RESUMEN
BACKGROUND: Gallbladder adenocarcinoma is often incidentally identified following cholecystectomy. We hypothesized that intraoperative bile spillage would be a negative prognostic factor. METHODS: A retrospective review of patients treated at a cancer center with histologically confirmed gallbladder adenocarcinoma, 2009-2017, was performed. Patient, disease, and treatment factors were analyzed in terms of progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-six patients were identified. Tumor stage was T1 (n = 8, 12%), T2 (n = 23, 35%), T3 (n = 35, 53%). Node stage was N0 (n = 22, 33%), N1+ (n = 26, 39%), Nx (n = 18, 27%). Operations included cholecystectomy alone (n = 27, 36%), cholecystectomy and partial hepatectomy (n = 30, 45%), or hepaticojejunostomy (n = 9, 14%). Median PFS was 7 months (interquartile range [IQR], 2-19); median OS was 16 months (IQR, 10-31). Subset multivariate proportional hazards regression of 41 patients who underwent initial cholecystectomy showed decreased PFS was associated with intraoperative spillage (n = 12, 29%; hazard ratio [HR], 5.5; P = .0014); decreased OS was associated with drain placement (n = 21, 51%; HR, 8.1; P = .006). CONCLUSIONS: Intraoperative bile spillage and surgical drain placement at initial cholecystectomy are negatively associated with PFS and OS in gallbladder adenocarcinoma. Explicit documentation of spillage and drain placement rationale is critical, possibly indicating locally advanced disease and prompting stronger consideration of systemic therapy before definitive resection.
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Adenocarcinoma/mortalidad , Bilis , Colecistectomía/mortalidad , Neoplasias de la Vesícula Biliar/mortalidad , Vesícula Biliar/lesiones , Complicaciones Intraoperatorias/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Femenino , Estudios de Seguimiento , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND AND OBJECTIVES: Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients. METHODS: We reviewed the National Cancer Database (2004-2014) for patients who underwent surgical resection of PLS. RESULTS: Of 237 patients identified, the majority were female (60.8%), with median age of 52 years. Histologies were: epithelioid hemangioendothelioma (n = 67), angiosarcoma (n = 64), leiomyosarcoma (n = 33), embryonal rhabdomyosarcoma (n = 31), carcinosarcoma (n = 16), giant cell sarcoma (n = 14), spindle cell sarcoma (n = 12). Ninety-seven (40.9%) patients underwent lobectomies or extended lobectomies, 41 patients (17.3%) underwent transplantation. Surgical margins were negative in 82.9%. Tumors were well differentiated in 11.3%. Histology type correlated with outcome with the best prognosis for epithelioid hemangioendothelioma (OS: not reached, similar for resection and transplantation) and the worst for angiosarcoma (OS:16.6 mo with resection; 6 mo with transplantation; P = 0.04). Resections with microscopically negative margins were associated with improved survival (58.7 vs 11.3 mo for positive margins; P < 0.001). Chemotherapy and radiation therapy were used in a minority of patients (32.9% and 4.3% respectively) with no improvement in outcomes. CONCLUSIONS: Both hepatic resection and liver transplantation can be associated with long term survival for selected primary liver sarcomas such as epitheliod hemangioendotheliomas. Histology type and the ability to resect the tumor with negative margins correlate with outcomes and the decision to operate should be carefully weighed for subtypes with particularly dismal prognosis such as angiosarcomas.
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Hemangioendotelioma Epitelioide/cirugía , Hemangiosarcoma/cirugía , Leiomiosarcoma/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/métodos , Sarcoma/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Hemangioendotelioma Epitelioide/patología , Hemangiosarcoma/patología , Humanos , Leiomiosarcoma/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sarcoma/patología , Tasa de Supervivencia , Adulto JovenRESUMEN
Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan-Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of PYCR1 mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both PYCR1 mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher PYCR1 mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For in vitro studies, inhibition of PYCR1 by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, PYCR1 might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Mitocondrias/genética , Pirrolina Carboxilato Reductasas/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Análisis por Conglomerados , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Mitocondrias/metabolismo , Clasificación del Tumor , Invasividad Neoplásica , Fenotipo , Pronóstico , Pirrolina Carboxilato Reductasas/metabolismo , Receptores de Estrógenos/metabolismo , delta-1-Pirrolina-5-Carboxilato ReductasaRESUMEN
Recent clinical evidence has demonstrated that microsatellite instability (MSI) or defective mismatch repair (MMR) and high tumor mutational load can predict response to the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab in metastatic colorectal cancer (mCRC). Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, contribute to an ultramutated but microsatellite stable (MSS) phenotype in colorectal tumors that is uniquely distinct from MSI tumors. This report presents the first case in the literature describing a clinical response to pembrolizumab in an 81-year-old man with treatment-refractory mCRC characterized by an MSS phenotype and POLE mutation identified on genomic profiling by next-generation sequencing. On tumor immunostaining, a large amount of CD8-positive tumor infiltrating lymphocytes (TILs) were present, with >90% of these expressing PD-1. More than 99% of PD-L1 expression was identified on nontumor cells in the tumor microenvironment that were close to the PD-1-positive CD8 TILs. mCRC tumors harboring POLE mutations represent a hypermutated phenotype that may predict response to anti-PD-1 therapy.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , ADN Polimerasa II/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adenocarcinoma/genética , Adenocarcinoma/patología , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/metabolismo , Biopsia , Linfocitos T CD8-positivos/metabolismo , Antígeno Carcinoembrionario/análisis , Colonoscopía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Repeticiones de Microsatélite/genética , Mutación , Recurrencia Local de Neoplasia , Proteínas de Unión a Poli-ADP-Ribosa , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Tomografía Computarizada por Rayos X , Microambiente TumoralRESUMEN
AIMS: Rare cases of B cell lymphomas do not express conventional B cell markers (CD20, CD79a and PAX5), and these types of lymphomas include anaplastic lymphoma kinase (ALK)-positive large B cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma and the solid variant of primary effusion lymphoma, extracavitary human herpesvirus 8 (HHV8)-positive large B cell lymphoma. Establishing accurate diagnoses of these B cell lymphomas can be challenging, and often requires a large panel of immunohistochemical stains, molecular assays and cytogenetic studies. B cell-specific transcription factors, Oct2 and Bob1, have been shown to be expressed consistently in most, if not all, B cell lymphomas, and therefore we investigated the utility of Oct2 and Bob1 immunohistochemistry in lineage determination of the aforementioned B cell lymphomas. METHODS AND RESULTS: We selected 34 cases of previously diagnosed B cell lymphomas with no or weak expression of CD20, CD79a and PAX5. Oct2 and Bob1 were positive in 74% (25 of 34) and 85% (29 of 34) of the cases, respectively. When we combined the results of these two immunostains, 94% (32 of 34) cases expressed at least one of these two markers. We also included 51 control cases of non-B cell neoplasms, and none of them expressed either Oct2 or Bob1. CONCLUSIONS: Oct2 and Bob1 are very reliable in determining B cell lineage in the absence of expression of other pan-B cell markers, and it should provide great diagnostic benefit to include them both in a panel of immunohistochemistry to assess undifferentiated malignant neoplasms.
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Biomarcadores de Tumor/análisis , Linfoma de Células B Grandes Difuso/diagnóstico , Proteínas de Transporte de Catión Orgánico/biosíntesis , Transactivadores/biosíntesis , Linaje de la Célula , Humanos , Proteínas de Transporte de Catión Orgánico/análisis , Transportador 2 de Cátion Orgánico , Sensibilidad y Especificidad , Transactivadores/análisisRESUMEN
Glypican-3 (GPC3) protein expression was determined by immunohistochemical analysis from 29 normal livers, 80 cirrhotic livers sample taken near hepatocellular carcinoma (HCC), and 87 cirrhotic livers without HCC. The levels for miR-657 and HCC-related gene mRNAs were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Also, a published microarray dataset was used for gene set enrichment analysis (GSEA) to investigate the relationship between GPC3- and HCC-related gene signatures. Kaplan-Meier analysis was used to evaluate the relationship between GPC3 and HCC recurrence. GPC3 protein expression was not detected in any of the 29 (0%) normal livers, but was detected in 32 of 87 (37%) cirrhotic livers without HCC, and 51 of 80 (64%) cirrhotic liver samples taken near HCC sites (P < 0.001). The GPC3-positive rate in cirrhotic livers of viral origin was 68% (27/40), which was significantly higher than for non-viral cirrhotic livers (11%, 5/47) (P < 0.001). Also, GPC3 expression positively correlated with mRNA expression of HCC-related genes in the qRT-PCR and GSEA evaluations. Furthermore, HCC recurrence in cirrhotic liver samples taken near HCC sites was significantly higher in the GPC3-positive group than the GPC3-negative group (Log-rank P = 0.02, HR = 3.26; 95% CI = 1.20-10.29). This study demonstrated that highly expression of GPC3 could enrich HCC-related genes' mRNA expression and positive associate with dysplasia in cirrhotic livers. Therefore, GPC3 may serve as a precancerous biomarker in cirrhotic livers.
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Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Glipicanos/biosíntesis , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Anciano , Carcinoma Hepatocelular/patología , Femenino , Glipicanos/genética , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/patología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Pronóstico , ARN Mensajero/genéticaAsunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Enteritis/inducido químicamente , Obstrucción Intestinal/inducido químicamente , Intestino Delgado/efectos de los fármacos , Biopsia , Neoplasias Colorrectales/patología , Tratamiento Conservador , Endoscopía Gastrointestinal , Enteritis/diagnóstico , Enteritis/terapia , Humanos , Obstrucción Intestinal/diagnóstico , Obstrucción Intestinal/terapia , Intestino Delgado/diagnóstico por imagen , Intestino Delgado/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: Ultrasound-guided core needle biopsy (UG-CNB) is a procedure that is often performed either after repeated inadequate or nondiagnostic ultrasound-guided fine-needle aspiration (UG-FNA) or in combination with UG-FNA in the evaluation of thyroid nodules. The purpose of this study was to compare the efficacy and safety of UG-CNB and UG-FNA for evaluating thyroid nodules. METHODS: This was a retrospective study of 350 consecutive patients who had thyroid nodules biopsied by UG-CNB or UG-FNA from January 2007 until November 2011 at our institution. Biopsy results were compared to the surgical specimen pathology reports for the 105 patients who subsequently underwent hemi- or total thyroidectomy in order to determine whether UG-CNB has advantages over UG-FNA for diagnosing thyroid malignancy and neoplasia. RESULTS: Out of 461 thyroid nodules biopsied from 350 patients, 365 (79%) involved UG-CNB and 96 (21%) involved UG-FNA. The UG-FNA biopsy group had a significantly higher rate of inadequate sampling than the UG-CNB group (P<.0001; Fisher's exact test). Out of 365 UG-CNB samples, 6 (2%) were deemed inadequate for histologic diagnosis, whereas 26 (27%) of the 96 UG-FNA samples were considered inadequate for cellularity. Comparison of biopsy results with the surgical specimen pathology reports revealed that the diagnostic accuracy of UG-CNB and UG-FNA for detecting malignancy was similar, at 89 and 94%, respectively (not significant by Fisher's exact test). However, the UG-CNB group had a higher detection rate for benign follicular lesions compared to the UG-FNA group (65% versus 48% for UG-FNA; P = .002). Although UG-FNA detected neoplasia with high sensitivity (100%), the specificity was poor (30%). Neither biopsy group had any significant immediate or delayed procedure-related complications. CONCLUSION: Our study demonstrated that UG-CNB is safe and is less likely to result in a nondiagnostic biopsy. The accuracy of the UG-CNB technique is similar to that of UG-FNA for detecting thyroid malignancy.
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Biopsia con Aguja Fina/métodos , Nódulo Tiroideo/patología , Ultrasonografía Intervencional , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Fina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Anticuerpos Monoclonales Humanizados , Endoscopía Gastrointestinal/métodos , Enterocolitis Seudomembranosa , Hepatitis B Crónica/complicaciones , Hepatitis C Crónica/complicaciones , Mucosa Intestinal , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/terapia , Coinfección , Enfermedad Hepática en Estado Terminal/etiología , Enfermedad Hepática en Estado Terminal/terapia , Enterocolitis Seudomembranosa/diagnóstico , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/etiología , Enterocolitis Seudomembranosa/fisiopatología , Glucocorticoides/administración & dosificación , Humanos , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P=0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.
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Carcinoma de Células de Merkel/virología , Linfoma/virología , Poliomavirus de Células de Merkel/genética , Neoplasias Primarias Desconocidas/virología , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Anciano , Anciano de 80 o más Años , Antígenos Virales de Tumores/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células de Merkel/metabolismo , Carcinoma de Células de Merkel/patología , ADN Nucleotidilexotransferasa/metabolismo , ADN Viral/genética , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Ganglios Linfáticos/patología , Metástasis Linfática , Linfoma/metabolismo , Linfoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/metabolismo , Neoplasias Primarias Desconocidas/patología , Factor de Transcripción PAX5/metabolismo , Reacción en Cadena de la Polimerasa , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/patologíaRESUMEN
UNLABELLED: Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Dysregulation of miR-657 has been observed in several types of cancers, but its biological function is still largely unknown. Our results showed that miR-657 expression can be induced by hepatitis viral proteins and is significantly increased in hepatocellular carcinoma (HCC) tissues. Moreover, introduction of miR-657 dramatically increases proliferation and colony formation of HCC cells in vitro and induces tumor development in immunodeficient mice. Further studies showed that miR-657 directly targets the transducin-like enhancer protein 1 (TLE1) 3' untranslated region (UTR) and activates nuclear factor kappa B (NF-κB) pathways that contribute to hepatocarcinogenesis. CONCLUSION: This study identified a mechanism whereby miRNA-657 contributed to HCC through novel cancer pathways and provides new insights into the potential molecular mechanisms of hepatic carcinogenesis.
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Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/metabolismo , Neoplasias Hepáticas/patología , MicroARNs/metabolismo , FN-kappa B/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal/fisiología , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Células Cultivadas , Proteínas Co-Represoras , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Técnicas In Vitro , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/genética , Transfección , Trasplante HeterólogoRESUMEN
BACKGROUND: Although breast cancer frequently metastasizes to the bones and brain, rarely breast cancer patients may develop isolated liver metastasis. There is increasing data that anti-HER2 targeted therapy in conjunction with systemic chemotherapy may lead to increased rates of pathologic complete response in the primary breast cancer. However, little is known about its effects on metastatic liver disease. CASE PRESENTATION: We report the treatment of a 54-year-old female who was diagnosed with HER2-positive invasive ductal carcinoma and synchronous breast cancer liver metastasis (BCLM). The patient underwent eight cycles of standard docetaxel with two anti-HER2 targeted agents, trastuzumab and pertuzumab. Subsequent radiographic imaging demonstrated complete radiographic response in the primary lesion with an approximate 75% decrease in the liver metastasis. After informed consent the patient underwent modified radical mastectomy that revealed pathologic complete response. Re-staging demonstrated no new disease outside the liver and a left hepatectomy was performed for resection of BCLM. Final pathologic examination revealed no residual malignant cells in the liver specimen, indicating pathologic complete response. Herein, we discuss the anti-HER2 targeted agents trastuzumab and pertuzumab and review the data on dual HER2 antagonism for HER2-positive breast cancer and the role of surgical resection of BCLM. CONCLUSIONS: The role of targeted agents for metastatic HER2-positive breast cancer is under active clinical trial investigation and we await the maturation of trial results and long-term survival data. Our results suggest that these agents may also be effective for producing considerable pathologic response in patients with BCLM.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Receptor ErbB-2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Persona de Mediana Edad , Terapia Molecular Dirigida , Receptor ErbB-2/antagonistas & inhibidores , TrastuzumabRESUMEN
BACKGROUND: Ribonucleotide reductase (RR) is an essential enzyme involved in DNA synthesis. We hypothesized that RR subunit M2 (RRM2) might be a novel prognostic and predictive biomarker for estrogen receptor (ER)-negative breast cancers. METHODS: Individual and pooled survival analyses were conducted on six independent large-scale breast cancer microarray data sets; and findings were validated on a human breast tissue set (ZJU set). RESULTS: Gene set enrichment analysis revealed that RRM2-high breast cancers were significantly enriched for expression of gene sets that increased in proliferation, invasiveness, undifferentiation, embryonic stem/progenitor-like phenotypes, and poor patient survival (p < 0.01). Independent and pooled analyses verified that increased RRM2 mRNA levels were associated with poor patient outcome in a dose-dependent manner. The prognostic power of RRM2 mRNA was comparable to multiple gene signatures, and it was superior to TNM stage. In ER-negative breast cancers, RRM2 showed more prognostic power than that in ER-positive breast cancers. Further analysis indicated that RRM2 was a more accurate prognostic biomarker for ER-negative breast cancers than the pathoclinical indicators and uPA. A new RR inhibitor, COH29, could significantly enhance the chemosensitivity to doxorubicin in ER-negative MDA-MB-231 cells, but not in ER-positive MCF-7 cells. CONCLUSION: RRM2 appears to be a promising prognostic biomarker and therapeutic target for ER-negative breast cancer patients.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Ribonucleósido Difosfato Reductasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Femenino , Humanos , Células MCF-7 , Persona de Mediana Edad , Pronóstico , Receptores de Estrógenos/metabolismo , Ribonucleósido Difosfato Reductasa/metabolismo , Análisis de Supervivencia , Adulto JovenRESUMEN
Axillary recurrence of breast cancer that involves the brachial neurovascular bundle is uncommon. However, for many patients with such recurrence, forequarter amputation can play a palliative role in relieving excruciating pain and paralysis of the upper limb. Further, for those patients who do not have distant metastasis or other local-regional recurrence, forequarter amputation provides a chance for a cure. Only a few case reports of curative amputations for recurrent breast cancer are present in the literature. Here, we report a case of forequarter amputation for curative treatment of axillary recurrent breast cancer, together with a literature review. To date, we have followed the patient for three years after amputation, during which there has been no evidence of recurrence or metastasis. Although radical resection is feasible, it can be accompanied by surgical wound complications and psychosocial stress. Therefore, an organized multidisciplinary approach is needed to ensure the success of radical resection.
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Amputación Quirúrgica/métodos , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Recurrencia Local de Neoplasia/cirugía , Axila , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , PronósticoRESUMEN
Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Anciano , Androstadienos/farmacología , Animales , Apoptosis/efectos de los fármacos , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Femenino , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Letrozol , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Nitrilos/farmacología , Panobinostat , Triazoles/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01-4.30] and 5.89 (95% CI, 1.51-39.13) in the COH and ZJU sets respectively. The Kaplan-Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03-3.36) and 2.06 (95% CI, 1.10-4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62-258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.
Asunto(s)
Neoplasias Colorrectales/mortalidad , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Adulto , Biomarcadores de Tumor/análisis , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Estimación de Kaplan-Meier , Metástasis de la Neoplasia/patología , Pronóstico , ARN Interferente Pequeño/farmacología , Estudios Retrospectivos , Ribonucleósido Difosfato Reductasa/biosíntesisRESUMEN
BACKGROUND: The standard treatment for locally advanced rectal cancer is preoperative chemoradiation and total mesorectal excision. After surgery, tumors are classified according to the depth of tumor invasion, nodal involvement, and tumor regression grade. However, these staging systems do not provide information about the distribution of residual cancer cells within the bowel wall. OBJECTIVE: This study aimed to determine the distribution of residual cancer cells in each layer of the bowel wall in rectal cancer specimens. DESIGN: This was a secondary analysis of data from a prospective phase II study. SETTING: This study was performed in a multi-institutional setting. PATIENTS: Included were 153 patients with stage II or stage III rectal cancer. INTERVENTIONS: Patients were treated with chemoradiation and surgery. The surgical specimen tumor tissue was analyzed, and the distribution of residual cancer cells in each layer of the bowel wall was determined. MAIN OUTCOME MEASURES: Statistical analysis was used to examine the correlation of residual cancer cells in each layer of the bowel wall with the clinical/pathologic stage and tumor regression grade. RESULTS: Forty-two of 153 (27%) patients had complete response in the bowel wall (ypT0). Of the remaining 111 patients who had residual cancer cells, 5 (3%) were ypTis, 12 (8%) were ypT1, 41 (27%) were ypT2, 50 (33%) were ypT3, and 3 (2%) were ypT4. Of the 94 patients with ypT2-4 tumors, 12 (13%) had cancer cells in the mucosa, and 53 (56%) had cancer cells in the submucosa; 92 (98%) had cancer cells in the muscularis propria. Pretreatment cT correlated with the distribution of residual cancer cells. Tumor regression grade was not associated with the distribution of residual cancer cells after chemoradiation. LIMITATIONS: : Patients received different chemotherapy regimens. CONCLUSIONS: Residual cancer cells in rectal cancer specimens after chemoradiation are preferentially located close to the invasive front. This should be considered when designing strategies to diagnose complete pathologic response and when investigating the mechanisms of tumor resistance to chemoradiation.
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Adenocarcinoma/patología , Mucosa Intestinal/metabolismo , Neoplasia Residual/metabolismo , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia Adyuvante , Femenino , Humanos , Inmunohistoquímica , Intestinos/citología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Dosificación Radioterapéutica , Neoplasias del Recto/metabolismoRESUMEN
Chronic graft-versus-host disease (cGVHD) is considered an autoimmune-like disease mediated by donor CD4(+) T cells, but the origin of the autoreactive T cells is still controversial. In this article, we report that the transplantation of DBA/2 donor spleen cells into thymectomized MHC-matched allogeneic BALB/c recipients induced autoimmune-like cGVHD, although not in control syngeneic DBA/2 recipients. The donor-type CD4(+) T cells from the former but not the latter recipients induced autoimmune-like manifestations in secondary allogeneic BALB/c as well as syngeneic DBA/2 recipients. Transfer of donor-type CD4(+) T cells from secondary DBA/2 recipients with disease into syngeneic donor-type or allogeneic host-type tertiary recipients propagated autoimmune-like manifestations in both. Furthermore, TCR spectratyping revealed that the clonal expansion of the autoreactive CD4(+) T cells in cGVHD recipients was initiated by an alloimmune response. Finally, hybridoma CD4(+) T clones derived from DBA/2 recipients with disease proliferated similarly in response to stimulation by syngeneic donor-type or allogeneic host-type dendritic cells. These results demonstrate that the autoimmune-like manifestations in cGVHD can be mediated by a population of donor CD4(+) T cells in transplants that simultaneously recognize Ags presented by both donor and host APCs.
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Autoantígenos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Enfermedad Injerto contra Huésped/inmunología , Antígenos H-2/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/patología , Autoanticuerpos/biosíntesis , Autoantígenos/administración & dosificación , Autoantígenos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/trasplante , Diferenciación Celular/genética , Enfermedad Crónica , Células Clonales , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Antígenos H-2/administración & dosificación , Antígenos H-2/genética , Antígeno de Histocompatibilidad H-2D , Antígenos de Histocompatibilidad Clase II/administración & dosificación , Antígenos de Histocompatibilidad Clase II/genética , Prueba de Histocompatibilidad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Modelos Animales , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/trasplanteRESUMEN
OBJECTIVE: To determine whether extending the interval between chemoradiation (CRT) and surgery, and administering additional chemotherapy during the waiting period has an impact on tumor response, CRT-related toxicity and surgical complications in patients with advanced rectal cancer. BACKGROUND: Locally advanced rectal cancer is usually treated with preoperative CRT followed by surgery approximately 6 weeks later. The Timing of Rectal Cancer Response to Chemoradiation Consortium designed a prospective, multicenter, Phase II clinical trial to investigate extending the interval between CRT and surgery, and administering additional chemotherapy during the waiting period. Here, we present preliminary results of this trial, reporting the tumor response, CRT-related toxicity and surgical complications. METHODS: Stage II and III rectal cancer patients were treated concurrently with 5-Fluorouracil (FU) and radiation for 5 to 6 weeks. Patients in study group (SG) 1 underwent total mesorectal excision (TME) 6 weeks later. Patients in SG2 with evidence of a clinical response 4 weeks after CRT received 2 cycles of modified FOLFOX-6 (mFOLFOX-6) followed by TME 3 to 5 weeks later. Tumor response, CRT-related toxicity and surgical complications were recorded. RESULTS: One hundred and forty-four patients were accrued. One hundred and thirty-six (66, SG1; 70, SG2) were evaluated for CRT-related toxicity. One hundred and twenty-seven (60, SG1; 67, SG2) were assessed for tumor response and surgical complications. A similar proportion of patients completed CRT per protocol in both SGs, but the cumulative dose of sensitizing 5-FU and radiation was higher in SG2. CRT-related toxicity was comparable between SGs. Average time from CRT-to-surgery was 6 (SG1) and 11 weeks (SG2). Pathologic complete response (pCR) was 18% (SG1) and 25% (SG2). Postoperative complications were similar between SGs. CONCLUSIONS: Intense neoadjuvant therapy consisting of CRT followed by additional chemotherapy (mFOLFOX-6), and delaying surgery may result in a modest increase in pCR rate without increasing complications in patients undergoing TME for locally advanced rectal cancer.
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Neoplasias del Recto/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Factores de TiempoRESUMEN
Primary effusion lymphoma (PEL) is associated with Kaposi sarcoma herpesvirus (KSHV) but its pathogenesis is poorly understood. Many KSHV-associated products can deregulate cellular pathways commonly targeted in cancer. However, KSHV infection alone is insufficient for malignant transformation. PEL also lacks the chromosomal translocations seen in other lymphoma subtypes. We investigated 28 PELs and ten PEL cell lines by 1 Mb resolution array comparative genomic hybridization (CGH) and found frequent gains of 1q21-41 (47%), 4q28.3-35 (29%), 7q (58%), 8q (63%), 11 (32%), 12 (61%), 17q (29%), 19p (34%), and 20q (34%), and losses of 4q (32%), 11q25 (29%), and 14q32 (63%). Recurrent focal amplification was seen at several regions on chromosomes 7, 8, and 12. High-resolution chromosome-specific tile-path array CGH confirmed these findings, and identified selectin-P ligand (SELPLG) and coronin-1C (CORO1C) as the targets of a cryptic amplification at 12q24.11. Interphase FISH and quantitative PCR showed SELPLG/CORO1C amplification (>4 extra copies) and low levels of copy number gain (1-4 extra copies) in 23% of PELs, respectively. Immunohistochemistry revealed strong expression of both SELPLG and coronin-1C in the majority of PELs, irrespective of their gene dosage. SELPLG is critical for cell migration and chemotaxis, while CORO1C regulates actin-dependent processes, thus important for cell motility. Their overexpression in PEL is expected to play an important role in its pathogenesis.