Hemispheric infiltrative grade II gliomas in adults: association of residual tumour volume and extent of tumour resection with malignant transformation.

OBJECTIVES: Evaluation of the impact of surgical treatment on malignant transformation (MT) of adult supratentorial infiltrative grade II gliomas (G2G) in a series of chemotherapy and radiotherapy-naïve patients. BACKGROUND: Despite G2G are slow-growing tumours, they typically undergo MT with a subsequent fatal disease course. An extensive resection alone likely changes their biological behaviour and defers MT; however, this impact is not unequivocally confirmed. METHODS: Thirty-eight chemotherapy and radiotherapy-naïve adult patients operated from 2005 till 2014 for a G2G were investigated. Based on postoperative magnetic resonance imaging (MRI) and/or positron emission tomography follow-up (FU) scans, the patients were classified as "transformers" (15 patients in whom MT occurred during the FU-period) and "non-transformers" (23 patients). RESULTS: The follow-up period of "non-transformers" was longer (p <0.0001). After adjustment for known risk factors - age, male sex, astrocytoma histology, preoperative tumour volume, preoperative contrast enhancement and positive isocitrate dehydrogenase 1 gene mutation status - a larger log postoperative tumour volume (p=0.031) and a smaller extent of resection (p=0.0086) were associated with a shorter MT-free survival. CONCLUSION: In our series, less extensive resections were associated with a shorter time to MT. Our data support an adoption of techniques enabling extensive G2G resections, such as intraoperative imaging and awake resections, into everyday routine (Tab. 1, Fig. 2, Ref. 40).

TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients.

OBJECTIVE: In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. RESULTS: Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. CONCLUSION: We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.

Dental pulp mesenchymal stem/stromal cells labeled with iron sucrose release exosomes and cells applied intra-nasally migrate to intracerebral glioblastoma.

We report on a simple iron oxide (Venofer) labeling procedure of dental pulp mesenchymal stem cells (DP-MSCs) and DP-MSCs transduced with yeast cytosinedeaminase::uracilphosphoribosyltransferase (yCD::UPRT-DP-MSCs). Venofer is a drug approved for intravenous application to treat iron deficiency anemia in patients. Venofer labeling did not affect DP-MSCs or yCD::UPRT-DP-MSCs viability and growth kinetics. Electron microscopy of labeled cells showed internalized Venofer nanoparticles in endosomes. MRI relativity measurement of Venofer labeled DP-MSCs in a phantom arrangement revealed that 100 cells per 0.1 ml were still detectable. DP-MSCs or yCD::UPRT-DP-MSCs and the corresponding Venofer labeled cells release exosomes into conditional medium (CM). CM from yCD::UPRT-DP-MSCs in the presence of a prodrug 5-fluorocytosine caused tumor cell death in a dose dependent manner. Iron labeled DP-MSCs or yCD::UPRT-DP-MSCs sustained their tumor tropism in vivo; intra-nasally applied cells migrated and specifically engrafted orthotopic glioblastoma xenografts in rats.

Dominant neurologic symptomatology in intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare variant of extranodal large B-cell lymphoma and it is characterized by selective intravascular proliferation of malignant cells. Typical features of the disease include aggressive behavior, rapid and frequently fatal course. Clinical picture is non-specific and heterogeneous, depending on the affected organ. It is not uncommon that this unique type of lymphoma is diagnosed post mortem. Herein, we report two cases of IVLBCL with neurologic symptomatology. In our clinical study patient 1 was an 80-year-old male with mixed paraparesis of lower extremities and difficulties with sphincter control. Patient 2 (56-year-old male) had vision malfunction, mental status changes and defect in phatic and motor functions. In both cases definite diagnosis was established by histological examination of necroptic material. We propose to include IVLBCL in differential diagnostic considerations in patients presenting with gradually impairing neurological status and spinal cord damage of unknown etiology (Fig. 2, Ref. 9).

Cristobalite and Hematite Particles in Human Brain.

Foreign substances get into the internal environment of living bodies and accumulate in various organs. Cristobalite and hematite particles in the glial cells of pons cerebri of human brain with diagnosis of Behhet disease with scanning electron microscopy (SEM), energy-dispersive microanalysis (EDX), and transmission electron microscopy (TEM) with diffraction were identified. SEM with EDX revealed the matter of irregular micrometer-sized particles sometimes forming polyhedrons with fibrilar or stratified structure. It was found in some particles Ti, Fe, and Zn. Some particles contained Cu. TEM and electron diffraction showed particles of cristobalite and hematite. The presence of the particles can be a result of environmental effect, disruption of normal metabolism, and transformation of physiologically iron-ferrihydrite into more stable form-hematite. From the size of particles can be drawn the long-term accumulation of elements in glial cells.

Evaluation of protein expression and DNA methylation profiles detected by pyrosequencing in invasive breast cancer.

Breast carcinoma is the most common cancer with high mortality caused by metastatic disease. New molecular biomarkers predicting the tumour's metastatic potential would therefore improve metastasis prevention and personalised care. The aim of the study was to investigate the relationship between DNA methylation levels in invasivity and metastasising associated genes with aberrant protein expression and also to evaluate whether a similar DNA methylation level is present in the tumour and circulating cell-free DNA for utilising plasma DNA methylation as prognostic biomarker. By using pyrosequencing, we analysed DNA methylation levels of 11 genes, namely APC, ADAM23, CXCL12, ESR1, PGR B, CDH1, RASSF1A, SYK, TIMP3, BRMS1 and SOCS1 in tumour, plasma and peripheral blood cells from 34 patients with primary breast cancer, as well as plasma and peripheral blood cells from 50 healthy controls. Simultaneously, the expression of related proteins in paraffin-embedded tumour samples was evaluated by immunohistochemistry. Statistical analysis was performed by SPSS statistics 15.0 software. Tumour DNA hypermethylation was found in most commonly methylated RASSF1A (71.9%), APC (55.9%), ADAM23 (38%) and CXCL12 (34.4%) genes with methylation levels up to 86, 86, 53 and 64 %, respectively. In tumours, significantly higher methylation levels were found in nine genes, compared with the patients´ peripheral blood cell DNA. Furthermore, in patients methylation levels in peripheral blood cell DNA were significantly higher than in controls in CXCL12, ESR1 and TIMP3 genes, but the values did not exceed 15%. On the other hand, no correlations were observed in patients between DNA methylation in tumours and cell-free plasma DNA. Moreover, in patients and controls nearly identical values of cumulative DNA methylation (43.6 % ± 20.1 vs. 43.7 % ± 15.0) were observed in plasma samples. A variable spectrum from high to none expressions presented in tumour tissues in all of the proteins evaluated, however in APC and CXCL12 genes a visible decreasing trend of mean DNA methylation level with increasing expression of the corresponding protein was observed. The DNA methylation profiles manifested in our group of breast carcinomas are cancer specific, but they are not the only cause that affects the silencing of evaluated genes and the decrease of relevant protein products. The clinical utility of DNA methylation testing in peripheral blood cell DNA for cancer diagnosis and therapy need to be further investigated.

Pineal germ cell tumors: review.

BACKGROUND: Primary intracranial germ cell tumors represent a rare category of neoplasms, which occur in children and young adults. The WHO classification divides intracranial tumors into germinomas and non-germinomas. The most frequent locality of these tumors is pineal and suprasellar region. Clinical signs and symptoms depend on the localization of the tumour - they most commonly include signs of increased intracranial pressure, Parinauds syndrome, bitemporal hemianopsy and signs of endocrine deficiency. Gadolinium enhanced MRI scan of the brain is the imagining examination of choice in the diagnostic strategy of intracranial germ cell tumors. However, the imagining studies do not provide sufficient information about histological type; therefore, biopsy is necessary. The exception represents cases with characteristically increased levels of tumor markers (AFP and ß-HCG) measured in the serum and cere-brospinal fluid. CASE: A pineal germ cell tumor was observed in a 26-year-old male with presentation of an eye-sight disorder with focusing difficulty and photophobia, accompanied by intensive fatigue and sleepiness, nausea with occasional vomiting, intermittent headaches and Parinauds syndrome. MRI examination of the brain showed tumor expansion in the pineal region and in the right part of the mesencephalon. Radical extirpation of the tumor in the pineal region was performed. The follow-up MRI scan of the brain revealed relapse of the disease. The patient underwent craniospinal radiation therapy with subsequent postoperative chemotherapy (regimen cisplatin and etoposide), three cycles in total. Currently, the patient is 30 months after finishing of oncological treatment in clinical remission of the disease. CONCLUSION: The treatment and prognosis of this neoplasm differ between particular categories. Germinomas have better survival rates than non-germinomas. A 5-year survival rate of germinoma patients after application of radiotherapy alone was > 90% of cases. The addition of chemotherapy lead to a decrease of the dose and minimalization of the irradiated area, with achievement of fewer side effects without a decrease of the curability. Non-germinomas are less radiosensitive than germinomas, but after the application of the adjuvant chemotherapy, survival benefit was achieved. However, the optimal management of these tumors remains controversial.

The immune status in situ of recurrent tonsillitis and idiopathic tonsillar hypertrophy.

OBJECTIVE: To analyze the immune status in situ of tonsils of patients with recurrent tonsillitis (RT) and idiopathic tonsillar hypertrophy (ITH) with the aim to discuss the indications of tonsillectomy (TE) and tonsillotomy (TT) in young children. METHODS: The histological and immunohistological study of tonsillar tissue of RT and ITH in correlation with immunological parameters in peripheral blood in 13 patients with RT and 16 patients with ITH. RESULTS: In the RT group, we found a higher degree of fibrosis with a higher density of memory lymphocytes (CD45R0+), B-lymphocytes (CD20+) and cytotoxic T-lymphocytes (CD8+) in surface epithelium of tonsils compared to the ITH group (NS). The density of immunoglobulin IgG in the crypt epithelium in RT was significantly higher than in the ITH group (p = 0.041). We also measured a higher sera concentration of immunoglobulines (IgG, IgM, IgA) and TNF-α in RT compared to the ITH group (NS) and TH-1 immune response in tonsillar tissue based on differences between local cytokine concentration TNF-α and IL-4. CONCLUSIONS: RT has a higher inflammatory reaction in tonsillar tissue as a result of persistent bacterial antigenic stimulation. In patients with RT, the tonsillectomy might be the only option for surgical treatment. In patients with ITH with mild symptoms, the tonsillotomy should be preferred (Tab. 3, Ref. 24).

Gliosarcoma with alveolar rhabdomyosarcoma-like component: report of a case with a hitherto undescribed sarcomatous component.

UNLABELLED: Gliosarcoma (GS) is a relatively rare glioblastoma variant characterized by biphasic glial and mesenchymal differentiation patterns. The sarcomatous part most commonly resembles fibrosarcoma or so-called malignant fibrous histiocytoma. Rarely, GS shows heterologous lines of differentiation in the form of osteosarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, squamous or glandular malignant epithelial differentiation, or primitive neuroectodermal tumor (PNET)-like foci. When rhabdomyoblastic differentiation occurs, it is in the form of malignant spindle cells, with cross-striated strap cells or rounded rhabdomyoblasts reminiscent of the embryonal type of rhabdomyosarcoma. We are reporting a case of GS with an alveolar rhabdomyosarcoma-like component. The tumor consisted of poorly differentiated primitive small round cells growing in a solid and alveolar pattern, with minimal cytoplasm, markedly elevated mitotic activity and numerous apoptotic nuclei. Rhabdomyosarcomatous differentiation was confirmed by desmin and myogenin immunopositivity. To the best of our knowledge, this histologic pattern has not been previously reported in GS. Differential diagnostic considerations are discussed. KEYWORDS: gliosarcoma - alveolar rhabdomyosarcoma - myogenin - desmin.

Recurring multifocal leiomyosarcoma of the urinary bladder 22 years after therapy for bilateral (hereditary) retinoblastoma: a case report and review of the literature.

We report on a case of urinary bladder leiomyosarcoma in a 23-year-old woman, 22 years after therapy for bilateral retinoblastoma. The tumor presented with dysuria and macroscopic haematuria. Cystoscopy revealed a tumor localized in the trigonum covered by an ulcerated urothelium. The patient underwent a transvesical tumor resection. Eight months later, a second leiomyosarcoma developed in the vertex, at a site different from the previous one. A cystoscopic trans-urethral tumor resection was performed, followed by combined chemotherapy. One year later another recurrence occurred at the site of the primary resection. Open laparotomic resection of the involved bladder wall was performed. The patient remains both recurrence and metastases free after twenty months of follow-up. Molecular analysis of the peripheral blood showed rare germline point mutation in the intron 24 of the RB1 gene. FISH analysis of the tumor tissue revealed polyploid cells with relative loss of normal RB1 gene locus, indicating deletion and second hit loss of the second RB1 allele function. Along with the ten previously reported cases, this report suggests a non-random association between the hereditary retinoblastoma and urinary bladder leiomyosarcoma. Therapy with cyclophosphamide seems to be an important risk factor. Life-long surveillance for second malignancies, including bladder leiomyosarcoma is therefore mandatory in these patients.

[Selected biomarkers in the primary tumors of the central nervous system: short review]. / Vybrané biomarkery primárnych nádorov centrálneho nervového systému: krátky prehlad.

Classification, grading and treatment of central nervous system tumors is currently based on morphology. Advances in molecular biology help to clarify pathogenesis, refine prognosis and detect potential targets for targeted therapy in a wide spectrum of CNS tumors. In this short review we present our view on selected diagnostic, prognostic and predictive biomarkers of primary CNS tumors, with an emphasis on application in daily praxis.

[Targeted therapy of melanoma: fact or fiction?]. / Cielená liecba melanómu: fakt alebo fikcia?

Advanced malignant melanoma is incurable by the current means of therapy. Traditional morphological classification (nodular melanoma, lentigo maligna melanoma, nevoid melanoma etc.) does not have any significant prognostic or predictive impact. Recent advances in molecular pathogenesis and the availability of targeted therapies have produced several positive results. In the near future, the main challenge for pathologists, geneticists and oncologists will be the identification of accurate therapeutic targets, as well as mechanisms of resistance, in melanoma in the particular patient in care.

Synaptophysin negative central neurocytoma.

BACKGROUND: Central neurocytoma is a rare primary brain tumour, mostly localised in the lateral ventricles in relation to the foramen of Monro. OBJECTIVES: To report a case of a rare central neurocytoma with a complete loss of Synaptophysin expression and provide the differential diagnosis. METHODS AND RESULTS: We describe a case of a 34-year old man with a headache, unsteady gait and dim vision. MRI demonstrated a tumorous expansion localised in both lateral ventricles. The patient underwent a subtotal resection. Histology showed a picture consistent with central neurocytoma, but tumour was completely negative for Synaptophysin. We describe our approach in such a diagnostically difficult case. CONCLUSIONS: In the rare case of Synaptophysin-negative central neurocytoma, its neuronal differentiation should be substantiated by electron-microscopic examination. Unfortunately in the routine work, biopsy samples are usually fixed in formalin fixative which does not preserve ultrastructure well. In such situations, an accurate diagnosis is disputable and based on careful assessment of the histological features, exclusion of tumours with similar morphology and detailed correlation with MRI pictures (Fig. 4, Ref. 6). Full Text (Free, PDF) www.bmj.sk.

MR imaging of late radiation therapy- and chemotherapy-induced injury: a pictorial essay.

Radiation to the brain and adjuvant chemotherapy may produce late delayed changes from several months to years after treatment of intracranial malignancies with a reported prevalence of 5-24%. The pattern of treatment-related injury may vary from diffuse periventricular white matter lesions to focal or multifocal lesions. Differentiation of treatment-related injury from tumor progression/recurrence may be difficult with conventional MR imaging (MRI). With both disease processes, the characteristic but nonspecific imaging features are vasogenic edema, contrast enhancement, and mass effect. This pictorial essay presents MRI spectra of late therapy-induced injuries in the brain with a particular emphasis on radiation necrosis, the most common and severe form. Novel MRI techniques, such as diffusion-weighted imaging (DWI), proton MR spectroscopy (MRS), and perfusion MRI, improve the possibilities of better characterization of treatment-related changes. Advanced MRI techniques allow for the assessment of metabolism and physiology and may increase specificity for therapy-induced changes.

[Post-radiation dedifferentiation of meningioma into chondroblastic osteosarcoma]. / Postradiacná dediferenciácia meningeómu do chondroblastického osteosarkómu.

We report a case of post-radiation dedifferentiation of meningothelial meningioma into chondroblastic osteosarcoma. The tumor developed in a 61-year-old man, seven years after adjuvant stereotactical radiotherapy of recurring meningioma. Histologically, there was a continuous transition from atypical meningioma into chondroblastic osteosarcoma. The patient died three weeks after the surgery, without additional oncological treatment. To our knowledge, this case represents only the second reported case of post-radiation dedifferentiation of meningioma into osteosarcoma.

Post-therapeutical changes in the brain: novel trends in imaging and their infuence on external beam radiotherapy.

UNLABELLED: Presented is the analysis of patients who underwent external beam radiotherapy (EBRT) to the brain in the period from 2003 to 2006 at the department of Radiation Oncology of the St. Elisabeth Cancer Institute.

The aim of our analysis was to identify risk factors of late delayed therapy induced injuries (LDTI) in the brain. The patients were regularly examined with magnetic resonance (MRI), including conventional and advanced techniques: perfusion imaging (pMRI), diffusion weighted imaging (DWI), MRI spectroscopy (MRS). The results from MRI were correlated with 18fluoro-deoxyglucose positron emission tomography (18FDG/PET) scans, as none of the listed method is sufficiently sensitive and specific by itself. Also clinical data records and treatment plans of these patients were analyzed.

In our cohort we found 6 patients with abnormal post-therapeutical changes, 4 of them with MR and 18FDG/PET scans characteristics for LDTI - radiation necrosis. In one patient biopsy was performed and radiation necrosis (RN) was confirmed.

[The 2007 World Health Organisation classification of tumours of the central nervous system, comparison with 2000 classification]. / WHO klasifikácia tumorov centrálneho nervového systému 2007: porovnanie s klasifikáciou z roku 2000.

WHO Classification of Tumours of the Central Nervous System from the 2007 is distinguished from the previous 2000 classification by a few conceptual modifications, changes in the terminology and seven newly codified tumour entities. The text shows a short comparison of both classifications emphasising the most important changes from the surgical neuropathology point of view. The newly codified entities are: angiocentric glioma, pilomyxoid astrocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor of the 4th ventricle, papillary tumour of the pineal region, spindle cell oncocytoma and pituicytoma. Mostly, they are rare tumours already known from the literature. Based on new knowledge from the molecular pathology the paragraphs about tumour genetics were markedly changed. The complexity and diversity of tumours of the nervous system is enormous, and, not surprisingly, some problematic questions of classification and grading remain unresolved.

Tumor targeted gene therapy with plasmid expressing human tumor necrosis factor alpha in vitro and in vivo.

We have assessed the effect of exogenous human tumor necrosis factor alpha (hTNFalpha) in three human cancer cell lines; MDA-MB-361 (breast adenocarcinoma), HCT 116 (colon carcinoma) and 8-MG-BA (glioma). In vitro transfection of a plasmid containing hTNFalpha under the control of a hybrid promoter resulted in expression of hTNFalpha gene in all three cell lines and secretion into the culture medium was seen with MDA-MB-361 cells. Flow cytometric analysis showed a significant increase in apoptotic and necrotic cells in MDA-MB-361 and to a lesser extent in HCT 116 cells. Increased apoptosis was confirmed by an increase in pro-caspase 3 activation. No effects of hTNFalpha expression were seen in 8-MG-BA cells. Intratumoral delivery of the hTNFalpha expression plasmid into MDA-MB-361 tumor xenografts grown in nude mice caused hemorrhagic tumor necrosis. This strategy may be a simple and promising gene therapy approach to the treatment of some human tumors.