms (n = 17), as seen previously in sporadic colonic neoplasms. In non-neoplastic UC epithelium, p16 was expressed in 33% of crypts (the proliferative compartment) compared to < 1% of normal controls. p16 expression did not correlate with degree of inflammation but did correlate with the degree of crypt architecture distortion (P = .002)-a reflection of epithelial regeneration. In coimmunofluorescence studies with Ki67, p16 expression was associated with cell cycle arrest (P < .001). Both UC and normal crypts displayed evidence for the activation of the DNA damage checkpoint pathway, and p16 was induced in primary cultures of normal epithelial cells by ionizing irradiation (IR). However, induction by IR displayed delayed kinetics, implying that p16 is not an immediate target of the checkpoint pathway. These findings support a model in which p16 is induced as an "emergency brake" in cells experiencing sustained replicative stress.