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Katarzyna Uzdrowska,1 Narcyz Knap,1 Jacek Gulczynski,2 Alicja Kuban-Jankowska,1 Wiktoria Struck-Lewicka,3 Michal J Markuszewski,3 Tomasz Bączek,3 Ewa Izycka-Swieszewska,2 Magdalena Gorska-Ponikowska1 1Department of Medical Chemistry, Medical University of Gdansk, Gdansk, 80-211, Poland; 2Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdansk, 80-211, Poland; 3Faculty of Pharmacy, Medical University of Gdansk, Gdansk, 80-416, PolandCorrespondence: Magdalena Gorska-Ponikowska, Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, Gdansk, 80-211, Poland, Tel +48 58 349 14 50, Fax +48 58 349 14 56, Email magdalena.gorska-ponikowska@gumed.edu.plAbstract: Graphene and graphene-based materials have attracted growing interest for potential applications in medicine because of their good biocompatibility, cargo capability and possible surface functionalizations. In parallel, prototypic graphene-based devices have been developed to diagnose, imaging and track tumor growth in cancer patients. There is a growing number of reports on the use of graphene and its functionalized derivatives in the design of innovative drugs delivery systems, photothermal and photodynamic cancer therapy, and as a platform to combine multiple therapies. The aim of this review is to introduce the latest scientific achievements in the field of innovative composite graphene materials as potentially applied in cancer therapy. The “Technology and Innovation Roadmap” published in the Graphene Flagship indicates, that the first anti-cancer drugs using graphene and graphene-derived materials will have appeared on the market by 2030. However, it is necessary to broaden understanding of graphene-based material interactions with cellular metabolism and signaling at the functional level, as well as toxicity. The main aspects of further research should elucidate how treatment methods (e.g., photothermal therapy, photodynamic therapy, combination therapy) and the physicochemical properties of graphene materials influence their ability to modulate autophagy and kill cancer cells. Interestingly, recent scientific reports also prove that graphene nanocomposites modulate cancer cell death by inducing precise autophagy dysfunctions caused by lysosome damage. It turns out as well that developing photothermal oncological treatments, it should be taken into account that near-infrared-II radiation (1000– 1500 nm) is a better option than NIR-I (750– 1000 nm) because it can penetrate deeper into tissues due to less scattering at longer wavelengths radiation.Keywords: graphene-based materials, oncological therapies, cancer treatment, biomedical innovations, drugs delivery systems

Background: There are many pathological conditions with hepatic iron overload. Classical definite diagnostic methods of these disorders are invasive and based on a direct tissue biopsy material. For the last years the role of MR imaging in liver diagnostics has been increasing. MRI shows changes of liver intensity in patients with hepatic iron overload. Changes in MR signal are an indirect consequence of change of relaxation times T2 and T2*, that can be directly measured. The purpose of the study was to evaluate usefulness of MR imaging in the detection of hepatic iron overload in patients with cirrhosis of different origins. Methods: MR imaging at 1.5T was prospectively performed in 44 patients with liver cirrhosis who had undergone liver biopsy with histopathological assessment of hepatic iron deposits. In all patients the following sequences were used: SE, Express, GRE in T2 and T1-weighted images. Signal intensity (SI) was measured on images obtained with each T2 weighted sequence by means of regions of interest, placed in the liver and paraspinal muscles. The correlation between iron overload, histopathological score, serum ferritin and SI ratio was analyzed. Results: In 20 patients with iron overload confirmed by the biopsy, the liver parenchyma demonstrated lower signal intensity than that of paraspinal muscles. This effect was visible only in 8 patients with hepatic iron overload in Express T2-weighted images. Higher signal intensity of liver than that of skeletal muscles on GRE - T2 weighted images was noted in 24 patients with cirrhosis and without elevated hepatic iron concentration. We observed a correlation between low and high iron concentration and liver to muscle SI ratio. Conclusion: MR imaging is a useful and fast noninvasive diagnostic tool for the detection of liver iron overload in patients with cirrhosis of different origins. Liver to muscle SI ratio in GRE-T2-weighted sequence facilitates to differentiate patients with low and high degree of hepatic iron overload, which correlates with the origin of liver cirrhosis. [ABSTRACT FROM AUTHOR]

A case of an epidural spinal peripheral primitive neuroectodermal tumor (pPNET) in a 13-year-old girl is presented. The tumor was disseminated at the moment of diagnosis, thus only diagnostic oligobiopsy of the epidural mass was performed. Histologically the tumor was composed of small round blue cells. The neoplastic cells expressed MIC2 and features of neural differentiation on immunohistochemical staining (neuron-specific enolase, synaptophysin and NCAM positivity). Fluorescent in situ hybridization (FISH) analysis was performed for the final diagnosis and the translocation t(11;22)(q24;q12) was detected. The present case emphasizes the usefulness of FISH in differential diagnosis of tumors, especially when only routinely fixed material is available. [ABSTRACT FROM AUTHOR]

A case of meningioangiomatosis, resected from the parietal lobe in a 31-year-old female is presented. Macroscopically, the lesion was composed of five calcified nodules embedded within hardened elastic tissue. Histologically, cortical and subcortical calcified masses were found surrounded by a palisade of spindle and/or oval cells. In adjacent nervous tissue many pathological microvessels were observed and some were ensheathed by a perivascular proliferation of spindle cells. Moreover, gliosis with Rosenthal fibers and prominent connective tissue elements were observed. Immunohistochemical analysis based on monoclonal antibodies was performed. The spindle cells both within the palisades and the perivascular proliferations were vimentin and usually epithelial membrane antigenpositive. The possible pathogenesis of meningioangiomatosis is discussed and the role of angiogenesis within this lesion emphasized. [ABSTRACT FROM AUTHOR]

Neuropeptide Y (NPY) is a sympathetic neurotransmitter widely distributed in the peripheral and central nervous system, affecting many physiological functions. Consequently, dysregulation of the NPY system contributes to numerous pathological disorders, including stress, obesity, and cancer. The pleiotropic functions of NPY in humans are mediated by G protein-coupled receptors (Y1R, Y2R, Y5R), which activate several signaling pathways and thereby regulate cell growth, differentiation, apoptosis, proliferation, angiogenesis, and metabolism. These activities of NPY are highly relevant to tumor biology and known hallmarks of cancer, including sustained proliferative potential, resisting cell death, angiogenesis, invasion, and metastases. In this comprehensive review, we describe the cellular functions of NPY and discuss its role in cancer pathobiology, as well as provide the current state of knowledge pertaining to NPY and its receptors in various cancer types. Moreover, we focus on potential clinical applications targeting the NPY system, such as its role as a prognostic and predictive factor, as well as its utility in cancer diagnostics, imaging, and treatment. Altogether, growing evidence supports the significant role of the NPY system in tumor pathobiology and implicates its potential therapeutic and diagnostic value in modern oncology., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Purpose: This guideline will discuss radiotherapeutic management of IDH-mutant grade 2 and grade 3 diffuse glioma, using the latest 2021 WHO (5th) classification of brain tumours focusing on: imaging modalities, tumour volume delineation, irradiation dose and fractionation., Methods: The ESTRO Guidelines Committee, CNS subgroup, nominated 15 European experts who identified questions for this guideline. Four working groups were established addressing specific questions concerning imaging, target volume delineation, radiation techniques and fractionation. A literature search was performed, and available literature was discussed. A modified two-step Delphi process was used with majority voting resulted in a decision or highlighting areas of uncertainty., Results: Key issues identified and discussed included imaging needed to define target definition, target delineation and the size of margins, and technical aspects of treatment including different planning techniques such as proton therapy., Conclusions: The GTV should include any residual tumour volume after surgery, as well as the resection cavity. Enhancing lesions on T1 imaging should be included if they are indicative of residual tumour. In grade 2 tumours, T2/FLAIR abnormalities should be included in the GTV. In grade 3 tumours, T2/FLAIR abnormalities should also be included, except areas that are considered to be oedema which should be omitted from the GTV. A GTV to CTV expansion of 10 mm is recommended in grade 2 tumours and 15 mm in grade 3 tumours. A treatment dose of 50.4 Gy in 28 fractions is recommended in grade 2 tumours and 59.4 Gy in 33 fractions in grade 3 tumours. Radiation techniques with IMRT are the preferred approach., Competing Interests: Declaration of competing interest MvdB: Receipt of grant/research support from Boehringer-Ingelheim, and receipt of honoraria or consultation fees from Boehringer-Ingelheim, Servier, Genenta, Nerviano, Incyte, Chimerix, Fore Biotherapeutics. Participated in a company sponsored speaker’s bureau for Servier; NG: Receipt of grant/research support from German Research Council (project number 428090865/SPP 2177), and receipt of honoraria or consultation fees from Blue Earth Diagnostics, Telix Pharmaceuticals; GM: Receipt of grant/research support from Horizon EU-funded LEGATO-Trial, and receipt of honoraria or consultation fees from Servier, AstraZeneca, Novocure; VK: Receipt of grant/research support from Hanarth Stichting, and receipt of honoraria or consultation fees from Eli Lilly (Consultation fees). Bayer stock shareholder; MN: Receipt of grant/research support from Deutsche Krebshilfe (DKH), Brainlab AG, Elekta AB, and participated in a company sponsored speaker’s bureau for AstraZeneca, Brainlab AG; SE: Receipt of honoraria or consultation fees from Servier; UR: Receipt of grant/research support from Institutional research grants from Brainlab, and receipt of honoraria or consultation fees from AstraZeneca, Accuray; RR: Receipt of grant/research support from Institutional research grants from Bayer, and receipt of honoraria or consultation fees from Novocure, Servier, Genenta, CureVac., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To present a single-centre experience in bi- and uni-segmentectomies for primary liver tumours in children., Methods: This study included 23 patients that underwent (bi)segmentectomy. There were 15 malignant tumours (hepatoblastoma-13 patients), 7 benign tumours, and 1 calcifying nested stromal epithelial tumour., Results: The median tumour diameter was 52 mm (range 15-170 mm). Bisegmentectomy 2-3 was most frequently performed (seven patients), followed by bisegmentectomy 5-6 (four patients). The median operative time was 225 min (range 95-643 min). Intraoperative complications occurred in two patients-small bowel perforation in one and an injury of the small peripheral bile duct resulting in biloma in the other. The median resection margin in patients with hepatoblastoma was 3 mm (range 1-15 mm). Microscopically negative margin status was achieved in 12 out of 13 patients. There were two recurrences. After a median follow-up time of 38 months (range 12-144 months), all 13 patients with HB were alive with no evidence of disease. Two relapsed patients were alive with no evidence of disease., Conclusions: From the available literature and data presented here, we propose that (bi)segmentectomy can become a viable surgical option in carefully selected paediatric patients and is sufficient to achieve a cure. Further studies evaluating the impact of parenchymal preservation surgery on surgical and oncological outcome should be conducted with a larger dataset.

Background: The mRNA splicing is regulated on multiple levels, resulting in the proper distribution of genes' transcripts in each cell and maintaining cell homeostasis. At the same time, the expression of alternative transcripts can change in response to underlying genetic variants, often missed during routine diagnostics., Aim: The main aim of this study was to define the frequency of aberrant splicing in BRCA1 and BRCA2 genes in blood RNA extracted from ovarian cancer patients who were previously found negative for the presence of pathogenic alterations in the 25 most commonly analysed ovarian cancer genes, including BRCA1 and BRCA2., Material and Methods: Frequency and spectrum of splicing alterations in BRCA1 and BRCA2 genes were analysed in blood RNA from 101 ovarian cancer patients and healthy controls (80 healthy women) using PCR followed by gel electrophoresis and Sanger sequencing. The expression of splicing events was examined using RT-qPCR., Results: We did not identify any novel, potentially pathogenic splicing alterations. Nevertheless, we detected six naturally occurring transcripts, named BRCA1ΔE9-10, BRCA1ΔE11, BRCA1ΔE11q, and BRCA2ΔE3, BRCA2ΔE12 and BRCA2ΔE17-18 of which three (BRCA1ΔE11q, BRCA1ΔE11 and BRCA2ΔE3) were significantly higher expressed in the ovarian cancer cohort than in healthy controls (p ≤ 0.0001)., Conclusions: This observation indicates that the upregulation of selected naturally occurring transcripts can be stimulated by non-genetic mechanisms and be a potential systemic response to disease progression and/or treatment. However, this hypothesis requires further examination., Competing Interests: Declaration of Competing Interest The author(s) declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease, affecting mainly patients of Slavic origin. It is caused by a defect in the NBN gene, resulting in defective nibrin protein formation. This leads to chromosomal instability, which predisposes to cancer, with lymphoid malignancies predominating. Nibrin is also involved in gonadal development and its disfunction in females with NBS frequently results in a pure gonadal dysgenesis (PGD) causing hypergonadotropic hypogonadism. However, only a few ovarian tumors in NBS patients have been reported to date. We describe the first case of a girl with NBS with PGD, who developed metachronous bilateral ovarian germ cell tumors (dysgerminoma and gonadoblastoma). Pathogenesis of PGD, neoplastic transformation and therapeutic approach in females with NBS are discussed.

Malignant peripheral nerve sheath tumor (MPNST) in children is a rare mesenchymal malignancy developing predominantly in the setting of neurofibromatosis type 1. The prognosis in advanced MPNST is poor therefore new prognostic markers are highly needed for optimal therapeutic decisions. In many solid tumors, the bidirectional interactions between hypoxia and inflammation in the tumor microenvironment via functions of tumor-associated cells, like neutrophils, lymphocytes and macrophages, have been investigated recently. There is no data whether in MPNST hypoxic microenvironment may translate into systemic inflammation, which is a well-established factor for worse prognosis in cancer patients. Therefore, we investigated the prognostic significance of markers of tumor hypoxia and systemic inflammation in 26 pediatric malignant peripheral nerve sheath tumors (MPNST). Tumor tissue microarrays were stained for hypoxia-inducible factor-1α (HIF1A), solute carrier family 2 member 1 (SLC2A1, also known as glucose transporter 1 (GLUT1)), carbonic anhydrase 9 (CA9), and vascular endothelial growth factor A (VEGFA) and classified into low- or high-expression groups. Baseline complete blood counts and C-reactive protein (CRP) levels were collected for all cases. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were calculated from age-adjusted complete blood count parameters. Both 10-year RFS and OS were significantly lower in patients with high NLR values (17% vs. 75%, p = 0.009, q = 0.018; and 31% vs. 100%, p = 0.0077, q = 0.014; respectively). Ten-year-OS was significantly lower in patients with high expression of SLC2A1 (20.00% vs. 94%, p < 0.001, log-rank), high expression of HIF1A (23% vs. 79%, p = 0.016, log-rank), and CRP higher than 31 mg/L (11% vs. 82%, p = 0.003, q = 0.009). Cox's proportional hazard regression analysis revealed that high expression of SLC2A1 (HR = 3.31, 95% CI = 1.08-10.09, p = 0.036) and VEGFA (HR = 4.40, 95% CI = 0.95-20.34, p = 0.058) were the independent factors predicting relapse, whereas high SLC2A1 was identified as the independent risk factor for death (HR = 12.20, 95% CI = 2.55-58.33, p = 0.002). Patients with high expression of hypoxic markers and low or high NLR/CRP values had the highest events rate, patients with low hypoxic markers and high NLR/CRP had intermediate events rate, while patients with low hypoxic markers and low NLR/CRP had the lowest events rate. SLC2A1 and VEGFA are promising novel prognostic factors in pediatric MPNST. Correlations between hypoxic and systemic inflammatory markers suggest the interplay between local tumor hypoxia and systemic inflammation.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Children suffering from high-risk and/or metastatic NB often show no response to therapy, and new therapeutic approaches are urgently needed. Malignant tumor development has been shown to be driven by the dysregulation of eukaryotic initiation factors (eIFs) at the translation initiation. Especially the activity of the heterotrimeric eIF4F complex is often altered in malignant cells, since it is the direct connection to key oncogenic signaling pathways such as the PI3K/AKT/mTOR-pathway. A large body of literature exists that demonstrates targeting the translational machinery as a promising anti-neoplastic approach. The objective of this study was to determine whether eIF4F complex members are aberrantly expressed in NB and whether targeting parts of the complex may be a therapeutic strategy against NB. We show that eIF4AI is overexpressed in NB patient tissue using immunohistochemistry, immunoblotting, and RT-qPCR. NB cell lines exhibit decreased viability, increased apoptosis rates as well as changes in cell cycle distribution when treated with the synthetic rocaglate CR-1-31-B, which clamps eIF4A and eIF4F onto mRNA, resulting in a translational block. Additionally, this study reveals that CR-1-31-B is effective against NB cell lines at low nanomolar doses (≤20 nM), which have been shown to not affect non-malignant cells in previous studies. Thus, our study provides information of the expression status on eIF4AI in NB and offers initial promising insight into targeting translation initiation as an anti-tumorigenic approach for NB.

Background: Activation of immune checkpoints, e.g. PD-1/PD-L1 axis, in cancer microenvironment, enables evasion of host anti-cancer immune response and drives tumor progression. To date, there have been only a few studies analyzing PD-1/PD-L1 expression in pediatric malignancies., Aim: In the current study, we aimed to assess PD-L1 and PD-1 expression in pediatric rhabdomyosarcoma (RMS) and to investigate their clinicopathological associations., Materials and Methods: The study enrolled 31 children with RMS. Tissue microarrays with representative tumor tissue samples were stained with anti-PD-1 NAT105 clone (Ventana, Roche) and two different antibodies against PD-L1: SP142 (Ventana, Roche) and 22C3 (DAKO). Adequate positive controls were applied. Their expression was assessed in tumor-associated immune cells (TAICs) and in the tumor cells separately., Results: We did not detect any positive PD-L1 staining in analyzed tumors using SP142 antibody; however, in 11 cases (35.48%) its expression was revealed by means of 22C3 clone. The staining was restricted to TAICs in all cases, which no reaction in tumor cells. The 5-year relapse free survival (RFS) rate was significantly higher in PD-L1 positive cases (61.5% vs 25.0%, p = 0.024), but it most likely results from more frequent PD-L1 expression in low-stage RMS. PD-1 expression on TAICs was detected in 7 cases and did not influence the prognosis., Conclusions: We found that PD-L1 expression on TAICs, as detected with the use of 22C3 clone but not SP142 antibody, tends to be associated with low-stage RMS in children. PD-1 expression on TAICs in RMS is neither associated with distinct clinical course nor with clinicopathological features., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: The study was to assess whether tumour expressions of hypoxia-inducible factor (HIF)-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX and vascular endothelial growth factor (VEGF) predict response to neo-adjuvant chemotherapy (naCHT) in children with inoperable rhabdomyosarcoma (RMS). Methods: Immunohistochemical expressions of hypoxia markers were determined semi-quantitatively in tumour tissue microarray of 46 patients with embryonal RMS (RME) and 20 with alveolar (RMA), treated with CWS protocols (1992-2013). Results: In paediatric RME, response to naCHT was influenced significantly by tumour expression of CA IX and GLUT-1. Patients with RMA with low expressions of analysed markers responded well to naCHT, while all poor-responders expressed highly hypoxia markers. Only 5.88% of RMA and 11.11% of RME tumours did not express any of the proteins. In both RME and RMA subgroups, most poor-responders demonstrated simultaneous high expression of ≥3 markers, while most patients expressing ≤2 markers responded well to naCHT. In the whole cohort, co-expression of ≥3 markers, was the only independent factor predicting poor-response to chemotherapy (odds ratio 14.706; 95% CI 1.72-125.75; p  = 0.014). Conclusions: Immunohistochemical expression pattern of four endogenous markers of hypoxia, in tumour tissue at diagnosis, emerges as a promising tool to predict response to naCHT in children with inoperable RMS.

Background: Malignant peripheral nerve sheath tumor (MPNST) is rare, aggressive soft tissue sarcoma which may affect children., Objective: We aimed to assess prognostic significance of immunohistochemical (IHC) markers, osteopontin, fibronectin, survivin, cyclin D1 and p53, in pediatric MPNST., Methods: A total of 26 pediatric MPNST patients were enrolled in the current study with a median follow-up of 51 months. IHC staining using commercially available monoclonal antibodies were employed to detect analyzed antigens on tissue microarrays. Eventually, all markers were subclassified to high (H) and low (L) expression categories in all analyzed tumors., Results: High IHC expressions of survivin, cyclin D1, osteopontin, fibronectin, and p53 were detected in 18 (69.2%), 13 (50%), 16 (61.5%), 16 (61.5%), and 13 (50%) tumors, respectively. A significant correlation was demonstrated between cyclin D1 and osteopontin (p= 0.004). Both markers were associated with neurofibromatosis type 1 (NF1) status (p= 0.041 and p= 0.037, respectively). H-fibronectin was more prevalent in deeply located tumors (p= 0.046). None of the markers was associated with IRS stage, age at diagnosis, and tumor size. Univariate analysis identified IRS stage, regional lymph node metastases, NF1, and cyclin D1 as variables associated with overall survival (OS), whereas tumor depth, osteopontin, and cyclin D1 - for relapse-free survival (RFS). Subsequent multivariate analysis identified cyclin D1 and p53 as independent variables predicting RFS, whereas cyclin D1 and regional lymph nodes status were independent predictors for OS.

Brain metastases are devastating complications of cancer. The blood-brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood-tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients' brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only. Despite combined oncological treatment, four children died during 20 months, and only one glioblastoma patient continued to live for another twelve years. Microscopically, the neoplasms consisted of small cells with some morphologic features of astrocytic lineage, having scanty or prominent processes. Microvascular proliferation and focal or diffuse necrosis were encountered in four cases. The GFAP reactivity in neoplastic cells was low or nil, together with the expression of Olig2, vimentin, and nestin. In two cases a subpopulation of synaptophysin-positive cells was present. Molecular immunohistochemical profiling revealed the expression of phosphorylated forms of PI3Kp110 and AKT, in parallel to a strong PTEN and p53 positivity. The tumors were of IDH1R132H-wild type and immunoreactive for ATRX, HER3, and EGFR. Secondary malignant gliomas in pediatric cancer survivors pose a diagnostic challenge. The present study shows that these tumors are of IDH wild type, PI3K/AKT-activated, having no PTEN and EGFR mutations. Therefore, the biopsy of brain tumors in such patients is crucial both for accurate diagnosis and material preservation for molecular typing.

Purpose: Selected cell-cycle regulators and extracellular matrix proteins were found to play roles in malignant peripheral nerve sheath tumor (MPNST) biology. We aimed to analyze whether initial tumor tissue expressions of survivin, p53, cyclin D1, osteopontin (OPN) and fibronectin (FN) correlate with the response to neo-adjuvant CHT (naCHT) in children with advanced inoperable MPNST., Methods: The study included 26 children with MPNST (M/F 14/12, median age 130 months) treated in Polish centers of pediatric oncology between 1992 and 2013. Tissue expression of markers was studied immunohistochemically in the manually performed tissue microarrays and assessed semi-quantitatively as low and high, based on the rate of positive cells and staining intensity., Results: Good response to naCHT was noted in 47.6%, while poor-in 52.4% of patients. The response to naCHT was influenced negatively by the presence of neurofibromatosis NF1 and high initial tumor tissue expression of OPN, survivin, p53 and cyclin D1. Patients with high tumor expression of either OPN, survivin or p53 and those with simultaneous high expression of ≥ 3 of the markers, responded significantly worse to naCHT, than patients, in whom expression of ≤ 2 markers were detected at diagnosis. Nearly, 85% of patients expressing ≥ 3 markers, responded poor to CHT; while 87.5% of children, expressing ≤ 2 markers, were good responders., Conclusion: The initial tumor tissue expression of OPN, survivin, p53 and cyclin D1 may serve as markers to predict response to naCHT in pediatric advanced MPNST. Future studies in more numerous group of patients are needed to confirm these preliminary results.

Background: Different clinical behaviour influences the importance of differentiating focal nodular hyperplasia (FNH) from other focal liver lesions (FLLs). The aim of this study was to compare the efficacy of contrast-enhanced CT and MRI in the diagnosis of FNH., Methods: 157 patients with equivocal FLLs detected in ultrasonography subsequently underwent multi-phase CT and MRI with the use of hepatotropic contrast agent (Gd-BOPTA) in a 1.5 T scanner. Examinations were evaluated by three independent readers. Diagnostic efficacy of different radiological signs of FNH in both CT and MRI was compared and AFROC analysis was performed., Results: 4 hepatocellular adenomas, 95 hepatocellular carcinomas, 98 hemangiomas, 138 metastases and 45 FNHs were diagnosed. In both CT and MRI the radiological sign of the highest accuracy was the presence of the central scar within FNH (0.93 and 0.96 relatively). The sum of two radiological signs in MRI: homogeneous enhancement in hepatic arterial phase (HAP) and enhancing lesion in hepatobiliary phase (HBP) was characterized with high values of sensitivity (0.89), specificity (0.97), PPV (0.82), NPV (0.98) and accuracy (0.96). After inclusion of clinical data into analysis the best discriminating feature in MRI was the presence of enhancing lesion in HBP in patients without cirrhosis. In this regard, efficacy parameters increased to 1.00, 0.99, 0.94, 1.00 and 0.99 accordingly. The area under the curve in AFROC analysis of MRI performance was significantly larger than of CT (p = 0.0145)., Conclusion: Gd-BOPTA-enhanced MRI is a more effective method in the differential diagnosis of FNH than multi-phase CT.

Objective: Osteopontin (OPN) is aglyco-phosphoprotein, involved in tissue remodeling, inflammation and boneresorption. In various adult neoplasms OPN was shown to correlate with cancer progression, invasiveness and metastasis., Aim: to define the role of OPN in malignancies of children and young adults., Material and Methods: a structured PubMed and Google Scholar literature analysis based on reports published in English between I'1995 and XII'2015., Results: 14 studies (four on hematological malignancies, four on bone tumors, three on CNS tumors, two on dendritic proliferative diseases and one on renal tumors) were identified. Higher levels of serum and cerebro-spinal fluid OPN protein, and high expressions of OPN mRNA and SPP1 gene were present in more aggressive and advanced childhood malignancies. In children with acute lymphoblastic leukemia with CNS involvement and with atypical teratoid/rhabdoid tumor (AT/RT) and medulloblastoma, the serum and CSF OPN levels reflected tumor bulk and response to therapy, while in children with AT/RT and multisystem Langerhans cell histiocytosis with high-risk organs involvement, high OPN serum levels correlated with poorer survival. To the contrary, in osteosarcoma, high OPN mRNA and SPP1 gene expressions correlated with better survival and good response to chemotherapy., Conclusions: The literature review suggests that OPN may play important roles in the development and progression of selected cancers of children and young adults, including acute lymphoblastic leukemia, malignant gliomas, AT/RT and Langerhans cell histiocytosis. However, limited number of published studies prevents from definite concluding on the clinical utility of OPN as a marker of diagnosis, prognosis and treatment monitoring in these pediatric cancers. Further studies performed in more numerous groups of patients with particular types of cancers of children and young adults are warranted.

We present a case of a rare neoplasm in a 77-year-old woman with previous oncological history, who developed a rapid onset of cerebellar symptoms. The neuroimaging detected a posterior fossa tumor suspected of meningioma which was completely resected soon after. Histologically the neoplasm had two components with different immunophenotype. One constituent was lobular, composed of monotonous mitotically active round cells with a predominant neuronal profile. The second, astrocytic component contained lipomatous cells intermixed with larger gemistocytic astrocytes. Fields of geographic necrosis as well as multifocal microvascular proliferation were observed. The Ki67 proliferation index was 12%. After two years of follow-up the patient remains free of symptoms and radiologic recurrence. The presented case of cerebellar liponeurocytoma is unusual in terms of its atypical histological features and prominent astrocytic component. The authors propose that the term 'lipomatous glioneuronal tumor' seems to be more appropriate for this type of lesion, considering its histologic spectrum and possible extracerebellar location.

Hypoxia has been implicated in the metastasis of Ewing sarcoma (ES) by clinical observations and in vitro data, yet direct evidence for its pro-metastatic effect is lacking and the exact mechanisms of its action are unclear. Here, we report an animal model that allows for direct testing of the effects of tumor hypoxia on ES dissemination and investigation into the underlying pathways involved. This approach combines two well-established experimental strategies, orthotopic xenografting of ES cells and femoral artery ligation (FAL), which induces hindlimb ischemia. Human ES cells were injected into the gastrocnemius muscles of SCID/beige mice and the primary tumors were allowed to grow to a size of 250 mm 3 . At this stage either the tumors were excised (control group) or the animals were subjected to FAL to create tumor hypoxia, followed by tumor excision 3 days later. The efficiency of FAL was confirmed by a significant increase in binding of hypoxyprobe-1 in the tumor tissue, severe tumor necrosis and complete inhibition of primary tumor growth. Importantly, despite these direct effects of ischemia, an enhanced dissemination of tumor cells from the hypoxic tumors was observed. This experimental strategy enables comparative analysis of the metastatic properties of primary tumors of the same size, yet significantly different levels of hypoxia. It also provides a new platform to further assess the mechanistic basis for the hypoxia-induced alterations that occur during metastatic tumor progression in vivo. In addition, while this model was established using ES cells, we anticipate that this experimental strategy can be used to test the effect of hypoxia in other sarcomas, as well as tumors orthotopically implanted in sites with a well-defined blood supply route.

Neuroblastoma (NB) is a pediatric malignant neoplasm of sympathoadrenal origin. Challenges in its management include stratification of this heterogeneous disease and a lack of both adequate treatments for high-risk patients and noninvasive biomarkers of disease progression. Our previous studies have identified neuropeptide Y (NPY), a sympathetic neurotransmitter expressed in NB, as a potential therapeutic target for these tumors by virtue of its Y5 receptor (Y5R)-mediated chemoresistance and Y2 receptor (Y2R)-mediated proliferative and angiogenic activities. The goal of this study was to determine the clinical relevance and utility of these findings. Expression of NPY and its receptors was evaluated in corresponding samples of tumor RNA, tissues, and sera from 87 patients with neuroblastic tumors and in tumor tissues from the TH-MYCN NB mouse model. Elevated serum NPY levels correlated with an adverse clinical presentation, poor survival, metastasis, and relapse, whereas strong Y5R immunoreactivity was a marker of angioinvasive tumor cells. In NB tissues from TH-MYCN mice, high immunoreactivity of both NPY and Y5R marked angioinvasive NB cells. Y2R was uniformly expressed in undifferentiated tumor cells, which supports its previously reported role in NB cell proliferation. Our findings validate NPY as a therapeutic target for advanced NB and implicate the NPY/Y5R axis in disease dissemination. The correlation between elevated systemic NPY and NB progression identifies serum NPY as a novel NB biomarker., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: The blood-brain barrier (BBB) is modified to a blood-tumor barrier (BTB) as a brain metastasis develops from breast or other cancers. We (i) quantified the permeability of experimental brain metastases, (ii) determined the composition of the BTB, and (iii) identified which elements of the BTB distinguished metastases of lower permeability from those with higher permeability., Experimental Design: A SUM190-BR3 experimental inflammatory breast cancer brain metastasis subline was established. Experimental brain metastases from this model system and two previously reported models (triple-negative MDA-231-BR6, HER2 + JIMT-1-BR3) were serially sectioned; low- and high-permeability lesions were identified with systemic 3-kDa Texas Red dextran dye. Adjoining sections were used for quantitative immunofluorescence to known BBB and neuroinflammatory components. One-sample comparisons against a hypothesized value of one were performed with the Wilcoxon signed-rank test., Results: When uninvolved brain was compared with any brain metastasis, alterations in endothelial, pericytic, astrocytic, and microglial components were observed. When metastases with relatively low and high permeability were compared, increased expression of a desmin + subpopulation of pericytes was associated with higher permeability (231-BR6 P = 0.0002; JIMT-1-BR3 P = 0.004; SUM190-BR3 P = 0.008); desmin + pericytes were also identified in human craniotomy specimens. Trends of reduced CD13 + pericytes (231-BR6 P = 0.014; JIMT-1-BR3 P = 0.002, SUM190-BR3, NS) and laminin α2 (231-BR6 P = 0.001; JIMT-1-BR3 P = 0.049; SUM190-BR3 P = 0.023) were also observed with increased permeability., Conclusions: We provide the first account of the composition of the BTB in experimental brain metastasis. Desmin + pericytes and laminin α2 are potential targets for the development of novel approaches to increase chemotherapeutic efficacy. Clin Cancer Res; 22(21); 5287-99. ©2016 AACR., Competing Interests: Dr. PSS receives research funding from Sanofi-Aventis and Genentech. The other authors have no conflicts of interest to declare., (©2016 American Association for Cancer Research.)