Significance of H3K27M mutation with specific histomorphological features and associated molecular alterations in pediatric high-grade glial tumors.

PURPOSE: Pediatric high-grade gliomas (pHGGs) constitute almost 15% of all childhood brain tumors. Recurrent mutations such as H3K27M mutation in H3F3A and HIST1H3B genes encoding histone H3 and its variants were identified in approximately 30% of pediatric glioblastomas. This study aimed to ascertain the morphological and molecular characteristics of pHGGs with H3K27M mutation. METHODS: In total, 61 cases of pHGGs (anaplastic astrocytoma, 12; glioblastomas, 49) from four university hospitals were studied. The histomorphological features were examined and immunohistochemistry was performed to evaluate the mutation status of H3K27M, ATRX, IDH1, BRAF V600E, and p53 genes. RESULTS: The study comprised 25 females and 36 males (age range, 1-18 years) with a clinical follow-up of up to 108 months. From the total, 31 patients were positive for H3K27M mutation located in the midline, mostly in the pons and thalamus. H3K27M mutation was commonly associated with ATRX loss (32.3%) and p53 (74.2%) immunoreactivity with a co-expression rate of 25.8%. While IDH1 mutation was not detected in pHGGs with H3K27M mutation, BRAFV600E mutation was rarely observed. Among the various histomorphological features, increased number of mitosis, increased Ki-67 proliferation index, and palisading and geographical necrosis along with small cell patterns were significantly associated with the H3K27M wild-type tumors. Focal infarct-like necrosis and pilomyxoid morphology was significantly associated with these tumors. CONCLUSION: H3K27M mutation occurs exclusively in pHGGs arising from the midline and presents with varied histomorphological features ranging from low-grade pilomyxoid astrocytoma to highly pleomorphic glioblastoma along with ATRX loss and p53 mutations.

Effect of hyperbaric oxygen therapy on cerebral vasospasm: a vascular morphometric study in an experimental subarachnoid hemorrhage model.

This study was undertaken to investigate the preventive or therapeutic effect of hyperbaric oxygen therapy (HBOT) on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH). Twenty rabbits were assigned randomly to one of four groups. Animals in Group I were not subjected to SAH or sham operation (control group, n = 5). Animals in Group II were subjected to sham operation and received no treatment after the procedure (sham group, n = 5). Animals in Group III were subjected to SAH and received no treatment after SAH induction (SAH group, n = 5). Animals in Group IV were subjected to SAH and received five sessions of HBOT at 2.4 atmospheres absolute (ATA) for 2 h (treatment group, n = 5). Animals were euthanized by perfusion and fixation 72 h after procedures. Basilar artery vasospasm indices, arterial wall thicknesses, and cross-sectional luminal areas were evaluated. Statistical comparisons were performed using Kruskal-Wallis and Mann-Whitney U tests. Mean basilar artery vasospasm index in the treatment group was significantly smaller than in the SAH group. Mean basilar artery wall thickness in the treatment group was significantly smaller than in the SAH group. Mean basilar artery cross-sectional luminal area in the treatment group showed an increase relative to the SAH group, but this difference remained statistically insignificant. Our results demonstrated that repeated application of HBOT at 2.4 ATA for 2 h attenuated vasospastic changes such as increased vasospasm index and arterial wall thickness. HBOT is thus a promising candidate for SAH-induced vasospasm. Further studies are needed to evaluate maximal effect and optimal application regimen.

Metastasis to paranasal sinuses and orbita of breast cancer with a rare metachronous tumor of the uterine cervix.

Breast cancer metastases are rarely seen in paranasal sinuses or orbit with a poor prognosis, and these cases were published as case reports. Moreover, metachronous tumors following breast cancer diagnosis are somewhat common, but uterine cervix is infrequent in them. In the present case, we report a 61-year-old female patient who had a biopsy-proven metastatic breast cancer to paranasal sinuses and orbita. She also had a cervical uterine cancer which is also unusually diagnosed following breast cancer. Palliative radiotherapy to paranasal sinuses (30 Gy) achieved a good response. However, she died due to leptomeningeal progression.

Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model.

OBJECTIVE: Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. METHODS: The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. RESULTS: The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. CONCLUSIONS: Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment.

Biologic tumor behavior in pilocytic astrocytomas.

PURPOSE: The aim is to describe the behavior of pilocytic astrocytoma (PAs) and its effects on patient prognosis by using flow cytometric, immunohistochemical and cytogenetic methods. We also aim to find out whether there is any difference between differently localized tumors by the above mentioned analyses. METHODS: We studied DNA index, expression of p53, p16, pRb, MMAC/PTEN1, VEGF, MIB-1 index and chromosomal anomalies which can be detected by array comparative genomic hybridization (CGH) technique. We analyzed the association of the results of these studies with clinical prognosis and tumor localization. We included 53 patients (18 cerebellar, 20 chiasmatic/hypothalamic and 15 hemispheric). Samples were studied from paraffin embedded tumors. RESULTS: We found that PAs are mostly diploid and ploidy pattern does not affect the prognosis. The expression of p53, p16, pRb, MMAC/PTEN1 and VEGF was not significantly different between different localizations and could not predict the prognosis. Frequently seen copy number aberrations (CNAs) are: amplification in 1p36.33, 2p11.2, 9p11.2, 9q12, 16p11.2, 19q13.12-q13.2, Xp22.2-p21.3, Xp11.3-p11.22, Xq11.1-q12, Xq13.1, Xq21.1-q21.31, Xq22.3, Xq26.3 and homozygous deletion in 2p11.2, 8p23.1, 16p12.3. Among them, 2p11.2 amp, 9p11.2 amp and 1p36.21 hom del were correlated with prognosis. Moreover, we found a significant correlation between 16p11.2 amp and tumor localization. CONCLUSIONS: Differently localized PAs have different properties which make them behave with different biological aggressiveness. PAs demonstrate a significant amount of CNAs that can be detected by a high-resolution study. However, tumor suppressor genes p53, p16, pRb, MMAC/PTEN1 and expression patterns do not play a significant role in PAs.

Intermediate-Grade Meningeal Melanocytoma in a 19-Month- Old Child with Difficulties in Differential Diagnosis and Management.

Intermediate-grade meningeal melanocytoma (IGM) is a rare tumor that has not been reported in children so far. It is speculated to have more aggressive clinical behavior with undefined best management options. In this study, we present a 19-month-old girl as the first case with IGM in English literature. Preoperative diagnosis was ambiguous, given the unclear patient history and radiological features resembling a growing skull fracture or a congenital parietal bone agenesis subtype. During surgery, a dark gray-black dural area (5 × 7 cm in size) was found and then excised. However, the surgery was complicated due to brain edema and swelling, warranting a second surgery for reconstruction and dural repair. Of the 16 reported adult patients, 14 showed a high recurrence rate without adjuvant radiotherapy; 2 showed no recurrence with adjuvant radiotherapy. No adjuvant radiotherapy was given to our patient since she was 19 months old at the time of diagnosis and showed no recurrence at 48-month follow-up until now. Close monitoring with radiological imaging is of paramount importance for such cases.

Past, Present, and Future of Therapies for Pituitary Neuroendocrine Tumors: Need for Omics and Drug Repositioning Guidance.

Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

Gamma knife radiosurgery for cranial neurocytomas.

Gamma-knife surgery may be an effective alternative for treatment of central neurocytomas owing to its relative safety compared with conventional radiotherapy. In this paper we present results of gamma-knife treatment (GKS) of residual or recurrent neurocytomas. Twenty-two patients (14 female, 8 male) with recurrent or residual neurocytomas who underwent GKS were included. Diagnosis was based on histological findings. The proliferative potential of the tumors was examined by immunostaining with MIB-1 antibody, which is specific for detection of Ki-67 antigen. Tumor volume was determined by using post-gadolinium magnetic resonance images. After GKS treatment, MR imaging was scheduled at three-month intervals in the first year, at six months intervals in the second year, and yearly thereafter. Histopathological diagnoses were: 18 cases of central neurocytomas, two liponeurocytomas, one cerebral neurocytoma and one cerebellar neurocytoma. The MIB1 labeling index (LI) varied from 0 to 5.7%. Marked reduction in tumor volume was seen in 15 patients. In six patients, the tumor volume remained unchanged, and progression was observed for one patient. No complications because of GKS were noted. Shrinking effect on tumor volume increased with increasing duration of follow-up. On the other hand, high MIB labeling index did not seem to have an effect on tumor response to GKS treatment. Findings of this study suggest that GKS is an effective and safe treatment alternative for residual or recurrent neurocytomas. However, its effectiveness should be confirmed with larger studies.

Tumoral calcinosis and epidural lipomatosis of the lumbar spine.

Lumbar spinal tumoral calcinosis and spinal epidural lipomatosis are rare conditions. We present a 70-year-old female patient with serology negative spondyloarthropathy who developed paresis due to tumoral calcinosis in the left facet joint between L5 and S1 levels and spinal epidural lipomatosis at L5 and S1 levels. Surgery was performed to excise the lesions en bloc. Neural decompression was provided. Neurological symptoms improved after surgery. Here, we report the first serology negative spondyloarthropathy case that had concomitant development of tumoral calcinosis and spinal epidural lipomatosis.

Effects of Ozone on Injury after Gamma Knife Radiosurgery.

BACKGROUND: At present, gamma knife radiosurgery plays an important role in neurosurgical procedures. Gamma knife radiosurgery has been used to treat many types of brain tumors and as a functional intervention. However, gamma knife treatment has a devastating effect on the normal brain parenchyma surrounding the target point. It causes increased vascular permeability, vasodilation, and swelling in endothelial cells. Ozone has antioxidant, antiapoptotic, and anti-inflammatory effects in the body. Thus, we evaluated the radioprotective effects of ozone in rats undergoing gamma knife radiation. METHODS: In the present study, 24 Sprague-Dawley male rats weighing 250-300 g in 3 groups of 8 rats each were used. The rats were selected randomly. The control group did not receive any gamma knife radiation. The other 2 groups received 50 Gy of radiation, with 1 group given ozone treatment and the other group not given ozone treatment after gamma knife radiosurgery. At 12 weeks after gamma knife radiation, the rats were sacrificed with high-dose anesthetic agents and the tissues prepared for evaluation. The slides were evaluated for necrosis, vacuolization, glial proliferation, and vascular proliferation using hematoxylin-eosin staining. Vascular endothelial growth factor (VEGF) and extracellular matrix metalloproteinase inducer (also known as CD147) were evaluated using immunohistochemical staining. RESULTS: VEGF expression in glial tissue was significantly less in the group receiving ozone (χ2 = 15.00; df = 4; P = 0.005) compared with the group that had not received ozone and was similar to the expression in the control group. CONCLUSIONS: The lower expression of VEGF in the group receiving ozone might cause less edema in the surrounding tissue owing to less degradation of vascular permeability in the rat brain tissue.

Analyses of Copy Number Variations in Myxopapillary Ependymomas of Cauda Equina.

AIM: To identify the copy number variations that are specific to myxopapillary ependymomas (MPEs) of the cauda equina. MATERIAL AND METHODS: The patient cohort included five patients who underwent resection of histologically confirmed MPEs. Tumor samples collected during surgery and stored in liquid nitrogen as well as corresponding blood samples collected were analyzed. Genomic DNA from the venous blood and tumor samples was obtained using standard techniques and hybridized to a Cytoscan 750K Array in accordance with the manufacturer’s introductions. RESULTS: As a novel finding, amplification on chromosome 14q32.33 was detected in all tumor and blood samples, except one tumor sample. All tumor tissues also showed amplification on chromosomes 5, 7, 9, and 16. CONCLUSION: Although further studies with larger cohorts are required to identify genes involved in MPE tumorigenesis and to validate our results, these findings provide a basis for advanced molecular biological and genetic studies of MPEs.

Effect of smoking on rat basilar artery: correlation with inducible nitric oxide synthase and endothelin converting enzyme-1.

AIM: Smoking is an extremely important risk factor for subarachnoid hemorrhage and seems to increase rupture risk of unruptured aneurysms by accelerating their growth rate. The aim of the study was to investigate the effect of smoking on the luminal diameter with wall thicknesses of rat basilar arteries and to detect alterations of inducible nitric oxide synthase and endothelin-converting enzyme -1 in the endothelial cells. MATERIAL AND METHODS: Rats were divided into two groups. The level of middle pons slices were embedded in paraffin before they were stained with hematoxylin and eosin. Rabbit anti-human inducible nitric oxide synthase and endothelin converting enzyme-1 antibodies were used. RESULTS: Significant decrease of the vessel luminal diameter and increase of the vessel wall thickness were found in chronic smokers in our study. There was a linear and significant (p= 0,023, r =0,704) correlation between thickness of the wall and endothelin converting enzyme-1 immune reaction. Correlation was not found with inducible nitric oxide synthase (p > 0.05). CONCLUSION: This study on the comparison of vessel luminal diameter and vessel wall thickness with inducible nitric oxide synthase and endothelin converting enzyme-1 immune reactions revealed that the main effect of smoking on the vessel wall is associated with endothelin converting enzyme-1.

De novo myeloid sarcoma as a rare cause of small bowel obstruction: CT findings and histopathologic correlation.

Small bowel obstruction caused by myeloid sarcoma in a patient with any hematological abnormality is very rare. Myeloid sarcoma occurs most commonly in patients with acute myelogenous leukemia (AML) and less with other hematological disorders. A 57-year-old female presented with abdominal pain, nausea, vomiting, and constipation. Radiological studies showed concentric bowel thickening in distal ileum that caused nearly total luminal compromise and signs of obstruction in proximal ileal bowel loops. She underwent laparotomic surgery and ileal resection was done. Diagnosis of myeloid sarcoma was made by histopathological examination of surgical specimens. Bone marrow biopsy was done to rule out systemic acute myelogenous leukemia (AML). Results of bone marrow biopsy were within normal limits. Finally, the patient was diagnosed as de novo myeloid sarcoma. Although the histopathological examination makes a definitive diagnosis, imaging allows to locate the lesion, evaluate its complications, and guide for correct biopsy. Accurate diagnosis of myeloid sarcoma has important prognostic value as transformation to AML can happen without chemotherapy or stem cell transplantation.

Acute megakaryoblastic leukemia mimicking small round cell tumor with novel t(1;5)(q21;p13).

Acute megakaryoblastic leukemia is a relatively rare form of acute leukemia that has heterogeneous blast morphology and karyotypic abnormalities. An 8-month-old boy with a retroperitoneal mass was diagnosed as having acute megakaryoblastic leukemia that initially presented as small round cell tumor of childhood. Bone marrow aspiration showed syncytial groups of atypical medium sized cells with scant cytoplasm and fine nuclear chromatin. Retroperitoneal mass biopsy showed several lymph nodes with cohesive clusters of neoplastic cells that demonstrated expression of Factor VIII. Flow cytometric analysis of the second bone marrow aspiration showed CD 61 positivity. Karyotypic analysis of bone marrow cells showed a novel translocation, (1;5)(q21;p13).

Apocrine carcinomas of the breast in Turkish women: hormone receptors, c-erbB-2 and p53 immunoexpression.

The aims of this study were twofold: (i) to determine the occurrence frequency of apocrine carcinoma of the breast (ApBCa) in Turkish breast cancer (BCa) patients; and (ii) to evaluate the expression of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), gross cystic disease protein-15 (GCDFP-15), c-erbB-2, and p53 in these cases. Six hundred and twenty-six cases of BCa were studied immunohistochemically (streptoavidin-biotin horseradish peroxidase method). The results of ApBCa were compared with those of invasive ductal carcinoma not otherwise specified type (IDC-NOS) cases of similar grade. Thirteen cases of ApBCa were encountered, accounting for 2.1% of all BCa cases. Immunohistochemically, ApBCa positivity was as follows: GCDFP-15 (100%), ER (39%), PR (8%), AR (54%), p53 (39%), and c-erbB-2 (85%). In the IDC-NOS group, GCDFP-15* was expressed in less than 50% of the tumors. The occurrence frequencies of the other markers were as follows: ER (69%), PR (69%)*, AR (46%), c-erbB-2 (0%)*, and p53 (31%), (*) indicating significant differences between the two groups. For Turkish BCa patients, (i) the occurrence rate of ApBCa (2.1%) was high; and (ii) the following combination would allow for an immunohistochemical identification of ApBCa: GCDFP-15(+), c-erbB-2(+), and PR(-).

Solitary fibrous tumor of the kidney. Case report.

Solitary fibrous tumors are rare spindle cell neoplasms usually arising in the pleura. They have, however, also been reported at extrapleural locations. Solitary fibrous tumor (SFT) of the kidney is rare. Despite its rarity, histological diagnosis of solitary fibrous tumor is crucial to avoid misdiagnosis with other more aggressive tumors arising in the kidney. We report a solitary fibrous tumor of the left kidney that presented as a malignant tumor in a 51-year-old woman, and include clinical and radiographic findings. The tumor was well circumscribed and composed of spindle cells in a collagenous stroma. Immunohistochemistry showed reactivity for vimentin, CD 34, BCL-2 protein and CD99. Immunohistochemical stains for cytokeratin, S-100, desmin, alpha-smooth muscle actin and HMB-45 were negative. A diagnosis of SFT was made based on light microscopy and immunohistochemistry.

The Role of EGFR, Hepatocyte Growth Factor Receptor (c-Met), c-ErbB2 (HER2-neu) and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma.

OBJECTIVE: Chordoma is a rare malignant bone tumor with a poor outcome. Although radiotherapy and gamma knife surgery have been used for treatment, providing a cure for the tumor is not easy, because of the frequent recurrences. Molecular targeted therapy against tyrosine kinases has been effective in the treatment of malignancies such as breast and lung cancers and brain tumors. We aimed to analyse the histopathological features of chordomas and the immunoexpression profiles of the three receptor tyrosine kinases of EGFR, c-Met and c-Erb-B2 in chordomas. We have correlated these results with recurrence and overall survival status of the patients. MATERIAL AND METHOD: We studied 49 chordoma patients in order to evaluate the histopathological features and immunohistochemical stainings by EGFR, c-Met and c-ErbB2 antibodies. Of the 49 patients, follow up data was available for 40 patients. Clinical data of the patients were correlated with histopathological features and survival analysis was performed. RESULTS: The immunostaining rate by EGFR and c-Met was 73.5% and 12.2% respectively. None of the cases showed immunoreactivity by c-ErbB2 (0%). Of the 40 cases, 17 cases showed recurrences. EGFR expression was detected in 14 recurrent (14/17) and 17 non-recurrent cases (17/23). Four of the 17 recurrent cases (4/17) were positive by c-Met, while none of the non-recurrent cases (0/23) were positive by this antibody. Significantly, all cases with positive c-Met expression showed recurrences (p < 0.05). CONCLUSION: Our study indicates that EGFR expression is detected in the majority of chordoma cases. c-Met expression can be used as a prognostic indicator for chordoma.

Solitary Fibrous Tumor of the Orbit: A Case Report and Review of the Literature.

Solitary fibrous tumor (SFT) is a rare, benign, spindle cell tumor that is most commonly found in the visceral pleura. The orbit is one of the most common extrapleural sites of occurrence. Though they can be seen in any age, they typically present in adults with proptosis as the prominent symptom. They show no significant gender predominance. Orbital solitary fibrous tumors routinely exhibit a benign course, but malignant forms with an increased propensity for local recurrence have been reported. Histopathologically, they share similar features with hemangiopericytoma, which is much more common. The diagnosis of SFT depends on the diffuse and intense positivity of CD34 staining by immunohistochemistry (14). Here, we report a case of SFT, which presented with proptosis and double vision on lateral gaze. We describe the clinical, radiographic, histopathological, and immunohistochemical findings. We also provide a discussion on its origin and differential diagnosis in the light of relevant literature.

The histomorphological findings of kidneys after application of high dose and high-energy shock wave lithotripsy.

INTRODUCTION: In this animal study, we reviewed the histomorphological findings in rabbit kidneys after a high number of high-energy shock wave applications and observed if there were any cumulative effects after repeated sessions. MATERIAL AND METHODS: We formed 2 groups, each consisting of 8 rabbits. Group 1 received 1 session and group 2 received 3 sessions of ESWL with a 7 day interval between sessions, consisting of 3500 beats to the left kidney and 5500 beats to the right kidney per session. The specimens of kidneys were examined histomorphologically after bilateral nephrectomy was performed. For statistical analysis, 4 groups of specimens were formed. The first and second groups received 1 session, 3500 and 5500 beats, respectively. The third and fourth groups received 3 sessions, at 3500 and 5500 beats per each session, respectively. The sections were evaluated under a light microscope to determine subcapsular thickening; subcapsular, intratubular and parenchymal hemorrhage; subcapsular, intersitital, perivascular and proximal ureteral fibrosis; paranchymal necrosis; tubular epithelial vacuolization; tubular atrophy; glomerular destruction and calcification. RESULTS: In histopathological examinations capsular thickening, subcapsular hematoma, tubuloepithelial vacuolisation, glomerular destruction, parenchymal hemorrhage, interstitial fibrosis, and perivascular fibrosis were observed in all groups. In statistical analysis, on the basis of perivascular fibrosis and tubular atrophy, there was a beats per session dependent increase of both. CONCLUSIONS: The detrimental effects from ESWL are dose dependent but not cumulative for up to 3 sessions. Histopathological experimental animal studies will aid in understanding local and maybe, by means of these local effects, systemic effects.