ABSTRACT
A 48-year-old man with history of recent travel to central Mexico and immunosuppression sought treatment with a 1-month-long history of progressive headache, fatigue, word-finding difficulties, and night sweats. The patient had a history of end-stage renal disease; he had undergone a kidney transplantation 7 years prior with good graft function with immunosuppression with tacrolimus, everolimus, and low-dose prednisone. At an outside hospital, he recently had been treated with empiric antibiotics for meningitis, but these were discontinued given the low suspicion for a bacterial cause. After discharge, he continued to have headaches, limited oral intake, persistent nausea, urinary frequency, and falls, prompting him to seek treatment at the ED. Physical examination findings were benign aside from disorientation. Laboratory workup was significant for hyponatremia of 122 mM, creatinine of 1.4 mg/dL (baseline, 1.4-1.5 mg/dL), WBC count of 7.2 109/L, hemoglobin of 13 g/dL, and platelet count of 349 109/L. Neither tacrolimus nor everolimus levels were supratherapeutic.
ABSTRACT
INTRODUCTION: Mesenchymal-epithelial transition factor gene (MET) gene copy number gain may be a predictive biomarker for mesenchymal-epithelial transition factor (MET) inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. METHODS: MET copy number was assessed by fluorescence in situ hybridization in lung adenocarcinoma. Positivity criteria included mean MET per cell values greater than 5 (low [≥5 to <6], intermediate [≥6 to <7], and high [≥7]) and mean MET-to-chromosome 7 centromere ratios (MET/CEP7) of at least 1.8 (low [≥1.8 to ≤2.2], intermediate [>2.2 to <5], and high [≥5]). Associated clinical and molecular characteristics were captured. RESULTS: Of 686 cases, 99 (14%) had a mean MET per cell value of 5 or greater, 52 of 1164 (4.5%) had a MET/CEP7 ratio of 1.8 or higher. Other oncogenic drivers (in EGFR, KRAS, anaplastic lymphoma receptor tyrosine kinase gene [ALK], erb-b2 receptor tyrosine kinase 2 gene [ERBB2], BRAF, NRAS, ROS1, or ret proto-oncogene [RET]) were detectable in 56% of the group with a mean MET per cell value of 5 or higher and 47% of the group with a MET/CEP7 ratio of 1.8 or higher, suggesting that many MET-positive cases are not truly MET addicted. The rates of concomitant drivers in the groups of patients in the low, indeterminate, and high categories of mean MET per cell were 32 of 52 (62%), 12 of 19 (63%), and 11 of 27 (41%) (p = 0.2), and the rates of concomitant drivers in the low, intermediate, and high categories of MET/CEP7 ratios were 15 of 29 (52%), 9 of 18 (50%), and 0 of 4 (0%), respectively (p = 0.04). A MET/CEP7 ratio of 1.8 or higher in the absence of other oncogenes was associated with a higher rate of adrenal metastases (p = 0.03) but not with never-smoking status. CONCLUSIONS: A fluorescence in situ hybridization MET/CEP7 ratio of 5 or higher defined a "MET-positive" group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition, it represents the clearest definition of a MET copy number gain-addicted state. However, a MET-associated phenotype may also exist across cases with a MET/CEP7 of 1.8 or higher when no other oncogene overlap occurs.
Subject(s)
Adenocarcinoma/genetics , Gene Dosage , In Situ Hybridization, Fluorescence/methods , Lung Neoplasms/genetics , Oncogenes , Proto-Oncogene Proteins c-met/genetics , Adenocarcinoma of Lung , Centrosome , Female , Humans , Male , Middle Aged , Proto-Oncogene Mas , Retrospective StudiesABSTRACT
The aim of this study was to compare tumor expression of prognostic biomarkers between interval breast cancers and screen-detected breast cancers overall, and according to age at diagnosis and familial risk. Tissue micro-arrays were constructed from 98 breast cancers (47 interval and 51 screen-detected) diagnosed in women in the Cancer Genetics Network. Arrays were immuno-stained to compare protein expression of six biomarkers including estrogen and progesterone receptor (ER/PR), Her2/neu, EGFR, cytokeratin 5/6, and Ki67. Fisher's Exact test was used to compare expression between interval and screen-detected cancers. Interval cancers were larger (P = 0.04), higher stage (P < 0.001), and more likely to have lobular histology (P = 0.01) than screen-detected cancers. Overall, interval cancers more often overexpressed EGFR (P = 0.01) and were somewhat more likely to be ER- (55% vs. 43%, P = 0.3), and triple negative (ER-/PR-/Her2-) (21 vs. 12%, P = 0.26). A greater difference in the proportion of interval versus screen-detected tumors that were ER- (53 vs. 35%; P = 0.29), PR- (35 vs. 21%; P = 0.25) and EGFR+ (17 vs. 0%; P = 0.02) was evident among women over 50. There was a trend toward differential expression among women with familial risk for PR- (P = 0.005) and triple negative status (P = 0.02). This study provides new data indicating that EGFR may be important in the etiology of interval cancer and be a possible therapeutic target. Our data also suggest that biological differences between interval and screen-detected cancers are more defined in older women. Future studies to confirm this finding and to elucidate novel markers for characterizing interval cancers may be more beneficial to this subgroup.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Adult , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Female , Humans , Middle Aged , PrognosisABSTRACT
Myocardial infarction is a common life-threatening condition. Multiple agents can be used to treat acute coronary syndrome (ACS). These therapeutic agents pose potential life-threatening complications when used outside the realm of the acute coronary syndrome. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder, occurring in 1 in 500 individuals, which may mimic ACS. The hypertrophy most typically involves the septum in patients with HCM. As many as 25% of Japanese patients with HCM have predominately apical involvement. Apical hypertrophic cardiomyopathy (AHC) occurs in only 1 to 2% of the non-Japanese population. Despite its low incidence, physicians caring for patients with chest pain need to consider AHC in their differential diagnosis. We present the case of a patient with chest pain and electrocardiographic changes suggestive of ACS who was later found to have AHC.