RESUMEN
BACKGROUND: Pelvic soft tissue sarcomas are rare. Potentially curative resection remains challenging due to anatomical constraints of true pelvis and tumour spread through various anatomical hiatus. We sought to review the oncological outcomes of surgically managed cases at our centre and determine whether outcomes differ for patients with localised (limited to pelvis) versus extensive disease (with extra-pelvic extension). METHODS: Sixty-seven patients who underwent surgical resection with curative intent at the centre for primary, non-metastatic, WHO intermediate to high-grade soft tissue sarcoma of the true pelvis from January 2012 through January 2020 were analysed. Establishment of the extent of disease was made by review of pre-treatment imaging and surgical notes. Oncologic endpoints examined were resection margin, recurrence rate, disease-free and overall survival. RESULTS: Rates of complete oncological resection and disease control were similar for tumours with localised or extensive disease. On logistic regression analysis, tumour grade, and a negative resection margin (R0) correlated with the risk of recurrence (p=<0.05). On further multinomial analysis, R0 resection was associated with improved local control, but not metastatic relapse (p = 0.003). 5-year local recurrence-free and distant metastasis-free survival were 61.3% and 67.1%, respectively. Five and 10-year overall survival were 64% and 36%, respectively. Age >50 years and high tumour grade were associated with a worse outcome (p < 0.05). CONCLUSIONS: When potentially curative surgery is performed for pelvic sarcoma, disease-extent does not influence oncologic outcomes. While a complete oncologic resection determines the risk of local recurrence, tumour grade and metastatic relapse remain primary prognostic determinants for overall survival.
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Pelvis Menor , Sarcoma , Humanos , Persona de Mediana Edad , Pelvis Menor/patología , Márgenes de Escisión , Estudios Retrospectivos , Recurrencia Local de Neoplasia/cirugía , Sarcoma/patología , Pelvis/patología , BiologíaRESUMEN
Enterobius vermicularis infection is uncommon in adults, compared to children, and rarely causes significant illness. Adult infection is usually colonic in nature and found incidentally at colonoscopy. Worm migration to other tissues is rare. We here-in describe the case of a 73-year-old woman found to have biliary tree E. vermicularis-an as yet undescribed site of migration.
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Colitis Ulcerosa/complicaciones , Síndrome de Sweet/patología , Procedimientos Quirúrgicos Electivos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Síndrome de Sweet/tratamiento farmacológico , Síndrome de Sweet/etiología , Síndrome de Sweet/cirugía , Resultado del TratamientoRESUMEN
Soft tissue sarcomas are a group of heterogeneous neoplasms with more than 50 histological subtypes exhibiting major differences in terms of pathogenesis, genetic alterations and clinical behavior. Sarcomas represent approximately 1% of malignancies with retroperitoneal sarcomas representing 10-15% of all soft tissue sarcomas. Surgery is currently the only modality which offers the chance of cure. Surgery for retroperitoneal sarcomas presents specific challenges due their location in a complex space surrounded by vital structures and visceral organs often prohibiting resection with wide margins. Furthermore, even after complete resection local recurrence is common and the leading cause of death. In this article the authors describe the initial investigations, prognostic factors and optimal surgical management. The evidence and current research as regards the role of multimodality treatment is reviewed and discussed.
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Neoplasias Retroperitoneales/cirugía , Sarcoma/cirugía , Humanos , Pronóstico , Radiografía , Neoplasias Retroperitoneales/diagnóstico por imagen , Neoplasias Retroperitoneales/patología , Sarcoma/diagnóstico por imagen , Sarcoma/patologíaRESUMEN
BACKGROUND: In Africa surgical trainees (residents) are often 'at the coalface' in managing surgical emergencies. A practical course on management of surgical emergencies was developed, as requested and guided by the learning needs of surgical trainees in East/Central Africa, to teach structured thinking processes in surgical emergencies; to thoroughly assess participants' knowledge, technical and non-technical skills; and to correlate assessment scores with participants' feedback on course quality. METHODS: Curriculum design was aimed at learners' needs, as guided by local trainers and previous teaching. A 5-day course was developed on emergencies in critical care and trauma, general surgery, orthopaedics, obstetrics and urology; delivered through lectures, tutorials and practical sessions, with individual mentoring. Participants' knowledge was assessed through end-of-course tests and, with their practical and non-technical skills, evaluated formatively. Opportunity for immediate detailed feedback was provided, and for follow-up 6 months later. RESULTS: All participants completed the course successfully, passed knowledge tests, and received satisfactory scores in continuous assessment. There was good correlation between formative and summative assessment scores. Candidates rated course content, delivery and usefulness very highly; 'open text' noted no such previous training. After six months 90 % of course participants indicated that the course had significantly improved their ability to manage surgical emergencies. CONCLUSIONS: An intensive course on management of surgical emergencies can be effectively delivered by a small core faculty for each specialty. Feedback from participants and local faculty indicated that this course filled a specific learning niche. Effective assessment can be based on continuous evaluation during course participation.
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Cuidados Críticos , Curriculum , Internado y Residencia/métodos , Especialidades Quirúrgicas/educación , Procedimientos Quirúrgicos Operativos/educación , África Central , África Oriental , Competencia Clínica , Urgencias Médicas , Estudios de Seguimiento , Humanos , Proyectos Piloto , Desarrollo de Programa , Evaluación de Programas y Proyectos de SaludRESUMEN
BACKGROUND: Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status. METHODS: We studied 160 patients with CAD and 169 subjects without CAD. The 4-variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor® device. Circulating biomarkers were assessed in plasma using xMAP® multiplexing technology. RESULTS: Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (ß = -0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E-selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress. CONCLUSIONS: Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease.
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Enfermedad de la Arteria Coronaria/fisiopatología , Tasa de Filtración Glomerular/fisiología , Riñón/irrigación sanguínea , Riñón/fisiopatología , Rigidez Vascular/fisiología , Anciano , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Femenino , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Análisis de la Onda del Pulso/métodosRESUMEN
Human sarcomas are rare but diverse malignant tumors derived from mesenchymal tissue. Clinical response to therapy is currently determined by the modified World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST), but these standards correlate poorly with sarcoma patient outcome. We introduced ligand-directed particles with elements of AAV and phage (AAVP) to enable integration of tumor targeting to molecular imaging. We report drug-response monitoring and prediction in a nude rat model of human sarcoma by AAVP imaging. As a proof-of-concept, we imaged Herpes simplex thymidine kinase in a clinic-ready setting with PET to show that one can a priori predict tumor response to a systemic cytotoxic. Given the target expression in patient-derived sarcomas, this platform may be translated in clinical applications. Sarcoma-specific ligands and promoters may ultimately lead to an imaging transcriptome.
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Bacteriófagos/genética , Dependovirus/genética , Sarcoma/genética , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/terapia , Animales , Línea Celular Tumoral , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Expresión Génica , Terapia Genética , Humanos , Ligandos , Ratones , Ratas , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Transgenes/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We investigated whether Rad51 overexpression plays a role in soft tissue sarcoma (STS) chemoresistance as well as the regulatory mechanisms underlying its expression. The studies reported here show that Rad51 protein is overexpressed in a large panel of human STS specimens. Human STS cell lines showed increased Rad51 protein expression, as was also observed in nude rat STS xenografts. STS cells treated with doxorubicin exhibited up-regulation of Rad51 protein while arrested in the S-G(2) phase of the cell cycle. Treatment with anti-Rad51 small interfering RNA decreased Rad51 protein expression and increased chemosensitivity to doxorubicin. Because we previously showed that reintroduction of wild-type p53 (wtp53) into STS cells harboring a p53 mutation led to increased doxorubicin chemosensitivity, we hypothesized that p53 participates in regulating Rad51 expression in STS. Reintroduction of wtp53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression. Using luciferase reporter assays, we showed that reconstitution of wtp53 function decreased Rad51 promoter activity. Deletion constructs identified a specific Rad51 promoter region containing a p53-responsive element but no p53 consensus binding site. Electrophoretic mobility shift assays verified activator protein 2 (AP2) binding to this region and increased AP2 binding to the promoter in the presence of wtp53. Mutating this AP2 binding site eliminated the wtp53 repressive effect. Furthermore, AP2 knockdown resulted in increased Rad51 expression. In light of the importance of Rad51 in modulating STS chemoresistance, these findings point to a potential novel strategy for molecular-based treatments that may be of relevance to patients burdened by STS.
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Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Recombinasa Rad51/fisiología , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Factor de Transcripción AP-2/fisiología , Proteína p53 Supresora de Tumor/fisiología , Ciclo Celular , Línea Celular Tumoral , Genes Reporteros , Humanos , Regiones Promotoras Genéticas , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Interferente Pequeño/metabolismo , Recombinasa Rad51/metabolismo , Elementos de RespuestaRESUMEN
Human soft tissue sarcoma (STS) is a highly lethal malignancy in which control of metastasis determines survival. Little is known about the molecular determinants of STS dissemination. Here, we show that human STS express high levels of matrix metalloproteinase-9 (MMP-9) and that MMP-9 expression levels correlate with sequence analysis-defined p53 mutational status. Reintroduction of wild-type p53 (wtp53) into mutant p53 STS cell lines decreased MMP-9 mRNA and protein levels, decreased zymography-assessed MMP-9 proteolytic activity, and decreased tumor cell invasiveness. Reintroduction of wtp53 into STS xenografts decreased tumor growth and MMP-9 protein expression. Luciferase reporter studies showed that reintroduction of wtp53 into mutant p53 STS cells decreased MMP-9 promoter activity. Deletion constructs of the MMP-9 promoter identified a region containing a p53-responsive element that lacked a p53 consensus binding site but did contain a nuclear factor-kappaB (NF-kappaB) site. Mutating this NF-kappaB binding site eliminated the wtp53-repressive effect. Electrophoretic mobility shift assays confirmed decreased NF-kappaB binding in STS cells in the presence of wtp53. Our findings suggest a role for MMP-9 in STS progression and expand the role of p53 in molecular control of STS growth and metastasis. Therapeutic interventions in human STS targeting MMP-9 activity directly or via reintroduction of wtp53 merit further investigation.
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Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 9 de la Matriz/genética , FN-kappa B/antagonistas & inhibidores , Sarcoma/genética , Sarcoma/secundario , Proteína p53 Supresora de Tumor/fisiología , Línea Celular Tumoral , Genes Reporteros , Humanos , Luciferasas/análisis , Luciferasas/genética , Metaloproteinasa 9 de la Matriz/análisis , Metaloproteinasa 9 de la Matriz/fisiología , FN-kappa B/metabolismo , Trasplante de Neoplasias , Regiones Promotoras Genéticas , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Sarcoma/enzimología , Eliminación de Secuencia , Activación Transcripcional , Proteína p53 Supresora de Tumor/genéticaRESUMEN
To better elucidate the role of vascular endothelial growth factor (VEGF)(165) in soft tissue sarcoma (STS) growth, metastasis, and chemoresistance, we generated stably transfected human STS cell lines with VEGF(165) to study the effect of VEGF(165) on STS cells in vitro and the effect of culture medium from these cells on human umbilical vascular endothelial cells. Severe combined immunodeficient mice bearing xenografts of transfected cell lines were used to assess the effect of VEGF overexpression and the effect of VEGF receptor (VEGFR) 2 inhibition on STS growth, metastasis, and response to doxorubicin. VEGF(165)-transfected xenografts formed highly vascular tumors with shorter latency, accelerated growth, enhanced chemoresistance, and increased incidence of pulmonary metastases. Blockade of VEGFR2 signaling using DC101 anti-VEGFR2 monoclonal antibody enhanced doxorubicin chemoresponse; this combined biochemotherapy inhibited tumor growth and decreased pulmonary metastases without overt toxicity. Combined therapy reduced microvessel counts while increasing vessel maturation index. VEGF overexpression did not affect on the sarcoma cells per se; however, conditioned medium from VEGF transfectants caused increased endothelial cell proliferation, migration, and chemoresistance. Addition of DC101 induced endothelial cell sensitivity to doxorubicin and suppressed the activity of matrix metalloproteinases secreted by endothelial cells. We therefore conclude that VEGF is a critical determinant of STS growth and metastasis and that STS chemoresistance, in our model, is a process induced by the interplay between STS cells and tumor-associated endothelial cells. STS growth and metastasis can be interrupted by combined low-dose doxorubicin and anti-VEGFR2, a strategy that attacks STS-associated endothelial cells. In the future, such therapeutic approaches may be useful in treating STS before the development of clinically apparent metastases.
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Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Sarcoma/genética , Sarcoma/patología , Factor A de Crecimiento Endotelial Vascular/genética , Animales , División Celular , Línea Celular Tumoral , Endotelio Vascular/citología , Endotelio Vascular/fisiología , Femenino , Humanos , Ratones , Ratones SCID , Invasividad Neoplásica , Análisis de Secuencia por Matrices de Oligonucleótidos , Transfección , Trasplante Heterólogo , Venas Umbilicales , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
PURPOSE AND EXPERIMENTAL DESIGN: Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT assay requires Southern analysis of high molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various types of tumors that are often telomerase negative. RESULTS: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47% of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%; leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT- sarcomas were equally aggressive in terms of grade and clinical outcome. CONCLUSION: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas, and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients with astrocytomas.
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Astrocitoma/metabolismo , Regulación Neoplásica de la Expresión Génica , Hibridación Fluorescente in Situ/métodos , Microscopía Fluorescente/métodos , Sarcoma/metabolismo , Telómero/ultraestructura , Adulto , Anciano , Apoptosis , Astrocitoma/genética , Southern Blotting/métodos , Línea Celular Tumoral , Núcleo Celular/metabolismo , Senescencia Celular , Niño , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/metabolismo , Persona de Mediana Edad , Osteosarcoma/diagnóstico , Osteosarcoma/metabolismo , Sarcoma/genética , Telomerasa/metabolismo , Neoplasias de la Tiroides/metabolismo , Factores de TiempoRESUMEN
The protein kinase C (PKC) family consists of serine/threonine protein kinases that play important roles in signal transduction, cell proliferation, and tumor formation. Recent studies found that PKCs are commonly overexpressed in human tumors, including soft tissue sarcoma (STS). Overexpression of PKCs contributes to invasion and migration of tumor cells and induction of angiogenesis. PKC can also phosphorylate the multidrug resistance (MDR) gene-encoded P-glycoprotein and induce MDR phenotype. Our previous studies showed that mutation of p53 enhanced STS metastasis and mediated the MDR phenotype. Restoring wild type (WT) p53 in STS cells containing mutant p53 sensitized the cells to chemotherapy. In the present study, we found that PKCalpha protein expression is inhibited by WT p53 partly due to reduced PKCalpha mRNA expression in STS cells, but p53 does not affect PKCalpha mRNA stability. Deletion and mutation analysis of the PKCalpha promoter fused to the luciferase reporter gene identified a Sp1 binding site (-244/-234) in the PKCalpha promoter that is required for p53-mediated inhibition of PKCalpha promoter activity. More importantly, PKCalpha phosphorylates and activates MDR1 P-glycoprotein, whereas inhibition of PKCalpha by p53 leads to decreased MDR1 phosphorylation in STS cells, which sensitizes STS cells to chemotherapeutic agents. These data indicate that WT p53 may resensitize STS to chemotherapeutic agents by reducing MDR1 phosphorylation via transcriptional repression of PKCalpha expression. Thus, molecular-based therapies targeting mutant p53 and PKCalpha may be an effective new strategy to improve chemotherapeutic efficacy in STS.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Proteína Quinasa C/biosíntesis , Factor de Transcripción Sp1/metabolismo , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo , Sitios de Unión , Northern Blotting , Western Blotting , Línea Celular Tumoral , Movimiento Celular , Núcleo Celular/metabolismo , Proliferación Celular , Dactinomicina/farmacología , Regulación hacia Abajo , Eliminación de Gen , Genes Reporteros , Genes p53 , Humanos , Inmunoprecipitación , Luciferasas/metabolismo , Modelos Genéticos , Mutación , Neovascularización Patológica , Fosforilación , Mutación Puntual , Regiones Promotoras Genéticas , Unión Proteica , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Proteína Quinasa C-alfa , ARN/química , ARN Mensajero/metabolismo , Transducción de Señal , Temperatura , Factores de Tiempo , TransfecciónAsunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Receptores ErbB/metabolismo , Glioma/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Silimarina/uso terapéutico , Animales , Neoplasias Encefálicas/metabolismo , Supervivencia Celular/efectos de los fármacos , Glioma/metabolismo , Humanos , Silybum marianum , Fosforilación/efectos de los fármacos , Ratas , SilibinaRESUMEN
Vascular endothelial growth factor (VEGF) and VEGF receptor 2 [fetal liver kinase 1 (Flk-1)/kinase insert domain-containing receptor] have been shown to play a major role in tumor angiogenesis. In this study, we investigated whether anti-Flk-1 monoclonal antibody DC101 could therapeutically inhibit growth and angiogenesis of human soft tissue sarcoma, and we explored its capacity to enhance the tumoricidal effects of doxorubicin. Treatment of well-established leiomyosarcoma SKLMS-1 and rhabdomyosarcoma RD xenografts in severe combined immunodeficient mice with DC101 resulted in significant antitumor activity. In a parallel study, we compared tumor inhibition with continuous low-dose "antiangiogenic" schedule versus once-every-2-weeks high-dose standard schedule of doxorubicin. We found that continuous low-dose treatment inhibited the tumor growth of RD xenografts about 46.5% of that with standard-schedule treatment, but that continuous low-dose treatment did not inhibit the tumor growth of SKLMS-1 xenografts. Notably, combined DC101 and continuous low-dose doxorubicin resulted in more effective growth inhibition of SKLMS-1 and RD xenografts than has been observed with any agent alone in a long-term s.c. tumor xenograft model. The combination therapy was associated with no additional toxicity to the host animal compared with low-dose doxorubicin alone. Histological examination of xenografts showed significantly reduced microvessel counts in the tumors given combined therapy compared with the tumors given either agent alone. These results are consistent with an enhanced inhibition of angiogenesis in vivo by combined DC101 and doxorubicin using Matrigel plug assay. Additionally, DC101 plus doxorubicin directly exerted enhanced inhibitory effects on endothelial cell migration, proliferation, and tube-like formation in vitro. Furthermore, the combination induced an enhanced apoptosis of endothelial cells that was associated with an increase of capase-3 activity. Thus, the inhibition of angiogenesis and induction of endothelial cell apoptosis are likely important mechanisms for the antitumor activity of combined DC101 and doxorubicin. Collectively, our data suggested that anti-VEGF receptor 2 in combination with continuous low-dose doxorubicin may provide a new therapeutic approach for human soft tissue sarcoma in the clinic.