Acute undifferentiated leukemia: data on incidence and outcomes from a large population-based database.

Acute undifferentiated leukemia (AUL) is rare and defined by the absence of bona fide myeloid and lymphoid markers. Little is known about its incidence, survival and optimal management in the recent time period. Based on a case observed in our clinic, we queried the Surveillance, Epidemiology, and End Results database between 2000 and 2016. A total of 1,888 cases of AUL were diagnosed (1.34 per million person-years). The incidence of AUL has significantly decreased over time. Compared to other acute leukemias, patients with AUL have the highest median age (74 years); in contrast to acute myeloid leukemia (AML, 65) and acute lymphoblastic leukemia (ALL, 12). Excluding patients with preexisting malignancies, 1,444 patients with AUL were analyzed for survival. Only 35% of AUL patients had received chemotherapy. Comparatively, 94% of ALL and 71% of AML cases received chemotherapy. Among AUL patients who received chemotherapy, the median survival was 12 months as opposed to 1 month in the group who did not receive chemotherapy (or unknown status). Among adults, AUL patients had the worst prognosis, with a median overall survival (OS) of 9 months, compared to 27 months in ALL and 13 months in AML. Among children, the median OS was superior for all three groups of leukemias, the OS of AUL patients being better than in AML and very similar to ALL. On multivariate analysis, older age and time period were associated with worse outcome. We describe here the largest series of cases with AUL published to date.

Measurement of BCR-ABL1 transcripts on the International Scale in the United States: current status and best practices.

Chronic myeloid leukemia (CML) results from the Philadelphia chromosome (Ph) translocation and expression of its fusion oncoprotein BCR-ABL1. BCR-ABL1 tyrosine kinase inhibitors (TKIs) are the standard therapy for Ph-positive CML. Achievement of deep molecular responses (typically defined as ≥4-log reduction in BCR-ABL1 RNA levels) is an emerging treatment goal becoming attainable for more patients due to the availability of second-generation TKIs. Deep molecular responses are associated with improved long-term outcomes and are required prior to attempting cessation of treatment in treatment-free remission clinical trials. The National Comprehensive Cancer Network and European LeukemiaNet recommend regular monitoring of BCR-ABL1 RNA levels using real-time quantitative polymerase chain reaction (RQ-PCR). However, BCR-ABL1 RQ-PCR is a complex laboratory-developed test; routine quantitative results from clinical diagnostic laboratories may differ from those used to establish the recommendations. Although an International Scale (IS) was developed for standardized reporting of BCR-ABL1 RNA levels, IS adoption has been slow in the United States, but is now used by the vast majority of laboratories. Here, we discuss the importance of molecular monitoring in CML, gaps between current and best molecular monitoring practices in the United States, and challenges and potential solutions for universal IS adoption in the United States.

Association of pellicle growth morphological characteristics and clinical presentation of Mycobacterium tuberculosis isolates.

Trehalose 6,6'dimycolate (TDM) is a glycolipid found in nearly pure form on the surface of virulent Mycobacterium tuberculosis (MTB). This manuscript investigated the production of TDM, growth rate and colony morphology of multiple strains of MTB, each of which had been isolated from both pulmonary (sputum) and extrapulmonary sites of multiple patients. Since sputum contains MTB primarily from cavities and extrapulmonary biopsies are typically granulomas, this provided an opportunity to compare the behavior of single strains of MTB that had been isolated from cavities and granulomas. The results demonstrated that MTB isolated from pulmonary sites produced more TDM (3.23 ± 1.75 µg TDM/mg MTB), grew more rapidly as thin spreading pellicles, demonstrated early cording, and climbed culture well walls. In contrast, extrapulmonary isolates produced less TDM (1.42 ± 0.58 µg TDM/mg MTB) (p < 0.001) and grew as discrete patches with little tendency to spread or climb. Both Beijing pulmonary isolates and the non-Beijing pulmonary isolates produced significantly more TDM (1.64 ± 0.46 µg TDM/mg MTB) and grew faster than the Beijing and non-Beijing extrapulmonary isolates (1.14 ± 0.63 µg TDM/mg MTB) (p < 0.001 and p < 0.005 respectively). These results indicate that MTB from pulmonary sites (cavities) grows faster and produces more TDM than strains isolated from extrapulmonary sites (granulomas). This report suggests a critical role for TDM in cavitary TB.

Targeted Next-Generation Sequencing in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Aids Diagnosis in Challenging Cases and Identifies Frequent Spliceosome Mutations in Transformed Acute Myeloid Leukemia.

OBJECTIVES: Optimal integration of next-generation sequencing (NGS) into clinical practice in hematologic malignancies remains unclear. We evaluate the utility of NGS in myeloid malignancies. METHODS: A 42-gene panel was used to sequence 109 cases of myelodysplastic syndrome (MDS, n = 38), chronic myelomonocytic leukemia (CMML, n = 14), myeloproliferative neoplasm (MPN, n = 24), and MDS and/or MPN transformed to acute myeloid leukemia (AML, n = 33). RESULTS: At least one pathogenic mutation was identified in 74% of cases of MDS, 100% of CMMLs, and 96% of MPNs. In contrast, only 47% of cases of MDS (18/38) and 7% (1/14) of CMMLs exhibited abnormal cytogenetics. In diagnostically difficult cases of MDS or CMML with normal cytogenetics, NGS identified a pathogenic mutation and was critical in establishing the correct diagnosis. Spliceosomal genes and epigenetic modifiers were frequently mutated. Spliceosome mutations were also frequently detected in AML arising from MDS, CMML, or MPN (39%) compared with the reported rate in de novo AML (7%-14%). CONCLUSIONS: In difficult cases of MDS or MPN, NGS facilitates diagnosis by detection of gene mutations to confirm clonality, and AMLs evolving from MDS or MPN carry frequent mutations in spliceosomal genes.

Certain surfactants show promise in the therapy of pulmonary tuberculosis.

BACKGROUND/AIM: The aim of the present study was to develop the basis for the use of surfactants in the treatment of pulmonary tuberculosis (TB). Bacteria are surrounded by a thick lipid coat primarily consisting of trehalose dimycolate (TDM) and, consequently, are well shielded from the immune system's response and antibiotics. This protective barrier was removed by exposing the bacteria to certain surfactants. MATERIALS AND METHODS: Dodecyl maltoside (DDM) and octyl glucoside (OG) were utilized as non-toxic surfactants. RESULTS: Electron microscopy (EM) studies revealed that aggregated bacteria were also covered with excessive TDM which exacerbate the treatment efforts. Light and EM studies demonstrated that DDM and OG disperse the aggregated bacteria and are bactericidal. CONCLUSION: The studies presented here establish that certain surfactants are proficient in removing MTB's shield and, because they are well known as cell permeabilizing agents, they may also enhance the effectiveness of antibiotics and the immune system's response in the treatment of pulmonary TB.

Lactoferrin enhances efficacy of the BCG vaccine: comparison between two inbred mice strains (C57BL/6 and BALB/c).

The current vaccine for tuberculosis (TB), an attenuated strain of Mycobacterium bovis Bacillus Calmette Guerin (BCG), is effective to prevent childhood onset of the disease, but its efficacy is reduced in adults. One strategy to improve the existing vaccine is to develop more effective adjuvants. Lactoferrin, an iron-binding glycoprotein possessing immune modulatory activities, is a promising adjuvant candidate. The studies presented here examine the effect of lactoferrin to enhance efficacy of the BCG vaccine using a vaccination/challenge protocol (8 weeks boost and challenge at 12 weeks post-boost) that focuses on reduction in development of pathological changes to lung tissue. C57BL/6 and BALB/c mice vaccinated with BCG/lactoferrin exhibited protection upon Mycobacterium tuberculosis (MTB) challenge, showing reduced pulmonary disease pathology and decreased organ bacterial load. In addition, BCG/lactoferrin-treated macrophages isolated from BALB/c mice, which express a relative reduced T(H)1 phenotypic response to MTB antigens compared to the C57BL/6 mouse, were able to activate a higher percentage of IFN-gamma-producing CD4+ splenocytes. Overall, lactoferrin stands as an adjuvant capable of enhancing efficacy of the BCG vaccine through induction of T(H)1 immune responses, even in hosts typically demonstrative of reduced T(H)1 responsiveness to BCG antigens.

Ovarian hyperstimulation syndrome after a molar pregnancy evacuation.

OBJECTIVE: To increase awareness of the development of ovarian hyperstimulation syndrome (OHSS) days after a molar pregnancy evacuation. DESIGN: Case report. SETTING: Community hospital. PATIENT(S): A 23-year-old woman with severe OHSS. INTERVENTION(S): Supportive management and observation in the hospital. MAIN OUTCOME MEASURE(S): Regression of the symptoms and physical signs of OHSS in a woman who developed severe OHSS 3 days after a molar pregnancy evacuation. RESULT(S): The patient improved and was discharged home. CONCLUSION(S): This case reinforces, besides the occurrence of OHSS after spontaneous pregnancy, the fact that the syndrome can present days after the usual curative dilatation and evacuation of a molar pregnancy, and that OHSS should be considered in the differential diagnosis.