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Atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are markers for an increased risk of breast cancer, yet outcomes for these diagnoses are not well-documented. In this study, all breast biopsies performed for radiologic abnormalities over a 10-year period were reviewed. Patients with AH or LCIS were followed for an additional 10 years to assess subsequent rates of cancer diagnosis. Long-term follow-up showed that 25 (7.8%) patients with AH and 5 patients with LCIS (5.7%) developed breast cancer over the follow-up period, a lower rate of breast cancer development than predicted by risk models.
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Carcinoma de Mama in situ , Neoplasias de la Mama , Carcinoma in Situ , Carcinoma Lobular , Mama/patología , Carcinoma de Mama in situ/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Carcinoma in Situ/patología , Carcinoma Lobular/diagnóstico por imagen , Carcinoma Lobular/epidemiología , Carcinoma Lobular/patología , Femenino , Humanos , Hiperplasia/patología , Estudios LongitudinalesRESUMEN
Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare liver tumor which has a more aggressive behavior and worse survival outcome than hepatocellular carcinoma (HCC), with a prognosis similar to that of intrahepatic cholangiocarcinoma (iCCA). With limited literature on the appearance of this tumor on MRI, it remains a diagnostic challenge. In this review, we looked at the currently described MRI findings in this uncommon entity. Based on studies conducted to date, a mixed pattern at imaging has demonstrated the highest specificity, seen as a combination of areas showing progressive enhancement of the lesion, arterial enhancement with washout, and areas of arterial enhancement without washout and/or hypovascularity. Tumor markers may aid in identification, particularly in cases where the imaging appearance mimics that of isolated HCC or iCCA. Intratumoral heterogeneity leads to difficulties with pathologic diagnosis from sampling due to the possibility of an incorrect diagnosis if the biopsy specimen does not contain adequate tissue comprising both histologic components.
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ALK internal deletions of nonkinase domain exons occur in 0.01% of lung cancers with ALK genomic aberrations. We report a lung adenocarcinoma with a previously undescribed somatic ALK deletion of exons 2 to 19 with dramatic and sustained (>23 mo) response to alectinib. Our and other reported cases with ALK nonkinase domain deletions (between introns and exons 1-19) can display positive results in nonsequencing-based lung cancer diagnostic tests (such as immunohistochemistry) used to screen for more common ALK rearrangements. This case report emphasizes that "ALK-driven" lung cancers should be expanded to encompass those harboring not only ALK rearrangements with other genes but also ALK nonkinase domain deletions.
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OBJECTIVE: Emerging evidence suggests that protease-activated receptors-1 and -2 (PAR1 and PAR2) can signal together in response to proteases found in the rapidly changing microenvironment of damaged blood vessels. However, it is unknown whether PAR1 and PAR2 promote or mitigate the hyperplastic response to arterial injury. Using cell-penetrating PAR1 pepducins and mice deficient in PAR1 or PAR2, we set out to determine the respective contributions of the receptors to hyperplasia and phenotypic modulation of smooth muscle cells (SMCs) in response to arterial injury. METHODS AND RESULTS: SMCs were strongly activated by PAR1 stimulation, as evidenced by increased mitogenesis, mitochondrial activity, and calcium mobilization. The effects of chronic PAR1 stimulation following vascular injury were studied by performing carotid artery ligations in mice treated with the PAR1 agonist pepducin, P1pal-13. Histological analysis revealed that PAR1 stimulation caused striking hyperplasia, which was ablated in PAR1(-/-) and, surprisingly, PAR2(-/-) mice. P1pal-13 treatment yielded an expression pattern consistent with a dedifferentiated phenotype in carotid artery SMCs. Detection of PAR1-PAR2 complexes provided an explanation for the hyperplastic effects of the PAR1 agonist requiring the presence of both receptors. CONCLUSIONS: We conclude that PAR2 regulates the PAR1 hyperplastic response to arterial injury leading to stenosis.
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Neointima/patología , Neointima/fisiopatología , Receptor PAR-1/fisiología , Receptor PAR-2/fisiología , Animales , Arterias Carótidas/patología , Arterias Carótidas/fisiopatología , Proliferación Celular , Femenino , Hiperplasia/patología , Hiperplasia/fisiopatología , Ratones , Ratones Noqueados , Modelos Animales , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Fenotipo , Receptor PAR-1/deficiencia , Receptor PAR-1/genética , Receptor PAR-2/deficiencia , Receptor PAR-2/genéticaRESUMEN
The purpose of this study was to compare viable and nonviable bilabeled mesenchymal stem cells (MSCs) in arthritic joints with magnetic resonance imaging (MRI) and optical imaging (OI). MSCs were labeled with ferucarbotran and DiD. MRI and OI of bilabeled cells were compared with controls. Six rats with arthritis received intra-articular injections of bilabeled viable MSCs into the right knee and nonviable MSCs into the left knee. Animals underwent MRI and OI preinjection and at 4, 24, 48, and 72 hours postinjection. The results were analyzed with a mixed random effects model and Fisher probability. Bilabeled MSCs showed increased MRI and OI signals compared to unlabeled controls (p < .0001). After intra-articular injection, bilabeled MSCs caused significant T2 and T2* effect on MRI and fluorescence on OI up to 72 hours postinjection (p < .05). There was no significant difference between viable and nonviable MSC signal in the knee joints; however, some of the viable cells migrated to an adjacent inflamed ankle joint (p < .05). Immunohistochemistry confirmed viable MSCs in right knee and ankle joints and nonviable MSCs in the left knee. Viable and nonviable cells could not be differentiated with MRI or OI signal intensity but were differentiated based on their ability to migrate in vivo.
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Imagen por Resonancia Magnética/métodos , Células Madre Mesenquimatosas/citología , Animales , Apoptosis/efectos de los fármacos , Artritis/terapia , Femenino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/fisiología , Mitomicina/farmacología , RatasRESUMEN
Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, and MMP-1 that culminates in activation of PAR1, a G protein-coupled protease-activated receptor up-regulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation, and metastasis were effectively inhibited by i.p. administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer.
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Ascitis/enzimología , Metaloproteasas/antagonistas & inhibidores , Neovascularización Patológica/enzimología , Oligopéptidos/farmacología , Neoplasias Ováricas/patología , Receptor PAR-1/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Líquidos Corporales/enzimología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Progresión de la Enfermedad , Docetaxel , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Invasividad Neoplásica , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Peritoneo/enzimología , Peritoneo/patología , Taxoides/administración & dosificación , Taxoides/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Most patients with ovarian cancer are diagnosed late in progression and often experience tumor recurrence and relapses due to drug resistance. Surface expression of matrix metalloprotease (MMP)-14 on ovarian cancer cells stimulates a tumor-stromal signaling pathway that promotes angiogenesis and tumor growth. In a cohort of 92 patients, we found that MMP-14 was increased in the serum of women with malignant ovarian tumors. Therefore, we investigated the preclinical efficacy of a MMP-14 monoclonal antibody that could inhibit the migratory and invasive properties of aggressive ovarian cancer cells in vitro. MMP-14 antibody disrupted ovarian tumor-stromal communication and was equivalent to Avastin in suppressing blood vessel growth in mice harboring Matrigel plugs. These effects on angiogenesis correlated with downregulation of several important angiogenic factors. Furthermore, mice with ovarian cancer tumors treated with anti-MMP-14 monotherapy showed a marked and sustained regression in tumor growth with decreased angiogenesis compared with immunoglobulin G (IgG)-treated controls. In a model of advanced peritoneal ovarian cancer, MMP-14-dependent invasion and metastasis was effectively inhibited by intraperitoneal administration of monoclonal MMP-14 antibody. Together, these studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer.