RESUMEN
Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.
RESUMEN
PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
Asunto(s)
Mutación de Línea Germinal , Neoplasias Urológicas/genética , Ácido Anhídrido Hidrolasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Quinasa de Punto de Control 2/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Estudios ProspectivosRESUMEN
AIMS AND BACKGROUND: Inflammation has been implicated in carcinogenesis and progression of pancreatic cancer. The neutrophil-to-lymphocyte ratio is an index of systemic inflammation. We examined the prognostic role of the neutrophil-to-lymphocyte ratio at baseline and the significance of intrapersonal variability of the ratio before and during chemotherapy. METHODS AND STUDY DESIGN: Advanced pancreatic adenocarcinoma patients who had received chemotherapy were included. Baseline clinical and biochemical parameters, including the neutrophil-to-lymphocyte ratio, were extracted and analyzed. The neutrophil-to-lymphocyte ratio threshold was determined via recursive partitioning and assessed at diagnosis, prior to chemotherapy and during treatment. Overall survival was estimated via the Kaplan-Meier method and compared between groups with the logrank test. RESULTS: Between 2005 and 2011, 85 patients with locally advanced (n = 38) and metastatic disease were identified: 68% with a neutrophil-to-lymphocyte ratio >3 had shorter median overall survival than patients with a neutrophil-to-lymphocyte ratio <3 (3.4 vs 9.4 months, P = 0.001). Pretreatment, 35% of repeat neutrophil-to-lymphocyte ratios crossed the threshold of 3. A persistently elevated neutrophil-to-lymphocyte ratio >3 suggested a worse overall survival than in patients with a decreasing, increasing or persistently low neutrophil-to-lymphocyte ratio (1.9 vs 8.2, 12.3 and 11.7 months, respectively, P <0.001). Twenty-three percent of patients had a >50% decrease in neutrophil-to-lymphocyte ratio following 4 weeks of chemotherapy, with a trend towards improvement in overall survival (12.5 vs 5.0 mo, P = 0.068). CONCLUSIONS: The baseline neutrophil-to-lymphocyte ratio is a validated marker for a poor prognosis. Multiple assessments of the pre-treatment neutrophil-to-lymphocyte ratio might be required. Reduction in the neutrophil-to-lymphocyte ratio during chemotherapy may be associated with improved survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/tratamiento farmacológico , Linfocitos , Neutrófilos , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Análisis de Varianza , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Valor Predictivo de las Pruebas , PronósticoAsunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/cirugía , Humanos , Neoplasias Renales/cirugía , Masculino , Metástasis de la Neoplasia/tratamiento farmacológico , Remisión Espontánea , SunitinibAsunto(s)
Sarcoidosis/etiología , Seminoma/terapia , Trasplante de Células Madre/efectos adversos , Neoplasias Testiculares/terapia , Terapia Combinada , Humanos , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Sarcoidosis/diagnóstico , Seminoma/patología , Neoplasias Testiculares/patología , Inmunología del Trasplante , Adulto JovenRESUMEN
BACKGROUND: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes. METHODS: Patients (pts) diagnosed with LAPC who survived >2 months were identified from institutional databases. Clinical details were collected. Sequential re-staging scans were reviewed. Progression-free survival (PFS), time from progression to death (TTD), and overall survival (OS) were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Between 2005 and 2011, 40 pts were identified. Median age was 66 yrs (range, 43-74) and 60 % (n=24) were male. All pts received chemotherapy. Median OS was 11.3 months. Twenty patients (50 %) had local progression only (LP) and 16 (40 %) had metastatic progression (MP) at first documentation of progression, while four patients (10 %) had stable disease. PFS was 4.0 vs 5.6 months (hazard ratio (HR) 0.97; 95 % CI 0.49-1.93, p=0.94) for LP and MP, respectively. Three of the patients with LP (15 %) eventually developed metastatic disease after a median of 4.2 months (3.7-9.6). For MP patients, five had concurrent local progression. Sites of disease were lung (eight), peritoneum (five), liver (three), and bone (one). TTD for LP and MP was 5.6 vs 1.4 months (HR 0.62; 95 % CI 0.28-1.39, p=0.24) and OS was 13.2 vs 8.0 months (HR 0.59; 95 % CI 0.28-1.25, p=0.017), respectively. CONCLUSIONS: We identified two subgroups of LAPC with distinctive behavior, one local dominant progression with low predilection for metastases and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome.
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Adenocarcinoma/mortalidad , Neoplasias Pancreáticas/mortalidad , Adenocarcinoma/clasificación , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adulto , Anciano , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Fenotipo , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Sorafenib is a multikinase inhibitor with an established role in treating renal cell carcinoma and hepatocellular carcinoma. In vivo studies have demonstrated sorafenib's inhibitory effects on various immune cells and cytokines which are essential to the maintenance of latency of granulomas in patients with latent tuberculosis infection. CASE REPORT: A 74-year-old male with clear cell renal cell carcinoma with pulmonary metastases was treated with sorafenib to good effect. However, he developed productive cough, sweats and weight loss. A computed tomography scan of the thorax demonstrated right lower lobe consolidation and cavitation. Sputum analysis was positive for tuberculous smear and culture. A diagnosis of sorafenib-induced tuberculosis reactivation was made. Sorafenib was held and anti-tuberculous antibiotics were commenced, which led to symptomatic and radiographic improvement. CONCLUSION: The authors postulate that sorafenib could increase the risk of progression from latent to active tuberculosis, and urge vigilance and possible screening for latent tuberculosis in patients who are treated with sorafenib.
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Antituberculosos/uso terapéutico , Tuberculosis Latente/inducido químicamente , Tuberculosis Latente/prevención & control , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/tratamiento farmacológico , Tuberculosis Latente/tratamiento farmacológico , Masculino , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Prevención Secundaria , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: A 44-year-old patient presented with intermittent macroscopic hematuria on a background of chronic left-sided hydronephrosis and intestinal metaplasia of the bladder. Cystoscopic examination revealed a mass at the dome of the urinary bladder, which was resected. Histopathologic analysis of the specimen confirmed the presence of muscle-invasive adenocarcinoma. Radical cystectomy with curative intent was planned, but review of systems and subsequent CT demonstrated pleural effusion with positive cytology, confirming metastatic disease. Owing to the histologic similarity between this patient's tumor and colorectal cancer, palliative FOLFOX6 (folinic acid, 5-fluorouracil and oxaliplatin) chemotherapy plus bevacizumab was administered. After 3 months of treatment the patient showed a good response, which was sustained for more than 10 months after diagnosis. However, his disease subsequently relapsed, and the patient died shortly thereafter. INVESTIGATION: Physical examination, cystoscopy, transurethral resection of bladder tissue, CT, histopathologic, cytopathologic and immunohistochemical analysis. DIAGNOSIS: Metastatic adenocarcinoma of the urinary bladder. MANAGEMENT: 12 cycles of infused and bolus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX6) plus bevacizumab.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Bevacizumab , Resultado Fatal , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Compuestos Organoplatinos/administración & dosificación , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patologíaAsunto(s)
Biomarcadores de Tumor/análisis , Carcinoma/diagnóstico , Carcinoma/tratamiento farmacológico , Neoplasias del Mediastino/diagnóstico , Proteínas Nucleares/análisis , Proteínas Oncogénicas/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Carcinoma/química , Carcinoma/patología , Diagnóstico Diferencial , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Inmunohistoquímica , Neoplasias del Mediastino/química , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/patología , Proteínas de Neoplasias , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Renal cell carcinoma is the second most common urological malignancy and it runs a highly variable clinical course. We describe a case of metastatic renal cell carcinoma in a 50-year-old lady with metastasis to the ampulla of Vater, clinically masquerading as cholelithiasis and biliary colic. The clinical, radiographic and endoscopic findings are presented. Ampullary metastases are rare, and prompt recognition and intervention are necessary before patient's performance status is compromised.