RESUMEN

BACKGROUNDS/AIMS: Metastatic lesions of the pancreas (PMET) account for 1%-5% of all malignant solid pancreatic lesions (SPL). In this study we evaluated the utility of endoscopic ultrasonography with fine needle aspiration (EUS-FNA) in diagnosing PMET. METHODS: Patients who underwent EUS-FNA at a community referral center between 2011-2017 for SPL were identified. Clinical, radiologic, and EUS-FNA features of those with PMET were compared to those with primary solid tumors of the pancreas: pancreatic adenocarcinoma (PDAC) and neuroendocrine tumors (PNET). RESULTS: A total of 191 patients were diagnosed with solid pancreatic malignancy using EUS-FNA: 156 PDAC, 27 PNET, and eight (4.2%) had PMET. Patients with PMET were less likely to have abdominal pain (25.0% vs. 76.3% vs. 48.2%; p < 0.01) or obstructive jaundice (37.5% vs. 58.3% vs. 0%; p < 0.01) compared to PDAC and PNET. Those with PMET were more likely to have mass lesions with/without biliary or pancreatic ductal dilatations (100% vs. 86.5% vs. 85.2%; p < 0.01) and lower CA19-9 (82.5 ± 43.21 U/mL vs. 4,639.30 ± 11,489.68 U/mL vs. 10.50 ± 10.89 U/mL; p < 0.01) compared to PDAC and PNET. Endosonographic features were similar among all groups. Seven (87.5%) patients with PMET had a personal history of malignancy prior to PMET diagnosis. The primary malignancy was renal cell carcinoma in five PMET. CONCLUSIONS: PMET are exceedingly rare, comprising less than 5% of SLP. Patients with PMET are less likely to present with symptoms and mostly identified by surveillance imaging for the primary malignancy.

RESUMEN

Adenoid cystic carcinoma (ACC) is a malignancy that typically arises in the salivary gland, yet can occur in other anatomic sites, including the lung. Primary pulmonary ACC is rare and comprises approximately 0.04-0.2 percent of all lung cancers. These tumors have the potential to recur and metastasize and are refractory to chemotherapy and radiation. Though histopathologic features are identical to ACC seen in the salivary glands on tissue biopsy, diagnosis on cytology specimens is challenging, as cytopathologic features of this entity have not been collectively described due to its low incidence and limited reports of the disease. We report a case of primary pulmonary ACC in a 43-year-old female that was missed on cytology, but was recognized on subsequent transbronchial biopsy. The biopsy revealed a neoplasm with cribriform architecture composed of round myoepithelial cells with inconspicuous nucleoli (see Figures 3 and 4). When correlating with the cytology specimen, the rare clusters of monomorphic, round cells with hyperchromatic nuclei, small nucleoli, and increased nuclear to cytoplasmic ratio (see Figures 1 and 2) were supportive of ACC, based on findings described from other reported cases. A small amount of homogenous, eosinophilic hyaline material was also associated with the neoplastic cells (see arrows in Figure 1). This case emphasizes the need to continue documenting cases of primary pulmonary ACC to expand the medical literature and increase awareness of this rare neoplasm in order to allow for accurate identification in cytologic specimens, especially when tissue biopsy is not obtained.

Asunto(s)

Carcinoma Adenoide Quístico , Neoplasias Pulmonares , Adulto , Biopsia , Carcinoma Adenoide Quístico/diagnóstico , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Recurrencia Local de Neoplasia

RESUMEN

Background: Adenocarcinoma is the most prevalent type of non-small cell carcinoma of the lungs. Patients with lung adenocarcinoma often present with cough, dyspnea, pain, and weight loss. They can also present with signs and symptoms of brain metastasis because the lungs are one of the most common origins of metastatic brain cancer. We describe a rare case of adenocarcinoma of the lungs presenting with pineal region metastasis. Case Report: A 61-year-old male presented to the emergency department with dizzy spells and gait disturbance. Magnetic resonance imaging of the brain demonstrated a solitary mass in the pineal region with marked obstructive hydrocephalus. A stereotactic biopsy was performed, and metastatic adenocarcinoma consistent with pulmonary origin was diagnosed. Computed tomography scan of the chest revealed a spiculated mass. The patient died shortly after the diagnosis was made. Conclusion: The pineal region is an unusual site for brain metastasis. Although such metastasis has rarely been described, it should be considered in the differential diagnosis of pineal region tumors, especially for patients with suggestive clinical or histopathologic features of primary malignancy elsewhere.

RESUMEN

BACKGROUND: The mainstay for the definitive diagnosis of pancreatic lesions is endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). However, there is evidence that EUS-FNA has low sensitivity in the setting of chronic pancreatitis (CP). This single-center retrospective study aimed to compare and analyze the diagnostic yield of EUS-FNA for solid pancreatic lesions in the presence and absence of CP, and to further investigate strategies for overcoming the low diagnostic yield in the setting of CP. METHODS: This study identified patients who underwent EUS-FNA at Sanford USD Medical Center (SD, USA) for a solid pancreatic lesion between July 15, 2011, and November 30, 2017. Data on demographics, clinical features, cross-sectional imaging findings, EUS findings, cytology/pathology, and clinical follow up were collected. RESULTS: The final diagnosis was adenocarcinoma in 156 patients (67%), neuroendocrine tumor in 27 (12%), lymphoma in 6 (3%), metastatic malignancy in 8 (4%), and benign etiologies in 35 (15%). CP was identified in 44/234 (19%) patients. The overall diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for EUS-FNA were 92.9%, 97.1%, 99.5%, 70.8%, and 93.5%, respectively. The sensitivity (80% vs. 95%, P=0.020) and accuracy (86% vs. 95%, P=0.043) were significantly lower in patients with CP compared to those without CP. CONCLUSION: CP can significantly affect the EUS-FNA diagnostic yield of solid pancreatic neoplasms. A high index of clinical suspicion is required in these cases to make a definitive diagnosis.

RESUMEN

Insulinomas are rare neuroendocrine tumors that produce excessive insulin and result in hypoglycemia. It can have a wide spectrum of symptoms and presentations which makes it difficult to diagnose at times. Here we present a 39-year-old woman who presented with intermittent diplopia, confusion, and staring episodes for one month. She had previously been seen by a neurologist who diagnosed her with possible absence seizures. However, evaluation showed that that patient had severe hypoglycaemia even with dextrose infusions. She was diagnosed with insulinoma based on lab work and a biopsy of a pancreatic tail mass. She underwent partial pancreatectomy, and has had a good outcome, with no recurrence of her symptoms. This case highlights the variable presentation of insulinomas, and the challenges faced with its diagnosis.

Asunto(s)

Insulinoma , Neoplasias Pancreáticas , Convulsiones , Adulto , Femenino , Humanos , Insulinoma/complicaciones , Insulinoma/diagnóstico , Insulinoma/cirugía , Recurrencia Local de Neoplasia , Pancreatectomía , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Convulsiones/etiología

RESUMEN

Urinary bladder cancer (UBC) is largely caused by exposure to toxic chemicals including those in cigarette smoke (i.e. BBN). An activating SNP in RGS6 is associated with a pronounced reduction in UBC risk, especially among smokers. However, the mechanism underlying this reduction remains unknown. Here we demonstrate that RGS6 is robustly expressed in human urothelium, where urothelial cell carcinoma originates, and is downregulated in human UBC. Utilizing RGS6-/- mice we interrogated a possible role for RGS6 as a tumor suppressor using the BBN-induced bladder carcinogenesis model that closely recapitulates human disease. As in humans, RGS6 is robustly expressed in mouse urothelium. RGS6 loss dramatically accelerates BBN-induced bladder carcinogenesis, with RGS6-/- mice consistently displaying more advanced pathological lesions than RGS6+/+ mice. Furthermore, BBN treatment promotes urothelial RGS6 mRNA and protein downregulation. RGS6 loss impairs p53 activation and promotes aberrant accumulation of oncogenic protein DNMT1 in urothelium. Tumor suppressor RASSF1A, a DNMT1-regulated gene, is also silenced, likely via methylation of its promoter during BBN exposure. We hypothesize that this BBN-induced RGS6 loss represents a critical hit in UBC as it irrevocably impairs the anti-proliferative actions of the ATM/p53 and RASSF1A pathways. Consistent with these findings, RGS6-/- mice treated with CP-31398, a p53-stablizing agent, and/or 5-Aza, a DNMT1 inhibitor, are protected from BBN-induced tumorigenesis. Together, our data identify RGS6 as a master tumor suppressor modulating two critical signaling pathways that are often dysregulated in UBC; therefore, RGS6 represents a potential novel biomarker for UBC diagnosis/prognosis and an appealing new target in its treatment.

Asunto(s)

ADN (Citosina-5-)-Metiltransferasa 1/genética , Proteínas RGS/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Vejiga Urinaria/genética , Animales , Butilhidroxibutilnitrosamina/toxicidad , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas RGS/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/metabolismo , Urotelio/efectos de los fármacos , Urotelio/metabolismo

RESUMEN

BACKGROUND: The outcome of surgically resected, apparently localized, clear cell renal carcinoma (ccRCC) is uncertain. OBJECTIVE: To evaluate if cell cycle progression (CCP) gene expression can predict future metastasis. METHODS: Pathologic T2a-T3b tumors at University of Iowa were reviewed. Patients with known or suspected metastasis, lymph node involvement or who received neoadjuvant or adjuvant radiation, chemotherapy or immunotherapy were excluded. Case and control cohorts were defined as those who did or did not develop metastatic disease within 5 years. Measured levels of 31 cell cycle genes and 15 control genes from the tumor were calculated as a CCP score. Additionally, gene expression data for a separate ccRCC cohort was downloaded from The Cancer Genome Atlas (TCGA). RESULTS: Univariate analysis of 26 cases and 38 controls revealed that the CCP score predicted progression to metastasis (OR 2.65, p = 0.0091). In multivariate logistic regression modeling, CCP expression remained a significant independent predictor for progression (p = 0.026). The CCP score was also significantly associated with distant metastasis in the TCGA renal cancer cohort in both univariate (p = 1.0 × 10-9) and multivariate (p = 5.6 × 10-3) analysis. CONCLUSION: The CCP score has prognostic value in predicting metastatic progression after resection of organ-confined ccRCC.

Asunto(s)

Biomarcadores de Tumor/genética , Carcinoma de Células Renales/secundario , Proteínas de Ciclo Celular/genética , Ciclo Celular/genética , Neoplasias Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/cirugía , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos

RESUMEN

Metaplastic breast cancer is a rare malignancy in the breast. Neurofibromatosis Type 1 is an autosomal dominant multisystem disorder associated with multiple neoplasms such as optic gliomas and peripheral nerve sheath tumors. The association of breast cancer with neurofibromatosis is very rare. We present a case of a metaplastic breast cancer in a patient with Type 1 neurofibromatosis. The patient presented with a palpable mass in her left breast with suspicious findings on mammogram and ultrasound. Ultrasound-guided percutaneous biopsy showed metaplastic breast carcinoma with metastasis to an axillary lymph node. This is the third case report in the English literature to show metaplastic breast carcinoma in a patient with Type 1 neurofibromatosis. In this report we review recent literature and discuss the association between these two entities.

RESUMEN

It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFß substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFßR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFß-SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal-luminal cross-talk in normal mammary tissue.

Asunto(s)

Neoplasias de la Mama/metabolismo , Proliferación Celular , Neoplasias Pulmonares/metabolismo , Células Madre Neoplásicas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Wnt/fisiología , Animales , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Ratones Endogámicos C57BL , Comunicación Paracrina , Proteína Smad2/metabolismo , Transcriptoma , Factor de Crecimiento Transformador beta/fisiología , Proteína Wnt-5a

RESUMEN

Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

Asunto(s)

Proliferación Celular , Fase G1 , Tumores Neuroendocrinos/patología , Proteínas Oncogénicas/fisiología , Neoplasias Pancreáticas/patología , Proteína de Retinoblastoma/fisiología , Fase S , Proteínas de Unión al GTP rab/fisiología , Línea Celular Tumoral , Humanos , Mitosis

Asunto(s)

Angiolipoma/patología , Neoplasias de la Mama/patología , Personas Transgénero , Angiolipoma/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Ultrasonografía

RESUMEN

PURPOSE: Recent findings suggest that combination treatment with antiestrogen and anti-RET may offer a novel treatment strategy in a subset of patients with breast cancer. We investigated the role of RET in potentiating the effects of antiestrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect extracellular signal-regulated kinase 1/2 (ERK1/2) activation in primary breast cancer. EXPERIMENTAL DESIGN: Growth response, ERK1/2 activation, Ki-67, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. RESULTS: Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (P = 0.01) and hormone insensitive (P < 0.001) estrogen receptor α (ERα)-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (P < 0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared with single agent (P = 0.003), with tamoxifen-reducing proliferative index and vandetanib-inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (P < 0.001) in RET-positive tumors versus 14% (P = ns) in RET-negative tumors. CONCLUSIONS: Vandetanib potentiated the antigrowth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of antiestrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Moduladores de los Receptores de Estrógeno/farmacología , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Quinazolinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Moduladores de los Receptores de Estrógeno/administración & dosificación , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Ratones Desnudos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Piperidinas/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Quinazolinas/administración & dosificación , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tamoxifeno/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

OBJECTIVE: We investigated directed therapy based on TFAP2C-regulated pathways to inform new therapeutic approaches for treatment of luminal breast cancer. BACKGROUND: TFAP2C regulates the expression of genes characterizing the luminal phenotype including ESR1 and RET, but pathway cross talk and potential for distinct elements have not been characterized. METHODS: Activation of extracellular signal-regulated kinases (ERK) and AKT was assessed using phosphorylation-specific Western blot. Cell proliferation was measured with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after siRNA (small interfering RNA) gene knockdown or drug treatment. Cell cycle, Ki-67, and cleaved caspase 3 were measured by fluorescence-activated cell sorting. Tumorigenesis was assessed in mice xenografts. RESULTS: Knockdown of TFAP2C or RET inhibited GDNF (glial cell line-derived neurotrophic factor)-mediated activation of ERK and AKT in MCF-7 cells. Similarly, sunitinib, a small-molecule inhibitor of RET, blocked GDNF-mediated activation of ERK and AKT. Inhibition of RET either by gene knockdown or by treatment with sunitinib or vandetanib reduced RET-dependent growth of luminal breast cancer cells. Interestingly, knockdown of TFAP2C, which controls both ER (estrogen receptor) and RET, demonstrated a greater effect on cell growth than either RET or ER alone. Parallel experiments using treatment with tamoxifen and sunitinib confirmed the increased effectiveness of dual inhibition of the ER and RET pathways in regulating cell growth. Whereas targeting the ER pathway altered cell proliferation, as measured by Ki-67 and S-phase, anti-RET primarily increased apoptosis, as demonstrated by cleaved caspase 3 and increased TUNEL (terminal deoxyneucleotidyl transferase dUTP nick end labeling) expression in xenografts. CONCLUSIONS: ER and RET primarily function through distinct pathways regulating proliferation and cell survival, respectively. The findings inform a therapeutic approach based on combination therapy with antiestrogen and anti-RET in luminal breast cancer.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-ret/metabolismo , Factor de Transcripción AP-2/metabolismo , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Indoles/administración & dosificación , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células MCF-7 , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Piperidinas/administración & dosificación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirroles/administración & dosificación , Quinazolinas/administración & dosificación , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Sunitinib , Tamoxifeno/administración & dosificación

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy.

RESUMEN

OBJECTIVES/HYPOTHESIS: The purposes of this preclinical study were to investigate histologic and rheologic outcomes of Microendoscopy of Reinke's space (MERS)-guided minithyrotomy and to assess its instrumentation. STUDY DESIGN: Human cadaveric and in vivo animal study. METHODS: Three human cadaveric larynges were treated with MERS-guided placement of Radiesse VoiceGel and immediately evaluated histologically for biomaterial location. In the second part of this investigation, two scarred porcine larynges were treated with MERS-guided placement of HyStem-VF and rheologically evaluated 6 weeks later. Student t tests determined differences in viscoelastic properties of treated/untreated vocal folds. Sialendoscopes and microendoscopes were subjectively compared for their visualization capacity. RESULTS: MERS imaged the subepithelial area and vocal ligament, guiding both tissue dissection and biomaterial positioning. Sialendoscopes provided adequate visualization and feature incorporated working channels. Enhanced image clarity was created in a gas-filled rather than saline-filled environment, per rater judgment. Histological analysis revealed desirable biomaterial positioning with MERS. Per rheological analysis, viscoelastic properties of the MERS-treated porcine vocal folds compared to uninjured vocal folds 6 weeks following treatment did not statistically differ. CONCLUSIONS: MERS-guided laryngoplasty using sialendoscopes yielded satisfactory biomaterial positioning in the short-term and normalized rheologic tissue properties in the long-term, contributing to proof of concept for MERS in the treatment of scarring. Strengths of MERS include direct, real-time visualization of Reinke's space and an ability to manipulate surgical instruments parallel to the vocal fold edge while maintaining an intact epithelium. Future work will explore the clinical utility of MERS for addressing scarring, sulcus vocalis, and other intracordal processes.

Asunto(s)

Mucosa Laríngea/cirugía , Laringoscopía/métodos , Pliegues Vocales/cirugía , Animales , Materiales Biocompatibles/administración & dosificación , Cadáver , Cicatriz/patología , Cicatriz/cirugía , Femenino , Humanos , Microdisección , Reología , Porcinos , Pliegues Vocales/patología

RESUMEN

BACKGROUND: In luminal breast cancer cell lines, TFAP2C regulates expression of key genes in the estrogen receptor-associated cluster and represses basal-associated genes including CD44. We examined the effect of TFAP2C overexpression in a basal cell line and characterized the expression of TFAP2C and CD44 in breast cancer specimens to determine if expression was associated with clinical response. METHODS: MDA-MB-231 breast cancer cells were treated with a TFAP2C-containing plasmid and evaluated for effects on CD44 expression. Pretreatment biopsy cores from patients receiving neoadjuvant chemotherapy for breast cancer were evaluated for TFAP2A, p53, TFAP2C, and CD44 expression by immunohistochemistry. RESULTS: Overexpression of TFAP2C in MDA-MB-231 cells resulted in decreased expression of CD44 mRNA and protein, P < 0.05. A pathologic complete response (pCR) following neoadjuvant chemotherapy was achieved in 17% of patients (4/23). Average expression for TFAP2C by immunohistochemistry in patients with a pCR was 93%, compared with 46% in patients with residual disease, P = 0.016; and in tumors that stained at ≥80% for TFAP2C, 4 of 9 (44%) achieved pCR, compared with 0 of 14 below 80%, P = 0.01. Additionally, in tumors that stained ≤80% for CD44, 4 of 10 (40%) achieved pCR, compared with 0 of 13 >80%, P = 0.02. In tumors that stained high for TFAP2C (≥80%) and low for CD44 (≤80%), 4 of 7 (57%) achieved pCR, compared with 0 of 16 in all other groups (P = 0.004). CONCLUSIONS: TFAP2C repressed CD44 expression in basal-derived breast cancer. In primary breast cancer specimens, high TFAP2C and low CD44 expression were associated with pCR after neoadjuvant chemotherapy and could be predictive of tumors that have improved response to neoadjuvant chemotherapy.

Asunto(s)

Neoplasias de la Mama , Carcinoma Ductal de Mama , Receptores de Hialuranos/genética , Terapia Neoadyuvante/métodos , Factor de Transcripción AP-2/genética , Adulto , Antineoplásicos/uso terapéutico , Biopsia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes erbB-2/genética , Humanos , Receptores de Hialuranos/metabolismo , Células MCF-7 , Persona de Mediana Edad , Regiones Promotoras Genéticas/fisiología , Factor de Transcripción AP-2/metabolismo , Células Tumorales Cultivadas

RESUMEN

Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6(-/-) mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6(-/-) mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6(-/-) animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6(-/-) mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6(-/-) mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6(-/-) but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors.

Asunto(s)

Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/patología , Proteínas RGS/genética , 9,10-Dimetil-1,2-benzantraceno/farmacología , Animales , Apoptosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Neoplasias de la Mama/metabolismo , Carcinogénesis/metabolismo , Línea Celular Tumoral , Daño del ADN/genética , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Proteínas RGS/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

MicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.

Asunto(s)

Neoplasias de la Mama/patología , MicroARNs/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Animales , Neoplasias de la Mama/genética , Procesos de Crecimiento Celular/genética , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Trasplante de Neoplasias , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Transducción de Señal/genética , Transgenes/genética

RESUMEN

Here we report that miR-93, a miRNA in the miR-106B~25 cluster, a paralog of the miR-17-92 cluster, was significantly upregulated in human breast carcinoma tissues. We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells. Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells. Lung metastasis assays were performed in a mouse metastatic model, and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue. In cell culture, expression of miR-93 enhanced cell survival and invasion. We examined the potential target that mediated miR-93's effects and found that the large tumor suppressor, homology 2 (LATS2) was a target of miR-93. Higher levels of LATS2 were associated with cell death in the tumor mass. Silencing LATS2 expression promoted cell survival, tube formation and invasion, while ectopic expression of LATS2 decreased cell survival and invasion. These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression. Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis.

Asunto(s)

Neoplasias de la Mama/metabolismo , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Secuencia de Bases , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/patología , Línea Celular , Movimiento Celular , Supervivencia Celular , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Ratones SCID , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Trasplante Heterólogo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética

RESUMEN

A patient presented with flu-like symptoms and a warm, tender area in the left axilla after working with an ancient piece of Cyprus wood. Antibiotics prescribed failed to improve symptoms. Followup physical examination and subsequent ultrasound found suspicious left-breast mass and an enlarged lymph node in the left axilla. Biopsy and lumpectomy of the left-breast mass revealed invasive ductal carcinoma. Biopsy and excision of the enlarged lymph node in the left axilla revealed necrotizing granulomatous inflammation without evidence of metastatic breast carcinoma. To our knowledge, this is the first case report to show the coexistence of breast cancer with necrotizing granulomatous inflammation in the ipsilateral axillary lymph node, likely due to exposure to ancient wood.