Bartłomiej Tomasik

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.

Effect of Insulin Dilution on Lowering Glycemic Variability in Pump-Treated Young Children with Inadequately Controlled Type 1 Diabetes.

BACKGROUND We investigated whether in young children with inadequately controlled type 1 diabetes and technical problems with continuous subcutaneous infusion of insulin at 100 units/mL the switch to insulin diluted to 10 units/mL (U10) can limit technical problems and improve glycemic control. SUBJECTS AND METHODS Diluted U10 insulin was started in three children 3.8, 3.2, and 1.3 years old with a hemoglobin A1c (HbA1c) level (mean±SD) of 8.1±0.17% (65±1.7 mmol/mol) and insulin dose of 8.80±2.93 units/day. Patients were evaluated with continuous glucose monitoring (iPro™2; Medtronic Minimed, Northridge, CA) and a quality of life questionnaire (PedsQL™; www.pedsql.org/ ) and surveyed for pump-related problems at baseline and after 3 and 9 months of U10 insulin therapy. RESULTS Continuous glucose monitoring records showed that glycemic variability assessed by SD and M100 decreased significantly (P=0.0085 and P=0.0482, respectively). HbA1c levels dropped to 7.3±1.00% (56±11.0 mmol/mol) after 3 months and to 6.7±0.55% (50±6.1 mmol/mol) after 9 months (P=0.12). Technical difficulties were minimized. CONCLUSIONS These results suggest that the use of U10 insulin decreases glycemic variability and improves hampered pump therapy in young children with inadequately controlled type 1 diabetes.

MMP, VEGF and TIMP as prognostic factors in recurring bladder cancer

OBJECTIVES To investigate the clinical correlates and prognostic utility of MMP, VEGF and TIMP genes expression in bladder cancer (BCa) recurrence. METHODS Expression of MMP1, MMP2, MMP9, VEGFA and TIMP1, TIMP3 was analyzed by qRT-PCR using SYBR Green in peripheral blood leukocytes (PBLs) of BCa patients at two time points (diagnosis (n=40), and first recurrence (n=40)) and an age-matched group of healthy controls (n=100). Plasma concentrations of MMP1 (pro- and active forms) were measured using ELISA in BCa patients. RESULTS The expression of MMP1 mRNA was significantly lower in BCa patients with first recurrence compared to control (p=0.019). Expression of other genes did not differ significantly between the groups. MMP9 gene expression was associated with differentiation grade (p=0.043), with the highest expression in poorly differentiated tumors (G3) and was higher in smokers than in non-smokers (p=0.039) in BCa patients at diagnosis. The results at two time points showed that MMP9 and VEGFA genes expression was increased in patients with moderately differentiated BCa (p=0.029), and advanced pathologic stage (p=0.048), respectively. Moreover, gene expression of TIMP1 was increased for G3 (p=0.043), and was decreased for early recurrence (p=0.003). CONCLUSIONS Our study suggests that the expression of MMP9 in PBLs of BCa patients at diagnosis is associated with the differentiation grade of the BCa, and smoking status. Genes expression of MMP9, VEGFA and TIMP1 in PBLs may play a pivotal role in regulation of progression of BCa. Additionally, TIMP1 gene expression may be important factor for early recurrence of BCa.

Being overweight has limited effect on SCARF osteotomy outcome for hallux valgus correction

PurposeThe purpose of this study was to investigate the association between body mass index (BMI) and the results of SCARF osteotomy of the first metatarsal for hallux valgus (HV) correction, as the literature on this is scant.MethodsThis prospective study was carried out between 2011 and 2015. One hundred and thirty-three patients diagnosed with moderate to severe HV underwent a SCARF corrective osteotomy. We divided the patients into two groups according to their BMI: normal and overweight. Postoperative follow-up was two years. All patients were examined twice by two medical doctors simultaneously: pre-operatively and post-operatively at two years’ follow-up. Data collected included biometrical records, X-rays [HV angle (HVA), intermetatarsal angle (IMA), American Orthopaedic Foot and Ankle Society Hallux Metatarsophalangeal Index (AOFAS-HMI) and visual analogue scale (VAS) for pain and satisfaction].ResultsThere was a significant difference between patient age (p = 0.001), age at onset (p < 0.001) and AOFAS-HMI (p = 0.035) at follow-up. Other parameters were similar in both groups.ConclusionRegardless of BMI, the radiological outcome was comparable. Despite a significant difference in AOFAS-HMI results, pain and satisfaction level were similar. The authors agreed that high BMI has protective role in the prevalence of HV.

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.

The antero-lateral approach with corpectomy in the management of the ventral meningioma of the spinal canal

The authors present the anterior approach to cervical spine, which enabled complete resection of tumor located in the anterior part of the spinal canal. Considering there are not many reports in the literature, the authors present a case of a meningioma at the level C5-C6 resected with good result through anterolateral approach.

Early Predictors of Post – Thyroidectomy Hypoparathyroidism

Thyroid surgery is the most commonly performed procedure in the field of endocrine surgery. Studies are still ongoing on the development of a single algorithm for diagnosis and care of patients at risk of postoperative hypoparathyroidism. The aim of the study was to determine the biochemical marker that would allow the most accurate diagnosis of patient groups at risk of developing hypoparathyroidism and to identify risk factors for this disorder. MATERIAL AND METHODS The prospective study included 142 consecutive patients undergoing total thyroidectomy for benign goiter from January 1st 2014 to December 31st 2015. Serum intact parathyroid hormone (iPTH), total calcium (Ca), phosphate (P), and magnesium (Mg) levels have been measured preoperatively and at 1, 6, 24, and 48 h postoperatively. RESULTS Clinical symptoms of hypoparathyroidism developed in 25 (17.6%) of 142 patients. The best diagnostic accuracy for hypoparathyroidism based on ROC curves was obtained for iPTH at 6h (AUC 0.942; 95% CI: 0.866-1.000, p<0.001) and its percentage change from baseline ΔiPTH at 6h (AUC 0.930; 95% CI: 0.858-1.000, p<0.001). In an multivariate analysis, the preoperative Ca level higher by 0.1 mmol/l, and iPTH level higher by 0.1 pmol/l were associated with a lower risk of hypoparathyroidism, by 68% (p=0.012) and 61% (p=0.007), respectively. A 1% decline in iPTH from baseline increased the risk of hypoparathyroidism by 15% (p<0.001). CONCLUSIONS The most reliable markers indicating a high risk of postoperative hypoparathyroidism are the decline in ΔiPTH at 6h by > 65% or iPTH level at 6h <1.57 pmol /l. A postoperative decline in iPTH levels is an independent risk factor for the development of hypoparathyroidism. Preoperative higher concentrations of Ca and iPTH are protective factors for the development of this disorder.

Neurofibromatosis type 2 (NF 2) or schwannomatosis? – Case report study and diagnostic criteria

INTRODUCTION Neurofibromatosis type 2 (NF2) and schwannomatosis are entities that may, due to the similarity of clinical symptoms, cause diagnostic difficulties. Incidence rate of both diseases is similar and estimated between 1:25,000 and 1:40,000. The genes associated with the development of the aforementioned disorders are located on chromosome 22 and lay in proxmity. Schwannomatosis is characterized by an incomplete penetrance and the risk of its transmission to the offspring is significantly lower than in the case of NF 2. Schwannomatosis clinical characteristic is similar to the NF2, however vestibular schwannomas are not present. Therefore the imaging studies evaluated by an experienced radiologist play a key role in the diagnostic process. CASE REPORT Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache. She was diagnosed with a schwannomatosis, recently distinguished, the third form of neurofibromatosis. MRI imaging revealed craniocervical junction tumor. Suboccipital craniectomy with concomitant C1-C2 laminectomy was done in order to remove the lesion. After the surgery the patient did not present any deficits in neurological examination and was discharged from hospital in good general condition. CONCLUSIONS The patient was diagnosed with schwannomatosis, recently established neurofibromatosis entity which may resemble NF2 clinically. In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely.

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.

Potential of serum microRNAs as biomarkers of radiation injury and tools for individualization of radiotherapy

Abstract Due to tremendous technological advances, radiation oncologists are now capable of personalized treatment plans and deliver the dose in a highly precise manner. However, a crucial challenge is how to escalate radiation doses to cancer cells while reducing damage to surrounding healthy tissues. This determines the probability of achieving therapeutic success whilst safeguarding patients from complications. The current dose constraints rely on observational data. Therefore, incidental toxicity observed in a minority of patients limits the admissible dose thresholds for the whole population, theoretically narrowing down the curative potential of radiotherapy. Future tools for measurements of individuals radiosensitivity before and during treatment would allow proper treatment personalization. Variation in tissue tolerance is at least partially genetically‐determined and recent progress in the field of molecular biology raises the possibility that novel assays will allow to predict the response to ionizing radiation. Recently, microRNAs have garnered interest as stable biomarkers of tumor radiation response and normal‐tissue toxicity. Preclinical studies in mice and nonhuman primates have shown that serum circulating microRNAs can be used to accurately distinguish pre‐ and postirradiation states and predict the biological impact of high‐dose irradiation. First reports from human studies are also encouraging, however biology‐driven precision radiation oncology, which tailors treatment to individual patients needs, still remains to be translated into clinical studies. In this review, we summarize current knowledge about the potential of serum microRNAs as biodosimeters and biomarkers for radiation injury to lung and hematopoietic cells.