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INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a biologically active protein and increased levels are associated with worse outcomes in critically ill patients. suPAR in bronchoalveolar fluid (BALF) may be helpful to differentiate between types of acute respiratory distress syndrome (ARDS) and may have potential for early detection of fungal infection. METHODS: We prospectively investigated levels of suPAR in BALF and serum in critically ill patients who underwent bronchoscopy for any reason at the ICU of the Department of Internal Medicine, Medical University of Graz, Graz, Austria. RESULTS: Seventy-five patients were available for analyses. Median age was 60 [25th-75th percentile: 50-69] years, 27% were female, and median SOFA score was 12 [11-14] points. Serum suPAR levels were significantly associated with ICU mortality in univariable logistic regression analysis. There was no correlation between BALF and serum suPAR. Serum suPAR was higher in ARDS patients at 11.2 [8.0-17.2] ng/mL compared to those without ARDS at 7.1 [3.7-10.1] (p < 0.001). BALF-suPAR was significantly higher in patients with evidence of fungal lung infection compared to patients without fungal infection both in the general cohort (7.6 [3.2-9.4] vs 2.5 [1.1-5.3], p = 0.013) and in the subgroup of ARDS (7.2 [3.1-39.2] vs 2.5 [1.0-5.2], p = 0.022). All patients were classified as putative/probable invasive aspergillosis. CONCLUSION: We found significant higher levels of serum suPAR in ARDS patients compared to those not fulfilling ARDS criteria. Serum and BALF-suPAR were significantly higher in those patients with evidence for invasive pulmonary aspergillosis. These findings may suggest testing this biomarker for early diagnosis of fungal infection in a greater cohort.
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Aspergilosis , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Síndrome de Dificultad Respiratoria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores , Enfermedad Crítica , Pronóstico , Estudios Prospectivos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/química , Síndrome de Dificultad Respiratoria/diagnósticoRESUMEN
BACKGROUND: Microangiopathic hemolytic anemias and thrombocytopenias in pregnant or postpartum women constitute an interdisciplinary diagnostic and therapeutic challenge in the evaluation of thrombotic microangiopathies (TMA), where urgent care must be considered. CASE PRESENTATION: We here report the case of a 21-year-old Somali woman, who was delivered by emergency caesarean section at 35 weeks of gestational age with acute dyspnea, placental abruption and gross edema due to severe preeclampsia/HELLP syndrome. After delivery, she developed acute kidney failure and thrombotic microangiopathy as revealed by kidney biopsy. The lack of early response to plasma exchange prompted extensive laboratory workup. Ultimately, the patient completely recovered with negative fluid balance and control of severe hypertension. CONCLUSIONS: This case report emphasizes the importance to differentiate between primary TMA syndromes and microangiopathic hemolytic anemias due to systemic disorders. Delayed recovery from preeclampsia/HELLP syndrome and malignant hypertension can clinically mimic primary TMA syndromes in the postpartum period.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Manejo de la Enfermedad , Atención Posnatal/métodos , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/terapia , Lesión Renal Aguda/complicaciones , Cesárea/efectos adversos , Cesárea/tendencias , Femenino , Humanos , Intercambio Plasmático/métodos , Intercambio Plasmático/tendencias , Embarazo , Adulto JovenRESUMEN
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as KRAS, BRAF, PIK3CA, and EGFR. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of KRAS in four patients (40%), which occurred either as novel focal amplifications (n = 3) or as high level polysomy of 12p (n = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as MET (n = 2) and ERBB2 (n = 1). Overrepresentation of the EGFR gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of KRAS, BRAF, PIK3CA, and EGFR did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/sangre , Cetuximab , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Receptores ErbB/inmunología , Femenino , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Panitumumab , Proteínas Proto-Oncogénicas c-met/sangre , Receptor ErbB-2/sangreRESUMEN
OBJECTIVES: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH. DESIGN: Observational pilot study. SETTING: Single-center tertiary academic ICU. PATIENTS: Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria. INTERVENTION: Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol. MEASUREMENT AND MAIN RESULTS: Nine patients (median age: 42 yr [25th-75th percentile: 32-54]; male: n = 6 males, median H-score: 299 [255-304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th-75th percentile: 7-12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period. CONCLUSION: In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.
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With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor-specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation-detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome-wide tumor-specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.
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Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Dosificación de Gen , Células Neoplásicas Circulantes/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Neoplasias de la Mama/sangre , Estudios de Casos y Controles , Neoplasias Colorrectales/sangre , ADN de Neoplasias/sangre , Femenino , Genes ras/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Thyroid cancer (TC) is the most commonly diagnosed endocrine malignancy in developed countries. Differentiated thyroid carcinoma (DTC), which includes papillary thyroid carcinoma and follicular thyroid carcinoma (FTC), composes more than 90% of all TC cases. When DTC recurs or metastasizes to distant sites despite the use of local and radiotherapeutic treatment modalities, the currently effective treatment options are limited. CASE REPORT: A then 40-year-old female Caucasian patient was diagnosed with FTC and underwent surgery and postoperative radioactive iodine therapy. The patient developed metastatic disease, and palliative first-line treatment with the proteasome inhibitor bortezomib was initiated. After 3 months, the patient suffered progressive pulmonary metastatic disease. Treatment with the multikinase inhibitor sorafenib was started, and after 3 months of therapy, tumor restaging demonstrated partial remission. The treatment is ongoing, and the current progression-free survival is 16 months. With the exception of mild diarrhea and hand-foot syndrome, the therapy was well tolerated, and no grade 3/4 adverse toxicities occurred. CONCLUSION: In our single case of metastatic FTC, sorafenib showed clinically meaningful antitumor activity accompanied by good tolerability. This case report supports the use of this drug as a potential treatment option for advanced/metastatic FTC.
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Adenocarcinoma Folicular/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adenocarcinoma Folicular/diagnóstico , Adulto , Ácidos Borónicos/uso terapéutico , Bortezomib , Femenino , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Pulmonares/diagnóstico , Niacinamida/uso terapéutico , Pirazinas/uso terapéutico , Sorafenib , Neoplasias de la Tiroides/diagnóstico , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
INTRODUCTION: To quantify the magnitude of benefit of metastasectomy as compared to medical treatment alone in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: We therefore conducted a propensity score analysis of overall survival (OS) in 106 mRCC patients with metachronous metastasis, of whom 36 (34%) were treated with metastasectomy, and 70 (66%) with medical therapy alone. RESULTS: The most frequent metastasectomy procedures were lung resections (n = 13) and craniotomies (n = 6). Median time-to-progression after metastasectomy was 0.7 years (25th-75th percentile: 0.3-2.7). After a median follow-up of 6.2 years and 63 deaths, 5-year OS estimates were 41% and 22% in the metastasectomy and medical therapy group, respectively (log-rank P = .00007; Hazard ratio (HR) = 0.38, 95%CI: 0.21-0.68). Patients undergoing metastasectomy had a significantly higher prevalence of favorable prognostic factors, such as fewer bilateral lung metastases and longer disease-free intervals between nephrectomy and metastasis diagnosis. After propensity score weighting for these differences and adjusting for immortal time bias, the favorable association between metastasectomy and OS became much weaker (HR = 0.62, 95%CI: 0.39-1.00, P = .050). Propensity-score-weighted 5-year OS estimates were 24% and 20% in the metastasectomy and medical therapy group, respectively (log-rank P = .001). In exploratory analyses, the benefit of metastasectomy was confined to patients who achieved complete resection of all known metastases. CONCLUSION: Within the limitations of an observational study, these findings support the concept of metastasectomy being associated with an OS benefit in mRCC patients. Metastasectomies not achieving complete resection of all known lesions are likely without OS benefit.
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Carcinoma de Células Renales , Neoplasias Renales , Metastasectomía , Humanos , Neoplasias Renales/patología , Metastasectomía/métodos , Nefrectomía/métodos , Pronóstico , Puntaje de Propensión , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: The question of whether cancer patients with severe respiratory failure benefit from veno-venous extracorporeal membrane oxygenation (vv-ECMO) remains unanswered. We, therefore, analyzed clinical characteristics and outcomes of a large cohort of cancer patients treated with vv-ECMO with the aim to identify prognostic factors. METHODS: 297 cancer patients from 19 German and Austrian hospitals who underwent vv-ECMO between 2009 and 2019 were retrospectively analyzed. A multivariable cox proportional hazards analysis for overall survival was performed. In addition, a propensity score-matched analysis and a latent class analysis were conducted. RESULTS: Patients had a median age of 56 (IQR 44-65) years and 214 (72%) were males. 159 (54%) had a solid tumor and 138 (47%) a hematologic malignancy. The 60-day overall survival rate was 26.8% (95% CI 22.1-32.4%). Low platelet count (HR 0.997, 95% CI 0.996-0.999; p = 0.0001 per 1000 platelets/µl), elevated lactate levels (HR 1.048, 95% CI 1.012-1.084; p = 0.0077), and disease status (progressive disease [HR 1.871, 95% CI 1.081-3.238; p = 0.0253], newly diagnosed [HR 1.571, 95% CI 1.044-2.364; p = 0.0304]) were independent adverse prognostic factors for overall survival. A propensity score-matched analysis with patients who did not receive ECMO treatment showed no significant survival advantage for treatment with ECMO. CONCLUSION: The overall survival of cancer patients who require vv-ECMO is poor. This study shows that the value of vv-ECMO in cancer patients with respiratory failure is still unclear and further research is needed. The risk factors identified in the present analysis may help to better select patients who may benefit from vv-ECMO.
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Oxigenación por Membrana Extracorpórea , Neoplasias , Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Adulto , Anciano , Oxigenación por Membrana Extracorpórea/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/terapia , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Estudios RetrospectivosRESUMEN
BACKGROUND: In renal failure metformin can lead to lactic acidosis. Additional inhibition of hepatic gluconeogenesis by accumulation of the drug may aggravate fasting-induced ketoacidosis. We report the occurrence of metformin-associated lactic acidosis (MALA) with concurrent euglycemic ketoacidosis (MALKA) in three patients with renal failure. CASE PRESENTATIONS: Patient 1: a 78-year-old woman (pH = 6.89, lactic acid 22 mmol/l, serum ketoacids 7.4 mmol/l and blood glucose 63 mg/dl) on metformin and insulin treatment. Patient 2: a 79-year-old woman on metformin treatment (pH = 6.80, lactic acid 14.7 mmol/l, serum ketoacids 6.4 mmol/l and blood glucose 76 mg/dl). Patient 3: a 71-year-old man on metformin, canagliflozin and liraglutide treatment (pH = 7.21, lactic acid 5.9 mmol/l, serum ketoacids 16 mmol/l and blood glucose 150 mg/dl). In all patients, ketoacidosis receded on glucose infusion and renal replacement therapy. CONCLUSION: This case series highlights the parallel occurrence of MALA and euglycemic ketoacidosis, the latter exceeding ketosis due to starvation, suggesting a metformin-triggered inhibition of gluconeogenesis. Affected patients benefit from glucose infusion counteracting suppressed hepatic gluconeogenesis.
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Acidosis Láctica/inducido químicamente , Cetosis/inducido químicamente , Fallo Renal Crónico/complicaciones , Metformina/efectos adversos , Anciano , Glucemia/metabolismo , Canagliflozina/efectos adversos , Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Gluconeogénesis/efectos de los fármacos , Humanos , Insulina/efectos adversos , Insulina/uso terapéutico , Liraglutida/efectos adversos , Liraglutida/uso terapéutico , Masculino , Metformina/uso terapéuticoRESUMEN
SOX9 has been previously shown to be involved in hepatocellular carcinoma (HCC) and other types of cancer. However, prognostic studies so far involved rather small cohorts or lack external validation and experimental data. In this study, we firstly determined the histological expression pattern of SOX9 in human HCC by immunohistochemistry (n = 84) and evaluated its prognostic value. External cohorts of publicly available datasets were used to validate its prognostic relevance in HCC (n = 359) and other types of cancer including breast (n = 3951), ovarian (n = 1306), lung (n = 1926) and gastric cancer (n = 876). Functional SOX9 knock-down studies using siRNA and cancer stem cell models were generated in a panel of liver and breast cancer cell lines. High level of SOX9 was associated with poor survival even after adjustment for other prognostic factors in multivariate analysis (HR = 2.103, 95%CI = 1.064 to 4.156, p = 0.021). SOX9 prevailed a poor prognostic factor in all cancer validation cohorts (p<0.05). Reduced SOX9 expression by siRNA decreased the growth of liver cancer cells (p<0.05). SOX9 expression was associated with stem cell features in all tested cell lines (p<0.05). In conclusion, this study demonstrated in a large number of patients from multiple cohorts that high levels of SOX9 are a consistent negative prognostic factor.
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Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/patología , Factor de Transcripción SOX9/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Factor de Transcripción SOX9/genéticaAsunto(s)
Agammaglobulinemia , COVID-19 , Humanos , Huésped Inmunocomprometido , SARS-CoV-2 , Cromosoma XAsunto(s)
Betacoronavirus , Infecciones por Coronavirus , Neoplasias Hematológicas , Pandemias , Neumonía Viral , COVID-19 , Humanos , SARS-CoV-2Asunto(s)
Choque/etiología , Síndrome de Zollinger-Ellison/complicaciones , Síndrome de Zollinger-Ellison/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Pantoprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Choque/terapia , Síndrome de Zollinger-Ellison/terapiaAsunto(s)
Candidiasis/diagnóstico , Candidiasis/etiología , Contaminación de Equipos , Oxigenación por Membrana Extracorpórea/efectos adversos , Infecciones Fúngicas Invasoras/etiología , Oxigenadores de Membrana/microbiología , Candida albicans/genética , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/microbiologíaRESUMEN
AIMS: Pancreatic cancer (PC) is a heterogeneous disease in terms of histological and molecular subtypes. The aim of this study was to evaluate the prognostic impact of different histological subtypes on cancer-specific survival (CSS) in a large single-centre Middle European cohort. METHODS: We retrospectively studied the records of 400 consecutive PC patients who were treated from 2004 to 2010 at a single tertiary academic centre. The association of histological subtypes and parameters such as tumour stage, tumour grade, levels of tumour markers carcinoembryonic antigen and CA19-9 at diagnosis, was studied. CSS was calculated using the Kaplan-Meier method, and the influence of each parameter on CSS was assessed with univariate and multivariable Cox proportional models. RESULTS: The survival time was significantly shorter in the ductal adenocarcinoma and acinar histological subtypes compared to neuroendocrine differentiation (p<0.001). No survival difference was observed between ductal adenocarcinomas and patients with a histological variant of ductal adenocarcinoma, namely, mucinous non-cystic adenocarcinoma (p=0.7). In multivariable analysis, ductal adenocarcinoma (HR=3.1, CI 1.6 to 6.1, p=0.001) and acinar carcinoma (HR=3.2, CI 1.3 to 8.5, p=0.016) were identified as independent predictors for CSS. CONCLUSIONS: Our findings suggest that the main histological subtype is an independent predictor of CSS in patients with PC. Thus, our data underline the importance of routine assessment of histological type in PC for individual risk assessment. However, no clinical rationale for the subdivision of ductal adenocarcinoma and mucinous non-cystic adenocarcinoma can be supported by our study.
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Adenocarcinoma Mucinoso/patología , Carcinoma de Células Acinares/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidad , Anciano , Austria , Biomarcadores de Tumor/metabolismo , Antígeno CA-19-9/metabolismo , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/mortalidad , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: With growing evidence on the role of inflammation in cancer biology, the presence of a systemic inflammatory response has been postulated as having prognostic significance in a wide range of cancer types. The derived neutrophil to lymphocyte ratio (dNLR), which represents an easily determinable potential prognostic marker in daily practise and clinical trials, has never been externally validated in pancreatic cancer (PC) patients. METHODS: Data from 474 consecutive PC patients, treated between 2004 and 2012 at a single centre, were evaluated retrospectively. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method. To evaluate the prognostic relevance of dNLR, univariate and multivariate Cox regression models were applied. RESULTS: We calculated by ROC analysis a cut-off value of 2.3 for the dNLR to be ideal to discriminate between patients' survival in the whole cohort. Kaplan-Meier curve reveals a dNLR≥2.3 as a factor for decreased CSS in PC patients (p<0.001, log-rank test). An independent significant association between high dNLR≥2.3 and poor clinical outcome in multivariate analysis (HRâ=â1.24, CI95%â=â1.01-1.51, pâ=â0.041) was identified. CONCLUSION: In the present study we confirmed elevated pre-treatment dNLR as an independent prognostic factor for clinical outcome in PC patients. Our data encourage independent replication in other series and settings of this easily available parameter as well as stratified analysis according to tumor resectability.
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Linfocitos/patología , Neutrófilos/patología , Neoplasias Pancreáticas/patología , Anciano , Biomarcadores/análisis , Femenino , Humanos , Inflamación/diagnóstico , Inflamación/inmunología , Inflamación/mortalidad , Inflamación/patología , Estimación de Kaplan-Meier , Recuento de Leucocitos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
BACKGROUND: Patients with prostate cancer may present with metastatic or recurrent disease despite initial curative treatment. The propensity of metastatic prostate cancer to spread to the bone has limited repeated sampling of tumor deposits. Hence, considerably less is understood about this lethal metastatic disease, as it is not commonly studied. Here we explored whole-genome sequencing of plasma DNA to scan the tumor genomes of these patients non-invasively. METHODS: We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, that is, Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. In parallel, we sequenced a panel of 55 high-interest genes and 38 introns with frequent fusion breakpoints such as the TMPRSS2-ERG fusion with high coverage. After intensive testing of our approach with samples from 25 individuals without cancer we analyzed 13 plasma samples derived from five patients with castration resistant (CRPC) and four patients with castration sensitive prostate cancer (CSPC). RESULTS: The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q. High-level copy number gains in the AR locus were observed in patients with CRPC but not with CSPC disease. We identified the TMPRSS2-ERG rearrangement associated 3-Mbp deletion on chromosome 21 and found corresponding fusion plasma fragments in these cases. In an index case multiregional sequencing of the primary tumor identified different copy number changes in each sector, suggesting multifocal disease. Our plasma analyses of this index case, performed 13 years after resection of the primary tumor, revealed novel chromosomal rearrangements, which were stable in serial plasma analyses over a 9-month period, which is consistent with the presence of one metastatic clone. CONCLUSIONS: The genomic landscape of prostate cancer can be established by non-invasive means from plasma DNA. Our approach provides specific genomic signatures within 2 days which may therefore serve as 'liquid biopsy'.
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Circulating tumor cells (CTC) released into blood from primary cancers and metastases reflect the current status of tumor genotypes, which are prone to changes. Here, we conducted the first comprehensive genomic profiling of CTCs using array-comparative genomic hybridization (CGH) and next-generation sequencing. We used the U.S. Food and Drug Administration-cleared CellSearch system, which detected CTCs in 21 of 37 patients (range, 1-202/7.5 mL sample) with stage IV colorectal carcinoma. In total, we were able to isolate 37 intact CTCs from six patients and identified in those multiple colorectal cancer-associated copy number changes, many of which were also present in the respective primary tumor. We then used massive parallel sequencing of a panel of 68 colorectal cancer-associated genes to compare the mutation spectrum in the primary tumors, metastases, and the corresponding CTCs from two of these patients. Mutations in known driver genes [e.g., adenomatous polyposis coli (APC), KRAS, or PIK3CA] found in the primary tumor and metastasis were also detected in corresponding CTCs. However, we also observed mutations exclusively in CTCs. To address whether these mutations were derived from a small subclone in the primary tumor or represented new variants of metastatic cells, we conducted additional deep sequencing of the primary tumor and metastasis and applied a customized statistical algorithm for analysis. We found that most mutations initially found only in CTCs were also present at subclonal level in the primary tumors and metastases from the same patient. This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse.
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Neoplasias Colorrectales/genética , Hibridación Genómica Comparativa/métodos , Células Neoplásicas Circulantes/metabolismo , Neoplasias Colorrectales/patología , Dosificación de Gen , Genoma , Humanos , Mutación , Análisis de Secuencia de ADN , Análisis de la Célula IndividualRESUMEN
BACKGROUND: Pain is one of the most common symptoms in patients suffering from advanced cancer and receiving palliative care and is often responsible for a poor quality of life. To date, there exists no published correlation between biological, measurable biomarkers and pain intensity. OBJECTIVES: The primary objective was to search and identify pain-associated cytokines (biomarkers) correlating with changes in numeric rating scale (NRS) pain scores in patients with cancer before and after pain treatment. The secondary objectives were to assess cytokine serum level differences between patients and healthy controls and to evaluate possible relationships between pain entities, pain intensity (in NRS), gender, location of primary tumor, and the patients' cytokine baseline concentrations. STUDY DESIGN: Controlled, prospective study. SETTING: University medical center. METHODS: Eligible patients with exacerbated cancer-related pain (NRS = 5) and healthy controls with no pain were included. Serum level changes of 19 cytokines were analyzed before and during opioid treatment. RESULTS: Of 19 analyzed biomarkers, 5 (IL-7, IL-18, MCP-1, MIP-1α, MIP-1ß and OPG) turned out to correlate significantly with pain relief. In healthy controls, all analyzed cytokines showed no significant differences. In the secondary analysis, only one significant correlation was detected between OPG and pain entities. Furthermore, IL-4, IL-7, IFN-γ and OPG appeared to account for the ability to predict a patient's gender. LIMITATIONS: Our findings should be considered as preliminary and need to be confirmed in further studies. CONCLUSION: Our results provide preliminary evidence of a significant correlation of pain relief in patients with cancer and at least 5 cytokines. These biomarkers may serve as the basis for development of diagnostic tools for pain assessment and could serve as potential new targets for pain control.