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The current postexposure prophylaxis regimen for tick-borne relapsing fever (TBRF) consists of 5 days' doxycycline. In this observational study of 77 spelunkers at high risk for TBRF, a single dose of 100 mg doxycycline taken up to 72 hours after exposure to ticks was 100% effective in preventing the disease.
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Febre Recorrente , Carrapatos , Animais , Doxiciclina/uso terapêutico , Humanos , Profilaxia Pós-Exposição , Febre Recorrente/prevenção & controleRESUMO
Impaired neutrophil extracellular trap (NET) formation compromises the host defense after engraftment following hematopoietic stem cell transplantation (HSCT) despite adequate neutrophil counts. The aims of the present study were to determine reference ranges for the activity of key enzymes of NET formation-neutrophil elastase (NE) and myeloperoxidase (MPO)-in a healthy population and to unravel the recovery dynamics of NET formation over time following HSCT, along with NE and MPO enzymatic activities. Reference ranges of NE and MPO activity were derived from 50 healthy volunteers. During 2017 to 2018, 11 consecutive pediatric patients undergoing allogeneic or autologous HSCT were recruited at a single referral center for pediatric hemato-oncology. Patients were followed for up to 1 year following engraftment. The mean reference value was 7.5 ± .4 mU for NE activity and 2.17 ± .4 U for MPO activity in the healthy population, and enzymatic activity of MPO was significantly higher in males. At 3 weeks following neutrophil engraftment, all study participants demonstrated extremely low enzymatic NE activity, whereas MPO activity was above the lower normal reference range at all time points. Reduced NE activity corresponded to the inability to form NETs. Neutrophil function improved over time, but partial impairment persisted for 7 months following transplantation. The ability of neutrophils to form NETs was significantly impaired for 3 weeks after engraftment in the setting of HSCT, exposing patients to bacterial infections. NE activity might serve as a surrogate marker for the capacity of neutrophils to form NETs.
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Infecções Bacterianas/sangue , Armadilhas Extracelulares/metabolismo , Transplante de Células-Tronco Hematopoéticas , Elastase de Leucócito/sangue , Neutrófilos/metabolismo , Adolescente , Adulto , Aloenxertos , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Peroxidase/sangueRESUMO
Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity.
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Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ribonucleotídeo Redutases/antagonistas & inibidores , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo , Transdução de Sinais , Análise de Sobrevida , Microambiente Tumoral/efeitos dos fármacos , GencitabinaRESUMO
It was suggested that the brain microenvironment plays a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion. In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial-derived neurotrophic factor (GDNF) on tumor invasion. Astrocytes-conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET-Fc chimera or anti-GDNF Ab and by small interfering RNA directed against GDNF expression by astrocytes. Glioma cells incubated with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream activation of AKT. Tumor migration and GDNF-RET-AKT activation was inhibited by the RET small-molecule inhibitor pyrazolopyrimidine-1 (PP1) and by the AKT inhibitor LY294002. Finally, blocking of RET by PP1 or knockout of the RET coreceptor GFRα1 in glioma cells reduced the size of brain tumors in immunocompetent mice. We suggest a mechanism by which astrocytes attracted to the glioma tumors facilitate brain invasion by secretion of GDNF and activation of RET/GFRα1 receptors expressed by the cancer cells.
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Astrócitos/metabolismo , Neoplasias Encefálicas/patologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glioma/patologia , Comunicação Parácrina , Animais , Astrócitos/citologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glioma/metabolismo , Humanos , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-ret/metabolismoRESUMO
OBJECTIVE: This study aimed to create a reliable and reproducible orthotopic mouse model of laryngeal malignancy that recapitulates its biologic behavior, local invasiveness, and spread as seen in patients. METHODS: Via direct laryngoscopy, human squamous cell carcinoma line FaDu (ATCC HTB-43) was implanted in the larynx (supraglottis and glottis) in nu/nu mice (n = 31). Animals were monitored with direct laryngoscopy and ultrasound for tumor growth and survival. Specimens of larynxes, neck lymphatics, livers, and lungs were removed for histopathologic evaluation to assess tumor extension, thyroid cartilage invasion, and nodal spread. RESULTS: Thirty-one successful direct laryngoscopies were performed. Supraglottic and glottic tumor uptake was 100% and 25%, respectively. Median survival for the animals with supraglottic tumors was 35 days. Histopathologic evaluation revealed pre-epiglottic extension, paraglottic extension, thyroid cartilage invasion, and lymph node metastasis. CONCLUSION: We describe the first orthotopic model for laryngeal cancer. Our model faithfully recapitulates the phenotype and malignant behavior that reproduces its natural biologic behavior as seen in laryngeal cancer patients. This model offers an opportunity to identify and specifically target therapy for larynx squamous cell carcinoma.
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Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Neoplasias Laríngeas/patologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Cartilagem Tireóidea/patologiaRESUMO
BACKGROUND: The minimal clinically important difference (MCID) is defined as the smallest difference in quality of life (QOL) that patients perceive as beneficial and that mandates a change in management. We aimed to determine the MCID among patients with oral cavity and oropharyngeal cancer and to identify domains that are significantly affected during treatment. METHODS: The cohort consisted of 1,011 patients analyzed by a metaanalysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. MCID values for the University of Washington Quality of Life Questionnaire (UW-QOLQ) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC C-30) and Head and Neck-35 questionnaires were calculated by using the distribution-based method. RESULTS: The mean MCID for Global QOL was 13.07 points for the UW-QOLQ and 9.43 in the EORTC C-30 questionnaire. High consistency in the MCID values was found between the two questionnaires examined. Heat map analysis indicated a clinically significant improvement in head and neck-associated domains and in domains associated with general cancer treatment 1 year or more after treatment relative to 3 months after treatment (p < 0.001 and p = 0.016, respectively). In contrast, improvement in general and functional domains was not evident 1 year or more after treatment (p = 0.69). CONCLUSIONS: This study suggests benchmark values for MCID and variation in QOL scores of oral and oropharyngeal cancer patients after treatment. Improvement in head and neck- and general cancer-associated domains may not be translated into a general and functional improvement during the first year of recovery.
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Neoplasias Bucais/psicologia , Neoplasias Bucais/terapia , Neoplasias Orofaríngeas/psicologia , Neoplasias Orofaríngeas/terapia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Prognóstico , Inquéritos e Questionários , Adulto JovemRESUMO
The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.
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BACKGROUND: An association between the survival of patients with oral cavity squamous cell carcinoma (OCSCC) and advancements in diagnosis and therapy has not been established. METHODS: This was a retrospective, longitudinal, international, population-based study of 2738 patients who underwent resection of OCSCC during 2 different decades. Characteristics of patients from 7 international cancer centers who received treatment between 1990 and 2000 (group A; n = 735) were compared with patients who received treatment between 2001 and 2011 (group B; n = 2003). RESULTS: Patients in group B had more advanced tumors and tended to develop distant metastases more frequently than patients in group A (P = .005). More group B patients underwent selective neck dissection and received adjuvant radiotherapy (P < .001). Outcome analysis revealed a significant improvement in 5-year overall survival, from 59% for group A to 70% for group B (P < .001). There was also a significant improvement in disease-specific survival associated with operations performed before and after 2000 (from 69% to 81%, respectively; P < .001). Surgery after 2000, negative margins, adjuvant treatment, and early stage disease were independent predictors of a better outcome in multivariate analysis. The decade of treatment was an independent prognostic factor for cancer-specific mortality (hazard ratio, 0.42; 95% confidence interval, 0.3-0.6). CONCLUSIONS: The survival rate of patients with OCSCC improved significantly during the past 2 decades despite older age, more advanced disease stage, and a higher rate of distant metastases. The current results suggest that the prognosis for patients with OCSCC has improved over time, presumably because of advances in imaging and therapy.
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Carcinoma de Células Escamosas/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias Bucais/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Comportamento Cooperativo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Cooperação Internacional , Estudos Longitudinais , Pessoa de Meia-Idade , Boca/diagnóstico por imagem , Boca/cirurgia , Neoplasias Bucais/patologia , Neoplasias Bucais/radioterapia , Neoplasias Bucais/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Radiografia , Cintilografia , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Adulto JovemRESUMO
BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, causing significant morbidity. Despite the dramatic improvement in treatment, many patients do not achieve complete remission, and biomarkers for subclinical disease, flares, and response to treatment are lacking. Neutrophils and neutrophil extracellular traps (NETs) play key roles in the pathogenesis of autoimmune and inflammatory conditions. In this study, we characterized neutrophil enzyme activity and NETs formation in oligoarticular and polyarticular JIA and explored their association with disease activity. METHODS: Neutrophils from 6 healthy controls and 7 patients with oligoarticular and polyarticular JIA were freshly isolated at time of diagnosis and after glucocorticoid intra-articular injection. Enzymatic activity of neutrophil granular enzymes was monitored by colorimetry and PMA-activated NETs formation was assessed using fluorescent microscopy. RESULTS: In this pilot and feasibility study, we revealed that NETs were significantly increased in oligoarticular JIA patients at time of diagnosis compared to healthy controls. Anti-inflammatory treatment using intra-articular steroid injection normalized NETs formation in these patients. Correlation between NETs formation and clinical Juvenile Activity Disease Activity Score-10 (cJADAS-10) was linear and significant (P = 0.007) in oligo but not in poly JIA patients. CONCLUSIONS: This is the first study exploring the link of NETs formation with oligo and poly JIA activity. We demonstrated a statistically significant linear correlation between cJADAS-10 and NETs formation in oligo but not in poly JIA patients. Hence, we suggest that NETs may reflect clinical disease activity in JIA, and may serve as a putative biomarker. Further work is needed to validate these initial results and determine the dynamics of NETs formation in JIA.
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Artrite Juvenil , Armadilhas Extracelulares , Criança , Humanos , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Neutrófilos , Projetos Piloto , BiomarcadoresRESUMO
Although adoptive T cell therapy provides the T cell pool needed for immediate tumor debulking, the infused T cells generally have a narrow repertoire for antigen recognition and limited ability for long-term protection. Here, we present a hydrogel that locally delivers adoptively transferred T cells to the tumor site while recruiting and activating host antigen-presenting cells with GMCSF or FLT3L and CpG, respectively. T cells alone loaded into these localized cell depots provided significantly better control of subcutaneous B16-F10 tumors than T cells delivered through direct peritumoral injection or intravenous infusion. T cell delivery combined with biomaterial-driven accumulation and activation of host immune cells prolonged the activation of the delivered T cells, minimized host T cell exhaustion, and enabled long-term tumor control. These findings highlight how this integrated approach provide both immediate tumor debulking and long-term protection against solid tumors, including against tumor antigen escape.
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Criogéis , Neoplasias , Humanos , Neoplasias/patologia , Imunoterapia Adotiva , Linfócitos T , Células Apresentadoras de AntígenosRESUMO
Importance: Immunohistochemistry (IHC) is the most widely used assay for identification of molecular biomarkers. However, IHC is time consuming and costly, depends on tissue-handling protocols, and relies on pathologists' subjective interpretation. Image analysis by machine learning is gaining ground for various applications in pathology but has not been proposed to replace chemical-based assays for molecular detection. Objective: To assess the prediction feasibility of molecular expression of biomarkers in cancer tissues, relying only on tissue architecture as seen in digitized hematoxylin-eosin (H&E)-stained specimens. Design, Setting, and Participants: This single-institution retrospective diagnostic study assessed the breast cancer tissue microarrays library of patients from Vancouver General Hospital, British Columbia, Canada. The study and analysis were conducted from July 1, 2015, through July 1, 2018. A machine learning method, termed morphological-based molecular profiling (MBMP), was developed. Logistic regression was used to explore correlations between histomorphology and biomarker expression, and a deep convolutional neural network was used to predict the biomarker expression in examined tissues. Main Outcomes and Measures: Positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristics curve measures of MBMP for assessment of molecular biomarkers. Results: The database consisted of 20â¯600 digitized, publicly available H&E-stained sections of 5356 patients with breast cancer from 2 cohorts. The median age at diagnosis was 61 years for cohort 1 (412 patients) and 62 years for cohort 2 (4944 patients), and the median follow-up was 12.0 years and 12.4 years, respectively. Tissue histomorphology was significantly correlated with the molecular expression of all 19 biomarkers assayed, including estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (formerly HER2). Expression of ER was predicted for 105 of 207 validation patients in cohort 1 (50.7%) and 1059 of 2046 validation patients in cohort 2 (51.8%), with PPVs of 97% and 98%, respectively, NPVs of 68% and 76%, respectively, and accuracy of 91% and 92%, respectively, which were noninferior to traditional IHC (PPV, 91%-98%; NPV, 51%-78%; and accuracy, 81%-90%). Diagnostic accuracy improved given more data. Morphological analysis of patients with ER-negative/PR-positive status by IHC revealed resemblance to patients with ER-positive status (Bhattacharyya distance, 0.03) and not those with ER-negative/PR-negative status (Bhattacharyya distance, 0.25). This suggests a false-negative IHC finding and warrants antihormonal therapy for these patients. Conclusions and Relevance: For at least half of the patients in this study, MBMP appeared to predict biomarker expression with noninferiority to IHC. Results suggest that prediction accuracy is likely to improve as data used for training expand. Morphological-based molecular profiling could be used as a general approach for mass-scale molecular profiling based on digitized H&E-stained images, allowing quick, accurate, and inexpensive methods for simultaneous profiling of multiple biomarkers in cancer tissues.
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Algoritmos , Inteligência Artificial , Neoplasias da Mama/diagnóstico , Receptores de Estrogênio/análise , Análise Serial de Tecidos/métodos , Biomarcadores Tumorais/análise , Colúmbia Britânica , Estudos de Viabilidade , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Receptor ErbB-2/análise , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
High-dose methotrexate is used to treat a range of adult and childhood cancers including osteosarcoma. Significant neurotoxicity is reported in 1% to 4.5% of patients treated with high-dose methotrexate and can present in a wide variety of symptoms. We present a case of a 14-year-old boy with a recent diagnosis of osteosarcoma who presented to the emergency department with status epilepticus, altered mental status, and very high fever secondary to methotrexate neurotoxicity. We review current literature and discuss some controversies related to this state. We also describe high fever as one of the possible symptoms associated with this condition and suggest using specific magnetic resonance imaging sequence to uncover abnormal findings related to this state. Since high-dose methotrexate is not a rare treatment in this era, we believe that in addition to oncologists, emergency department and intensive care providers should be aware of the potential role of methotrexate in causing significant neurotoxicity and include it in the differential diagnosis when treating a patient presenting with new neurological symptoms in the setting of recent high-dose methotrexate treatment.
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Antimetabólitos Antineoplásicos/toxicidade , Encefalopatias/induzido quimicamente , Febre/induzido quimicamente , Metotrexato/toxicidade , Estado Epiléptico/induzido quimicamente , Adolescente , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Serviço Hospitalar de Emergência , Humanos , Masculino , Metotrexato/uso terapêutico , Osteossarcoma/tratamento farmacológicoRESUMO
Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, â¼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.
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Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Colagenases/farmacologia , Nanopartículas/química , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colágeno/química , Colágeno/genética , Colagenases/química , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Fibrose/tratamento farmacológico , Fibrose/patologia , Fibrose/prevenção & controle , Humanos , Lipossomos/química , Lipossomos/farmacologia , Camundongos , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to gemcitabine, which acts to inhibit cell growth by termination of DNA replication. Tumor-associated macrophages (TAM) were recently shown to contribute to gemcitabine resistance; however, the exact mechanism of this process is still unclear. Using a genetic mouse model of PDAC and electron microscopy analysis, we show that TAM communicate with the tumor microenvironment via secretion of approximately 90 nm vesicles, which are selectively internalized by cancer cells. Transfection of artificial dsDNA (barcode fragment) to murine peritoneal macrophages and injection to mice bearing PDAC tumors revealed a 4-log higher concentration of the barcode fragment in primary tumors and in liver metastasis than in normal tissue. These macrophage-derived exosomes (MDE) significantly decreased the sensitivity of PDAC cells to gemcitabine, in vitro and in vivo This effect was mediated by the transfer of miR-365 in MDE. miR-365 impaired activation of gemcitabine by upregulation of the triphospho-nucleotide pool in cancer cells and the induction of the enzyme cytidine deaminase; the latter inactivates gemcitabine. Adoptive transfer of miR-365 in TAM induced gemcitabine resistance in PDAC-bearing mice, whereas immune transfer of the miR-365 antagonist recovered the sensitivity to gemcitabine. Mice deficient of Rab27 a/b genes, which lack exosomal secretion, responded significantly better to gemcitabine than did wildtype. These results identify MDE as key regulators of gemcitabine resistance in PDAC and demonstrate that blocking miR-365 can potentiate gemcitabine response.Significance: Harnessing macrophage-derived exosomes as conveyers of antagomiRs augments the effect of chemotherapy against cancer, opening new therapeutic options against malignancies where resistance to nucleotide analogs remains an obstacle to overcome. Cancer Res; 78(18); 5287-99. ©2018 AACR.
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Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , MicroRNAs/metabolismo , Neoplasias Pancreáticas/terapia , Adenocarcinoma/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral , Regulação para Cima , Proteínas rab27 de Ligação ao GTP/genética , GencitabinaRESUMO
BACKGROUND: The role of human papillomavirus (HPV) infection in oropharyngeal cancer (SCC) is well established. The annual incidence of oropharyngeal SCC in Israel is considerably lower than that in the United States. The purpose of this study was to assess the rate of HPV-related oropharyngeal SCC in Israel. METHODS: The cohort included patients with oropharyngeal SCC who were treated during 1999 to 2011 in Israel. HPV typing was carried out using reverse hybridization and immunohistochemistry. RESULTS: Of the 74 patients analyzed, 25 (33.7%) had detectable HPV DNA. Patients in the HPV-positive group tended to be younger, with a higher rate of nodal metastases, and no history of smoking (p < .02). CONCLUSION: This study demonstrated a rate of HPV-related oropharyngeal SCC in Israel as approximately 3-fold lower than in Western countries. Low exposure to HPV-16, a lower rate of transformation, to cancer or protective genetic factors may contribute to the lower rate of oropharyngeal SCC in Israel. © 2015 Wiley Periodicals, Inc. Head Neck 38: E274-E278, 2016.
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Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/virologia , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/complicações , Adulto JovemRESUMO
PURPOSE: Digital pathology diagnostics are often based on subjective qualitative measures. A murine model of early-phase pancreatic ductal adenocarcinoma provides a controlled environment with a priori knowledge of the genetic mutation and stage of the disease. Use of this model enables the application of supervised learning methods to digital pathology. A computerized diagnostics system for histological detection of pancreatic adenocarcinoma was developed and tested. METHODS : Pathological H&E-stained specimens with early pancreatic lesions were identified and evaluated with a system that models cancer detection using a top-down object learning paradigm, mimicking the way a pathologist learns. First, the dominant primitives were identified and segmented in the images, i.e., the ducts, nuclei and tumor stroma. A boost-based machine learning technique was used for duct segmentation, classification and outlier pruning. Second, a set of morphological features traditionally used for cancer diagnosis which provides quantitative image features was employed to quantify subtle findings such as duct deformation and nuclei malformations. Finally, a visually interpretable predictive model was trained to distinguish between normal tissue and premalignant cancer lesions, given ground truth samples. RESULTS : A predictive success rate of 92% was achieved using tenfold cross-validation and 93% on an independent test set. Comparison was made with state-of-the-art classification algorithms that are not interpretable as visible features yielded the contribution of individual primitive features to the prediction outcome. CONCLUSIONS: Quantitative image analysis and classification were successful in preclinical histology diagnosis for early-stage pancreatic adenocarcinoma. The usage of annotated contours coupled with interpretable supervised learning methods and outlier pruning can be adapted to other medical imaging tasks. The usage of interpretable supervised learning techniques may improve the success of CAD in histopathological diagnosis.
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Carcinoma Ductal Pancreático/patologia , Diagnóstico por Computador/métodos , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Pancreáticas/patologia , Algoritmos , Animais , Modelos Animais de Doenças , CamundongosRESUMO
BACKGROUND: The purpose of this study was to characterize the incidence, pattern of spread, and prognostic correlation of nerve invasion in patients with adenoid cystic carcinoma (ACC). METHODS: Using 3 different pathological categories of perineural invasion, intraneural invasion, and perineural inflammation, we investigated the prognostic value of nerve invasion in a total of 495 ACCs from 9 international patient cohorts with median follow-up 90 months (range, 12-288 months). RESULTS: Of 239 patients (48%) with nerve invasion, 174 (73%) had perineural invasion, 65 (27%) intraneural invasion, and 37 (15%) perineural inflammation. Multivariate Cox regression analysis identified tumor site (p = .008; hazard ratio [HR] = 1.8; 95% confidence interval [CI] = 0.07-3.7) and intraneural invasion (p < .001; HR = 5.9; 95% CI = 0.8-12.3) as independent prognostic markers for both overall survival (OS) and disease-specific survival (DSS), but not of distant metastases. CONCLUSION: Although perineural invasion has no impact on survival, intraneural invasion is an independent predictor of poor prognosis. Recognition of intraneural invasion may help optimize treatment of patients with head and neck ACC.
Assuntos
Carcinoma Adenoide Cístico/patologia , Neoplasias de Cabeça e Pescoço/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/mortalidade , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Análise de Regressão , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: The patterns of regional metastasis in adenoid cystic carcinoma (ACC) of the head and neck and its association with outcome is not established. METHODS: We conducted a retrospective multicentered multivariate analysis of 270 patients who underwent neck dissection. RESULTS: The incidence rate of neck metastases was 29%. The rate observed in the oral cavity is 37%, and in the major salivary glands is 19% (p = .001). The rate of occult nodal metastases was 17%. Overall 5-year survival rates were 44% in patients undergoing therapeutic neck dissections, and 65% and 73% among those undergoing elective neck dissections, with and without nodal metastases, respectively (p = .017). Multivariate analysis revealed that the primary site, nodal classification, and margin status were independent predictors of survival. CONCLUSION: Our findings support the consideration of elective neck treatment in patients with ACC of the oral cavity.
Assuntos
Carcinoma Adenoide Cístico/secundário , Neoplasias de Cabeça e Pescoço/patologia , Linfonodos/patologia , Esvaziamento Cervical/métodos , Pescoço , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/cirurgia , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Incidência , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. METHODS: ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. FINDINGS: Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1-306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. INTERPRETATION: Using an international collaborative database we have created the first nomograms which estimate outcome in individual patients with ACC. These predictive nomograms will facilitate patient counseling in terms of prognosis and subsequent clinical follow-up. They will also identify high risk patients who may benefit from clinical trials on new targeted therapies for patients with ACC. FUNDING: None.
Assuntos
Carcinoma Adenoide Cístico/terapia , Técnicas de Apoio para a Decisão , Recidiva Local de Neoplasia , Nomogramas , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Comportamento Cooperativo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Estadiamento de Neoplasias , Seleção de Pacientes , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES/HYPOTHESIS: In the present study we sought to define the outcome of patients with delay in diagnosis and treatment (>1 year) of well-differentiated thyroid carcinoma (WDTC) due to initial benign cytology (IBC). STUDY DESIGN: Retrospective medical record review and analysis of survival outcomes. METHODS: The records of 47 patients with delayed diagnosis of thyroid cancer were reviewed. In 38, surgery was performed for growing nodules and in nine due to malignant cytology during follow-up. Median time to delayed surgery was 52 months (range, 13-205 months). Multivariate analysis was performed to assess variables associated with outcome. RESULTS: Most patients (32/47) underwent total thyroidectomy, whereas 15/47 had hemithyroidectomy. With a median follow-up of 96 months (range, 12-184 months), the 5-year disease-free survival of these patients was 96%. Multivariate analysis showed that the outcome of these patients was not statistically different than that of patients (n = 162) who underwent immediate surgery for similar disease. CONCLUSIONS: We show that patients with delayed diagnosis and treatment for WDTC due to IBC have excellent outcome. LEVEL OF EVIDENCE: 4.