Chou-Han Lin

TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.

Afatinib combined with cetuximab for lung adenocarcinoma with leptomeningeal carcinomatosis

We report a patient with non-small cell lung cancer (NSCLC) developed leptomeningeal carcinomatosis (LMC) after 4 years of multiple treatments. High-dose tyrosine kinase inhibitor (TKI) was given for LMC at first but was not effective. She then received dual therapy combining of afatinib and cetuximab. Brain magnetic resonance imaging (MRI) showed a partial response of disease and the patient experienced a clinical benefit. Our case suggests that dual targeting of epidermal growth factor receptor (EGFR) by a combination of afatinib and cetuximab can be a potential novel treatment option in treating LMC when high-dose TKI failed.

Soluble triggering receptor expressed on myeloid cells-1 as an infection marker for patients with neutropenic fever.

Objective:To assess the value of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of infection in patients with neutropenic fever comparing with procalcitonin and C-reactive protein. Design:Prospective, comparative, single-center study. Setting:Hematology ward at a university hospital. Subjects:Seventy-five patients with neutropenic fever after chemotherapy for their hematologic malignancies. Intervention:None. Measurements and Main Results:A total of 137 episodes of neutropenic fever in 75 patients were classified into 75 episodes of documented infections and 62 low likelihood of infection. The level of soluble triggering receptor expressed on myeloid cells-1 was significantly elevated in the group of documented infection. The area under the receiver operating characteristic curve for the diagnosis of infection was 0.719 (95% confidence interval, 0.632–0.806; p < .0001) for soluble triggering receptor expressed on myeloid cells-1, which was larger than the values of 0.501 for procalcitonin (0.465–0.657; p = .218) and 0.491 for C-reactive protein (0.394–0.589, p = .858). The fitted marginal logistic regression model of all episodes contained two statistically significant predictors of infection: soluble triggering receptor expressed on myeloid cells-1 (per 1-pg/mL increase; odds ratio [OR], 1.0002; 95% CI, 1.0001–1.0003; p < .0001) and procalcitonin (per 1-ng/mL increase; OR, 1.0094; 95% CI, 1.0005–1.0184; p = .0002). In a diagnostic panel with soluble triggering receptor expressed on myeloid cells-1 and procalcitonin, the sensitivity and specificity were 88% and 48%, respectively. Conclusions:Soluble triggering receptor expressed on myeloid cells-1 is better than procalcitonin in the prediction of infection at the onset of neutropenic fever. By applying soluble triggering receptor expressed on myeloid cells-1 and procalcitonin together, low or high risk for infection can be defined at the onset of neutropenic fever.

Prospective Evaluation of Procalcitonin, Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases

Background Both procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases. Methods Fifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 35). sTREM-1, PCT and CRP concentrations at fever onset were compared between the two groups of patients. Results sTREM-1 and CRP did not differ between the two groups. PCT [median (range), ng/ml] was higher in the infection group than in the disease flare group [0.53 (0.02–12.85) vs. 0.12 (0.02–19.23), p = 0.001]. The area under the receiver-operating characteristic (ROC) for diagnosis of infection was 0.75 for PCT (p = 0.001), 0.63 for CRP (p = 0.09) and 0.52 for sTREM-1 (p = 0.79). Using 0.2 ng/ml as the cutoff value for PCT, sensitivity was 0.75 and specificity was 0.77. Negative predictive values for PCT were 92%, 87% and 82% for a prevalence of infection of 20%, 30%, and 40%, respectively. Neither immunosuppressants nor biomodulators affected the level of the three biomarkers. However, in patients treated with corticosteroids, the levels of sTREM-1 and CRP were significantly decreased compared with the untreated patients. Conclusions Setting PCT at a lower cutoff value could provide useful information on excluding infection in febrile patients with autoimmune diseases. The possible effect of corticosteroids on the level of sTREM-1 as an infection marker deserves further study.

The trend and the disease prediction of vascular endothelial growth factor and placenta growth factor in nontuberculous mycobacterial lung disease.

Nontuberculous mycobacteria (NTM)-lung disease (LD) is an increasing health problem worldwide. The diagnosis of this disease remains difficult, however the application of placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) has not yet been studied. We screened patients with Mycobacterium avium complex or M. abscessus isolated from sputum, and enrolled 32 patients with NTM-LD and 93 with NTM pulmonary colonization. The NTM-LD group had a lower body mass index, higher proportion of bronchiectasis, more respiratory symptoms and pulmonary lesions, and higher titers of sputum acid-fast stain than the NTM pulmonary colonization group. The plasma level of PlGF was lower in the NTM-LD group than in the NTM colonization group, whereas the level of VEGF was higher in the NTM-LD group. In multivariable logistic regression analysis excluding NTM cultures, the predictive model for NTM-LD included sputum AFS titer, a nodular-bronchiectasis radiographic pattern, plasma VEGF/PlGF ratio, and chest radiographic score (VEGF/P1GF ratio became not significant as a factor in multivariable generalized linear model). The four-factor predictive index had good positive likelihood ratio and negative likelihood ratio for predicting NTM-LD in the patients with NTM in their sputum.

The New Nodular Lesions at the Brain Base

(See page 295 for the Photo Quiz.) Diagnosis: intracranial tuberculomas The cultures of both cerebrospinal fluid (CSF) and T12 spinal tissue samples (from a CT-guided biopsy) yielded isoniazid monoresistant Mycobacterium tuberculosis (resistant to isoniazid, 0.2 lg/mL). The result of a test for HIV antibodies was negative. We continued the use of isoniazid, rifampin, ethambutol, and pyrazinamide.

Shortness of breath while lying down: a woman with orthopneic asthma

A 36-year-old woman with a six-month history of worsening shortness of breath was admitted to hospital for investigation. She had received a diagnosis of bronchial asthma six months earlier, for which treatment with steroids and bronchodilators had been ineffective. Her history included allergic

A Case of Septic Shock due to Mycobacterium tuberculosis: An Uncommon and Forgotten Disease Entity?

Septic shock caused by Mycobacterium tuberculosis has rarely been reported following the advent of effective anti-tuberculous drugs. Since the emergence of human immunodeficiency virus (HIV) infection, there have been several reports regarding septic shock due to M. tuberculosis in these immunocompromised patients. Recently, this presentation has also been found in non-HIV patients. We described a non-HIV patient presenting with a rapidly fatal course; M. tuberculosis was the only causative micro-organism identified. Pulse contour cardiac output (PiCCO) was used for the first time to document the hemodynamic change in septic shock due to M. tuberculosis.