Level III.

In contrast to IKZF1 deletions (ΔIKZF1), IKZF1 sequence mutations (mutIKZF1) have been reported to be rare in B-cell precursor acute lymphoblastic leukemia and their clinical implications are unknown. We performed targeted deep sequencing of all exons of IKZF1 in 140 pediatric cases, eight (5.7%) of which harbored a mutIKZF1. The probabilities of relapse (pRel) and event-free survival (pEFS) did not differ between cases with or without mutIKZF1, whereas pEFS was decreased and pRel increased in ΔIKZF1-positive case. Coexisting microdeletions, mutations (FLT3, JAK2, SH2B3, and SPRED1), and rearrangements (ABL1, CRLF2, JAK2, and PDGFRB) in 35 ΔIKZF1 and/or mutIKZF1-positive cases were ascertained using fluorescence in situ hybridization, single nucleotide polymorphism array, Sanger, and targeted deep sequencing analyses. The overall frequencies of copy number alterations did not differ between cases with our without ΔIKZF1/mutIKZF1. Deletions of HIST1, SH2B3, and the pseudoautosomal region (PAR1), associated with deregulation of CRLF2, were more common in ΔIKZF1-positive cases, whereas PAR1 deletions and JAK2 mutations were overrepresented in the combined ΔIKZF1/mutIKZF1 group. There was no significant impact on pRel of the deletions in ΔIKZF1-positive cases or of JAK2 mutations in cases with ΔIKZF1/mutIKZF1. In contrast, the pRel was higher (P = 0.005) in ΔIKZF1/mutIKZF1-positive cases with PAR1 deletions.

Background: Determining the need for prostate biopsy is frequently difficult and more objective criteria are needed to predict the presence of high grade prostate cancer (PCa). To reduce the rate of unnecessary biopsies, we explored the potential of using biomarkers in urine and plasma to develop a scoring system to predict prostate biopsy results and the presence of high grade PCa.Methods: Urine and plasma specimens were collected from 319 patients recommended for prostate biopsies. We measured the gene expression levels of UAP1, PDLIM5, IMPDH2, HSPD1, PCA3, PSA, TMPRSS2, ERG, GAPDH, B2M, AR, and PTEN in plasma and urine. Patient age, serum prostate-specific antigen (sPSA) level, and biomarkers data were used to develop two independent algorithms, one for predicting the presence of PCa and the other for predicting high-grade PCa (Gleason score [GS] ≥7).Results: Using training and validation data sets, a model for predicting the outcome of PCa biopsy was developed with an area under receiver operating characteristic curve (AUROC) of 0.87. The positive and negative predictive values (PPV and NPV) were 87% and 63%, respectively. We then developed a second algorithm to identify patients with high-grade PCa (GS ≥7). This algorithm's AUROC was 0.80, and had a PPV and NPV of 56% and 77%, respectively. Patients who demonstrated concordant results using both algorithms showed a sensitivity of 84% and specificity of 93% for predicting high-grade aggressive PCa. Thus, the use of both algorithms resulted in a PPV of 90% and NPV of 89% for predicting high-grade PCa with toleration of some low-grade PCa (GS <7) being detected.Conclusions: This model of a biomarker panel with algorithmic interpretation can be used as a “liquid biopsy” to reduce the need for unnecessary tissue biopsies, and help to guide appropriate treatment decisions.

These data suggest that cf-DNA when analyzed using NGS is a reliable approach for detecting molecular abnormalities in MDS and should be used to determine if bone marrow aspiration and biopsy are necessary.

Tissue-based determination of Ki-67, a marker of cellular proliferation, has shown prognostic value in solid tumors and hematological malignancies. We developed and validated an electrochemiluminescence-based method for sensitive measurement of circulating Ki-67 in plasma (cKi-67). This assay demonstrated significantly higher levels of cKi-67 in patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=27; median, 762; range, 0-4574 U/100 μL) than in healthy control subjects (n=114; median, 399; range, 36-2830 U/100 μL). Moreover, elevated plasma cKi-67 was associated with significantly shorter survival in ALL patients (P=0.05). These findings suggest that Ki-67 can be detected in circulation and has potential for use as a biomarker for predicting clinical behavior in ALL.