RESUMO
Purpose: To evaluate whether changes in genomic expression that occur beginning with breast cancer (BC) diagnosis and through to tumor resection after neoadjuvant chemotherapy (NCT) reveal biomarkers that can help predict therapeutic response and survival. Materials and Methods: We determined gene expression profiles based on microarrays in tumor samples from 39 BC patients who showed pathologic complete response (pCR) or therapeutic failure (non-pCR) after NCT (cyclophosphamide-doxorubicin/epirubicin). Based on unsupervised clustering of gene expression, together with functional enrichment analyses of differentially expressed genes, we selected NUSAP1, PCLAF, MME, and DST. We evaluated the NCT response and the expression of these four genes in BC histologic subtypes. In addition, we study the presence of tumor-infiltrating lymphocytes. Finally, we analyze the correlation between NUSAP1 and PCLAF against disease-free survival (DFS) and overall survival (OS). Results: A signature of 43 differentially expressed genes discriminated pCR from non-pCR patients (|fold change >2|, false discovery rate <0.05) only in biopsies taken after surgery. Patients achieving pCR showed downregulation of NUSAP1 and PCLAF in tumor tissues and increased DFS and OS, while overexpression of these genes correlated with poor therapeutic response and OS. These genes are involved in the regulation of mitotic division. Conclusions: The downregulation of NUSAP1 and PCLAF after NCT is associated with the tumor response to chemotherapy and patient survival.
RESUMO
Red cell overproduction is seen in polycythemia vera (PV), a bone marrow myeloproliferative neoplasm characterized by trilinear cell proliferation (WBC, platelets), as well as in secondary erythrocytosis (SE), a group of heterogeneous disorders characterized by elevated EPO gene transcription. We aimed to verify the concordance of the International Classification of Diseases (ICD) code-based diagnosis of "polycythemia" or "erythrocytosis" with the true clinical diagnosis of these conditions. We retrospectively reviewed the electronic medical records (January 1, 2005, to December 31, 2016) of adult patients with ICD codes of polycythemia and/or erythrocytosis who had testing done for the presence of the JAK2V617F mutation. We verified the accuracy of the ICD code-based diagnoses by meticulous chart review and established whether these patients fulfilled the criteria by the evaluating physician for PV or SE and according to the World Health Organization 2016 diagnostic guidelines. The reliability of ICD coding was calculated using Cohen's kappa. We identified and chart reviewed a total of 578 patient records. Remarkably, 11% of the patients had concurrent diagnosis codes for PV and SE and were unable to be classified appropriately without individual chart review. The ICD code-based diagnostic system led to misidentification in an important fraction of cases. This represents a problem for the detection of PV or SE cases by ICD-based registries and their derived studies. Research based exclusively on ICD codes could have a potential impact on patient care and public health, and limitations must be weighed when research findings are conveyed.
Assuntos
Policitemia Vera , Policitemia , Adulto , Humanos , Janus Quinase 2/genética , Policitemia/diagnóstico , Policitemia/genética , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
INTRODUCTION: Considering the evolving diagnostic criteria of polycythemia vera (PV), we analyzed the utility of serum erythropoietin (EPO) as a predictive marker for differentiating polycythemia vera (PV) from other etiologies of erythrocytosis. PATIENTS AND METHODS: We conducted a retrospective study after a review of electronical medical records from January 2005 to December 2016 with diagnosis of erythrocytosis using International Classification of Disease-specific codes. To evaluate the diagnostic performance of EPO levels and JAK2-V617F mutation, we constructed a receiver-operated characteristic curve of sensitivity versus 1-specificity for serum EPO levels and JAK2-V617F mutation as predictive markers for differentiating PV from other causes of erythrocytosis. RESULTS: We surveyed 577 patients with erythrocytosis. Median patient age was 59.2 years, 57.72% (n = 329) were male, 86.3% (n = 491) were white, and only 3.3% (n = 19) were African American. A total of 80.88% (n = 351) of those diagnosed with PV had a JAK2-V617F mutation compared to only 1.47% (n = 2) whose primary diagnosis was secondary polycythemia. When comparing JAK2-V617 mutation to the EPO level, the area under the curve of JAK2-V617 (0.8970) was statistically larger than that of EPO test (0.6765). Therefore, the PV diagnostic methodology using JAK2-V617 is better than the EPO test. An EPO level of < 2 mIU/mL was > 99% specific to predict PV but was only 12% sensitive. CONCLUSION: In the appropriate clinical setting, cytogenetic and molecular studies such as JAK2 mutation status prevail as the most useful tools for PV case identification. The use of isolated EPO to screen patients with erythrocytosis is not a good diagnostic approach.
Assuntos
Eritropoetina/sangue , Janus Quinase 2/genética , Policitemia Vera/diagnóstico , Policitemia/etiologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Institutos de Câncer , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Policitemia Vera/sangue , Policitemia Vera/complicações , Policitemia Vera/genética , Valor Preditivo dos Testes , Curva ROC , Estudos RetrospectivosRESUMO
Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of surfactant-like lipoprotein material within distal bronchioles and alveoli due to impaired clearance. Clinically, PAP presents with dyspnea and cough. A 58-year-old Hispanic man presented with 6 months of productive cough, weight loss, and progressively worsening dyspnea. He reported a long history of poorly controlled type 2 diabetes that led to diabetic nephropathy. The patient had a strong passive smoking history for over 30 years and exposure to woodsmoke. He had pulmonary tuberculosis in 2007 and 2012. In 2011, he was diagnosed with renal failure, was dialyzed for a year, and received a renal transplant in 2012. His posttransplant medication regimens included tacrolimus, mycophenolic acid, and prednisone. Six months after the transplant, he suffered graft rejection, managed with steroids and switching from tacrolimus to sirolimus. His physical examination demonstrated scattered inspiratory crackles, and a chest X-ray showed bilateral perihilar ground-glass opacities. PAP was diagnosed through lung biopsy, which showed eosinophilic granular infiltrate withing the alveoli. Sirolimus was switched back to tacrolimus 2 mg in September 2018. PAP diagnosis included hematoxylin and eosin and PAS. Clinical follow-up included oxygen saturation with pulse oximeter and chest X-rays. A 2-month follow-up showed only partial improvement in both symptoms and radiological findings. In January 2019, a follow-up showed complete radiological and symptomatologic resolution. After 5 months, the patient remains asymptomatic with adequate exertion tolerance. PAP remains a diagnosis of exclusion in patients undergoing immunomodulatory therapy with sirolimus and pulmonary symptoms. Reversal can be achieved by switching agents.