Marcin Braun

Biallelic loss of CDKN2A is associated with poor response to treatment in pediatric acute lymphoblastic leukemia

Abstract The inactivation of tumor suppressor genes located within 9p21 locus (CDKN2A, CDKN2B) occurs in up to 30% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its independent prognostic significance remains controversial. In order to investigate the prognostic impact of deletions and promoter methylation within 9p21, 641 children with newly diagnosed BCP-ALL using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were investigated. A total of 169 (26.4%) microdeletions in 9p21 were detected, of which 71 were homozygous. Patients with CDKN2A homozygous deletions were older at diagnosis (p < .001), more frequently steroid resistant (p = .049), had higher WBC count (p < .001), higher MRD at Day 15 (p = .013) and lower relapse-free survival [p = .028, hazard ratio: 2.28 (95% confidence interval: 1.09–4.76)] than patients without these alterations. CDKN2A homozygous deletions coexisted with IKZF1 and PAX5 deletions (p < .001). In conclusion, CDKN2A homozygous deletions, but not promoter methylation, are associated with poor response to treatment and increased relapse risk of pediatric BCP-ALL.

The Stricter the Better? The Relationship between Targeted HbA1c Values and Metabolic Control of Pediatric Type 1 Diabetes Mellitus

Introduction. It remains unclear how HbA1c recommendations influence metabolic control of paediatric patients with type 1 diabetes mellitus. To evaluate this we compared reported HbA1c with guideline thresholds. Materials and Methods. We searched systematically MEDLINE and EMBASE for studies reporting on HbA1c in children with T1DM and grouped them according to targeted HbA1c obtained from regional guidelines. We assessed the discrepancies in the metabolic control between these groups by comparing mean HbA1c extracted from each study and the differences between actual and targeted HbA1c. Results. We included 105 from 1365 searched studies. The median (IQR) HbA1c for the study population was 8.30% (8.00%–8.70%) and was lower in “6.5%” than in “7.5%” as targeted HbA1c level (8.20% (7.85%–8.57%) versus 8.40% (8.20%–8.80%); p = 0.028). Median difference between actual and targeted HbA1c was 1.20% (0.80%–1.70%) and was higher in “6.5%” than in “7.5%” (1.70% (1.30%–2.07%) versus 0.90% (0.70%–1.30%), resp.; p < 0.001). Conclusions. Our study indicates that the 7.5% threshold results in HbA1c levels being closer to the therapeutic goal, but the actual values are still higher than those observed in the “6.5%” group. A meta-analysis of raw data from national registries or a prospective study comparing both approaches is warranted as the next step to examine this subject further.

Efficacy and safety of B-cell receptor signaling pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis of randomized clinical trials

Abstract Ibrutinib and idelalisib, B-cell receptor (BCR) signaling pathway inhibitors, have been recently approved for use against relapsed/refractory chronic lymphocytic leukemia (CLL). To assess the efficacy and safety of BCR pathway inhibitors in relapsed/refractory CLL, we conducted a systematic review and meta-analysis of five randomized controlled trials (1866 patients). Our study demonstrated that BCR pathway inhibitors significantly prolonged progression-free survival (PFS; pooled HR = 0.24; 95% CI: 0.19–0.30) and overall survival (HR = 0.58; 0.46–0.73) compared with control treatment. BCR pathway inhibitors increased the probability of response (RR = 3.54; 95% CI: 1.69–7.41) and decreased the risk of progression (RR = 0.21, 95% CI: 0.13–0.34). However, BCR pathway inhibitors increased the risk of grade 3 and 4 adverse events (AEs; RR = 1.25; 95% CI: 1.08–1.44) and serious AEs (RR = 1.32; 95% CI: 1.17–1.50). AEs causing discontinuation (RR = 1.26; 95% CI: 0.88–1.81) or death (RR = 1.06; 95% CI: 0.72–1.57) were not significantly increased. No statistically significant difference in any aspect of meta-analysis was noted between ibrutinib and idelalisib.

MicroRNAs in regulation of triple-negative breast cancer progression

PurposeDysregulation of miRNA profile has been associated with a broad spectrum of cellular processes underlying progression of various human malignancies. Increasing evidence suggests that specific microRNA clusters might be of clinical utility, especially in triple-negative breast carcinoma (TNBC), devoid of both predictive markers and potential therapeutic targets. Here we provide a comprehensive review of the existing data on microRNAs in TNBC, their molecular targets, a putative role in invasive progression with a particular emphasis on the epithelial-to-mesenchymal transition (EMT) and acquisition of stem-cell properties (CSC), regarded both as prerequisites for metastasis, and significance for therapy.MethodsPubMed and Medline databases were systematically searched for the relevant literature. 121 articles have been selected and thoroughly analysed.ResultsSeveral miRNAs associated with EMT/CSC and invasion were identified as significantly (1) upregulated: miR-10b, miR-21, miR-29, miR-9, miR-221/222, miR-373 or (2) downregulated: miR-145, miR-199a-5p, miR-200 family, miR-203, miR-205 in TNBC. Dysregulation of miR-10b, miR-21, miR-29, miR-145, miR-200 family, miR-203, miR-221/222 was reported of prognostic value in TNBC patients.ConclusionAvailable data suggest that specific microRNA clusters might play an important role in biology of TNBC, understanding of which should assist disease prognostication and therapy.

Polymorphism in IKZF1 gene affects clinical outcome in diffuse large B-cell lymphoma

IKZF1 encodes a transcription factor involved in B-cell maturation and differentiation. We genotyped 218 diffuse large B-cell lymphoma (DLBCL) patients and 715 unrelated controls using a TaqMan allelic discrimination assay. No statistical difference was observed in the genotype distribution of the IKZF1 rs4132601 polymorphism between DLBCL patients and controls. However, the 2-year PFS rate of patients with the IKZF1 TT genotype was 54.3% compared to 68.6% in those with the IKZF1 G+ genotypes. Moreover, the IKZF1 rs4132601 polymorphism retained its independent prognostic impact on PFS. A more pronounced effect of the IKZF1 TT genotype on PFS was detected in patients with low/intermediate low IPI-risk group. When analysis was restricted to patients with GCB-type pattern, those with the IKZF1 TT genotype achieved a lower 5-year OS rate than the patients with the IKZF1 G+ genotypes (19.6 vs. 56%). This study provides the first evidence for the association of IKZF1 variants with DLBCL outcome.

A malignant astrocytoma with uncommon angiocentric features and dot-like EMA expression

Angiocentric features are uncommon in high-grade World Health Organisation (WHO) brain tumours, whilst they are typical for WHO grade I tumours, e.g. angiocentric gliomas. We present an unusual glial tumour that occurred in a 59-year-old man. The tumour had equivocal radiologic and histopathologic features, especially a characteristic angiocentric pattern, low-to-moderate Ki67, and dot-like epithelial membrane antigen expression. The tumour did not show features characteristic for glioblastoma; however, it recurred as glioblastoma four months later. Based on this case, we show that high-grade WHO brain tumours may show an angiocentric pattern typical for low-grade WHO brain tumours, such as angiocentric gliomas.

Recurrent Pineocytomalike Papillary Tumor of The Pineal Region: A Case Report and Literature Review

BACKGROUND Papillary tumors of the pineal region (PTPRs) are malignant World Health Organization grade II/III tumors; however, they may perfectly mimic benign tumors (e.g., pineocytomas [World Health Organization grade I]). CASE DESCRIPTION We present a case of a 28-year-old man with a 35-mm tumor of the pineal region. Considering the typical radiological and pathologic presentation, the tumor was first diagnosed as pineocytoma. However, despite first total resection, the tumor recurred after 7 years. The recurrent neoplasm was composed mainly of papillary structures with low-grade atypical cells positive for CKAE1/AE3 and CK18. This categorization led to the final diagnosis of PTPR. The patient underwent adjuvant radiotherapy, which vastly improved his neurologic condition and resulted in significant tumor regression. CONCLUSIONS This case exemplifies that PTPRs can perfectly mimic pineocytomas and simple staining for cytokeratins may warrant correct diagnosis and better treatment.

Surface expression of Cytokine Receptor-Like Factor 2 increases risk of relapse in pediatric acute lymphoblastic leukemia patients harboring IKZF1 deletions

We prospectively examined whether surface expression of Cytokine Receptor-Like Factor 2 (CRLF2) on leukemic blasts is associated with survival and induction treatment response in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Flow cytometric analysis of bone marrow-derived leukemia cells revealed that 7.51% (29/286) of 386 pediatric BCP-ALL patients were CRLF2-positive (CRLF2pos) at diagnosis. The median minimal residual disease (MRD) was lower in CRLF2pos than CRLF2-negative (CRLF2neg) patients on day 15 (MRD15) after induction therapy [0.01% (0.001-0.42%) vs. 0.45% (0.05-3.50%); p=0.001]. By contrast, the MRD15 was higher in Ikaros family Zinc Finger Protein 1 (IKZF1)-deleted BCP-ALL patients than in BCP-ALL patients without IKZF1 deletions [1.18% (0.06-12.0%) vs 0.33% (0.03-2.6%); p=0.003]. Subgroup analysis showed that MRD15 levels were lower in IKZF1Δ/CRLF2pos patients than in IKZF1Δ/CRLF2neg patients [0.1% (0.02-5.06%) vs. 2.9% (0.25-12%); p=0.005]. Furthermore, MRD15 levels were higher in IKZF1WT/CRLF2neg patients than in IKZF1WT/CRLF2pos patients [0.40% (0.04-2.7%) vs. 0.001% (0.001-0.01%)]. Despite the low MRD15 levels, IKZF1Δ/CRLF2pos patients showed poorer relapse-free survival (RFS) than other patient groups (p=0.003). These findings demonstrate that surface CRLF2 expression is associated with increased risk of relapse in pediatric BCP-ALL patients harboring IKZF1 deletions.

Intratumor heterogeneity and tissue distribution of KRAS mutation in non-small cell lung cancer: implications for detection of mutated KRAS oncogene in exhaled breath condensate

PurposeMutated KRAS oncogene in exhaled breath condensate (EBC) can be a genetic marker of non-small cell lung cancer (NSCLC). However, a possibility of inhomogeneous distribution in cancer tissue and intratumor heterogeneity of KRAS mutation may decrease its significance. We investigated a status of KRAS point mutation and its sequence at codon 12 in 51 NSCLC patients after tumor resection. The comparison of KRAS mutation status between EBC–DNA and cancer tissue was performed in 19 cases.MethodsFive cancer tissue samples from disparate tumor regions and one from normal lung were harvested at surgery. EBC was collected for DNA analysis the previous day. KRAS point mutations at codon 12 were detected using mutant-enriched PCR technique and pyrosequenced.ResultsForty-six cancers revealed concordance of KRAS mutation status: 27 contained mutated KRAS and 19 had only wild KRAS. Five NSCLCs revealed inhomogeneous distribution of KRAS mutation. Two different mutations were found in 14 NSCLCs and the most frequent one was G12D and G12V (n = 8). No mutated KRAS was found in normal lung. The concordance ratios of KRAS sequence in codon 12 between EBC–DNA and cancer were 18/19 for NSCLC patients and 11/12 for KRAS mutation positive NSCLC.ConclusionsIntratumor heterogeneity and inhomogeneous distribution of KRAS point mutation in codon 12 in cancer tissue can occur in NSCLCs. There was a high accordance between KRAS mutation status in EBC–DNA and cancer tissue in NSCLC patients what suggests usefulness of monitoring KRAS mutation in EBC–DNA as a biomarker of NSCLC.

Heterozygous carriers of germline c.657_661del5 founder mutation in NBN gene are at risk of central nervous system relapse of B-cell precursor acute lymphoblastic leukemia

Isolated central nervous system (CNS) relapse is observed in 3-8% of patients with acute lymphoblastic leukemia (ALL) and accounts for 30-40% of all disease recurrence. Although introduction of intensive CNSdirected therapy significantly improved 5-year overall survival of patients diagnosed with leukemia CNS relapse, such aggressive treatment results in long-term side effects. Therefore, more accurate risk stratification of CNS relapse in newly-diagnosed ALL pediatric patients is needed. In contrast to somatic gene defects, only a small number of studies have investigated the host genetic factors and their association with leukemia relapse. Since germline NBN c.657_661del5 mutation increases the risk of developing pediatric ALL and other types of cancers in Slavic populations, and there is a high frequency in the Polish population (1:190 individuals), we investigated its possible effect on leukemia development and progression among heterozygous carriers. NBN germline c.657_661del5 mutation leads to an impaired function of the nibrin protein, which acts as an element of the Mre11-Rad50-Nbs1 (MRN) complex in DNA double-strand breaks (DSB) repair processes. Patients with a homozygous deletion in the NBN gene, diagnosed with Nijmegen-breakage syndrome (NBS, OMIM #251260), are known to often present CNS involvement at diagnosis of pediatric ALL. In contrast to patients with NBS, who mainly develop lymphoma or Tcell ALL, heterozygous carriers of the c.657_661del5 deletion in the NBN gene are mainly diagnosed with B-cell precursor ALL (BCP-ALL). Therefore, in this unique group of patients, it is possible to investigate whether germline c.657_661del5 heterozygous mutation in the NBN gene has an impact on the biology and course of childhood BCPALL. We retrospectively evaluated 578 pediatric patients diagnosed with BCP-ALL (median age 4.51 years, range 0.1317.99 years; details are available in the Online Supplementary Methods). In total, 17 (2.94%) patients harbored the c.657_661del5 heterozygous mutation in the NBN gene. There was no significant difference in baseline clinical and biological features of leukemia and risk group