Pre-Radiotherapy Progression after Surgery of Newly Diagnosed Glioblastoma: Corroboration of New Prognostic Variable.

BACKGROUND: The aim of this retrospective study is to assess the incidence, localization, and potential predictors of rapid early progression (REP) prior to initiation of radiotherapy in newly diagnosed glioblastoma patients and to compare survival outcomes in cohorts with or without REP in relation to the treatment. METHODS: We assessed a consecutive cohort of 155 patients with histologically confirmed irradiated glioblastoma from 1/2014 to 12/2017. A total of 90 patients with preoperative, postoperative, and planning MRI were analyzed. RESULTS: Median age 59 years, 59% men, and 39 patients (43%) underwent gross total tumor resection. The Stupp regimen was indicated to 64 patients (71%); 26 patients (29%) underwent radiotherapy alone. REP on planning MRI performed shortly prior to radiotherapy was found in 46 (51%) patients, most often within the surgical cavity wall, and the main predictor for REP was non-radical surgery (p < 0.001). The presence of REP was confirmed as a strong negative prognostic factor; median overall survival (OS) in patients with REP was 10.7 vs. 18.7 months and 2-year survival was 15.6% vs. 37.7% (hazard ratio HR 0.53 for those without REP; p = 0.007). Interestingly, the REP occurrence effect on survival outcome was significantly different in younger patients (≤ 50 years) and older patients (> 50 years) for OS (p = 0.047) and non-significantly for PFS (p = 0.341). In younger patients, REP was a stronger negative prognostic factor, probably due to more aggressive behavior. Patients with REP who were indicated for the Stupp regimen had longer OS compared to radiotherapy alone (median OS 16.0 vs 7.5; HR = 0.5, p = 0.022; 2-year survival 22.3% vs. 5.6%). The interval between surgery and the initiation of radiotherapy were not prognostic in either the entire cohort or in patients with REP. CONCLUSION: Especially in the subgroup of patients without radical resection, one may recommend as early initiation of radiotherapy as possible. The phenomenon of REP should be recognized as an integral part of stratification factors in future prospective clinical trials enrolling patients before initiation of radiotherapy.

Real-World Evidence in Glioblastoma: Stupp's Regimen After a Decade.

The aim of this retrospective study is to provide real-world evidence in glioblastoma treatment and to compare overall survival after Stupp's regimen treatment today and a decade ago. A current consecutive cohort of histologically confirmed glioblastoma irradiated from 1/2014 to 12/2017 in our cancer center was compared with an already published historical control of patients treated in 1/2003-12/2009. A total of new 155 patients was analyzed, median age 60.9 years, 61% men, 58 patients (37%) underwent gross total tumor resection. Stupp's regimen was indicated in 90 patients (58%), 65 patients (42%) underwent radiotherapy alone. Median progression-free survival in Stupp's regimen cohort was 6.7 months, median OS 16.0 months, and 2-year OS 30.7%. OS was longer if patients were able to finish at least three cycles of adjuvant chemotherapy (median 23.3 months and 43.9% of patients lived at 2 years after surgery). Rapid early progression prior to radiotherapy was a negative prognostic factor with HR 1.87 (p = 0.007). The interval between surgery and the start of radiotherapy (median 6.7 weeks) was not prognostically significant (p = 0.825). The median OS in the current cohort was about 2 months longer than in the historical control group treated 10 years ago (16 vs. 13.8 months) using the same Stupp's regimen. Taking into account differences in patient's characteristics between current and historical cohorts, age, extent of resection, and ECOG patient performance status adjusted HR (Stupp's regimen vs. RT alone) for OS was determined as 0.45 (p = 0.002).

Gastric antral vascular ectasia and solitary rectal ulcer syndrome - two rare diagnoses as the cause of anemia in a single patient: case report.

Gastric antral vascular ectasia (GAVE) and solitary rectal ulcer syndrome (SRUS) are both mentioned in the literature as rare causes of iron deficiency anemia and gastrointestinal (GI) bleeding. GAVE accounts for up to 4 % of upper non-variceal GI bleeding; SRUS is a rare benign disorder that presents with rectal bleeding. We present the case of a 75-year-old patient who was admitted to our facility with anemia. In the same patient, we encountered chronic bleeding from GAVE and SRUS. Both diagnoses were treated endoscopically: GAVE by argon plasma coagulation and a subsequent treatment with proton pump inhibitors and SRUS by adrenaline injection and clipping, consecutively treated with mesalazine enemas. The patient was successfully cured, resulting in a stable level of hemoglobin and no recurrent GI bleeding. We report a unique case of chronic GI bleeding caused by two uncommon diagnoses. The co-occurrence of GAVE and SRUS has not been previously described or published.Key words: anemia - endoscopy - gastric antral vascular ectasia (GAVE) - gastrointestinal bleeding - solitary rectal ulcer syndrome (SRUS).

Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues.

OBJECTIVES: The aim of this study was to evaluate transcript levels of all 49 human ATP-binding cassette transporters (ABCs) in one of the most drug-resistant cancers, namely, the pancreatic ductal adenocarcinoma (PDAC). Association of ABCs levels with clinical-pathologic characteristics and KRAS mutation status was followed as well. METHODS: Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients. The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and sequencing. RESULTS: Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics. KRAS mutations did not change the global expression profile of ABCs. CONCLUSIONS: The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues. The observed up-regulation of ABCB4, ABCB11, ABCC1, ABCC3, ABCC5, ABCC10, and ABCG2 in tumors may contribute to the generally poor treatment response of PDAC. The up-regulation of ABCA1, ABCA7, and ABCG1 implicates a serious impairment of cellular cholesterol homeostasis in PDAC. On the other hand, the observed down-regulation of ABCA3, ABCC6, ABCC7, and ABCC8 suggests a possible role of stem cells in the development and progression of PDAC.

Laparoscopic radiofrequency ablation of functioning pancreatic insulinoma: video case report.

Insulinomas are the most common functioning endocrine tumors of the pancreas. Most of them are well-differentiated tumors, with benign or uncertain behavior at the time of diagnosis. Surgery is considered to be the only curative treatment modality. We present the first case report of a 75-year-old woman with functioning insulinoma of the pancreatic body, which was destroyed by laparoscopic-assisted radiofrequency ablation. Hypoglycemic paroxysms disappeared immediately after surgery. The postoperative course was uneventful. The patient was discharged on the eighth postoperative day. There was a new onset of diabetes mellitus, without any further hypoglycemic paroxysm from surgery to the present-4 months. Laparoscopic-assisted radiofrequency ablation is shown to be a feasible and safe method for the treatment of functioning pancreatic insulinoma.

Clinicopathological correlations of nestin expression in surgically resectable pancreatic cancer including an analysis of perineural invasion.

BACKGROUND AND AIMS: Nestin is considered to be a marker of stem/progenitor cells in different tissues. Nestin expression was also described in various tumors. In pancreatic ductal adenocarcinoma (PDAC), its role in cancer cell migration, invasion, and metastases has been suggested. The study aimed at examining the expression of nestin in PDAC, and to evaluate its clinicopathological correlations. METHODS: The expression of nestin was immunohistochemically examined in 117 PDAC resection specimens, analyzed, and correlated with clinico-pathological parameters including perineural invasion (PNI). Analysis of nestin expression in nerve fibers in tissues of chronic pancreatitis (CP) was added. RESULTS: Immunohistochemical analysis of nestin expression showed 79 nestin negative (67.5 %) and 38 nestin positive (32.5 %) PDACs. No significant correlations of nestin expression in tumor cells with the analyzed clinicopathological parameters were demonstrated. Tumor grade (p<0.001) and nodal status (p=0.009) proved to represent independent prognostic factors. PNI was identified in 94 PDAC (80.3 %), and did not correlate with nestin expression. Nestin immunostaining was displayed in nerve fibers of both CP and PDAC tissues. CONCLUSION: An intimate link of nestin to a biological process of pancreatic cancer was confirmed. The expression of nestin did not prove to be a valuable prognostic factor and an immunohistochemical assessment of nestin expression is not superior to conventional prognostic factors in PDAC. A correlation between nestin expression in tumor cells and PNI was not confirmed and expression of nestin in nerve fibers of both PDAC and CP tissues seems to reflect the process of neural remodeling responsible for pancreatic neuropathy.

Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: an unexpected prognostic significance?

The role of nonclassical human leukocyte antigens G and E (HLA-G and HLA-E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA-G and HLA-E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA-G and HLA-E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA-G and HLA-E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA-G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA-E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro-host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.

Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: a role in innate immunity?

The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia-glioblastoma cell interactions with respect to the expression of these molecules deserves further study.

Hypertext atlas of fetal and neonatal pathology.

Hypertext atlas of fetal and neonatal pathology is a free resource for pregraduate students of medicine, pathologists and other health professionals dealing with prenatal medicine. The atlas can be found at http://www.muni.cz/atlases. The access is restricted to registered users. Concise texts summarize the gross and microscopic pathology, etiology, and clinical signs of both common and rare fetal and neonatal conditions. The texts are illustrated with over 300 images that are accompanied by short comments. The atlas offers histological pictures of high quality. Virtual microscope interface is used to access the high-resolution histological images. Fetal ultrasound video clips are included. Case studies integrate clinical history, prenatal ultrasonographic examination, gross pathology and histological features. The atlas is available in English (and Czech) and equipped with an active index. The atlas is suitable both for medical students and pathologists as a teaching and reference tool. The atlas is going to be further expanded while keeping the high quality of the images.

cPLA2-interacting protein, PLIP, causes apoptosis and decreases G1 phase in mesangial cells.

The balance between proliferation and apoptosis of mesangial cells is a critical component of proliferative glomerulonephritis. The regulation of cell proliferation and apoptosis is linked at the level of the cell cycle (Shankland SJ. Kidney Int 52: 294-308, 199). cPLA2-interacting protein (PLIP), the Tip60 splice variant, interacts with cPLA2 and enhances the susceptibility of renal mesangial cells to serum deprivation-induced apoptosis (Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, and Bonventre JV. Mol Cell Biol 21: 4470-4481, 2001). We report that adenoviral-driven PLIP expression results in enhanced apoptosis of non-serum-deprived mesangial cells associated with a marked decrease in G0/G1 phase cells. The effect of PLIP on the cell cycle may be independent of its interaction with cPLA2 because a mutation of PLIP that does not interact with cPLA2 also causes a decrease in G0/G1 cells. Endogenous PLIP and Tip60 protein levels are increased in cells exposed to injurious stimuli including X-irradiation and H2O2, but the intracellular localization of the splice variants may differ. Whereas PLIP localizes in the nucleus of all mesangial cells, Tip60 localizes in the cytosol of untreated mesangial cells and of cells exposed to low concentrations (50-200 microM) of H2O2. Tip60 is targeted to the nucleus of cells exposed to high concentrations (1-2 mM) of H2O2. We conclude that PLIP may cause cells to exit from the cell cycle after the S phase and may function as part of a G2/M checkpoint mechanism. Tip60 splice variants may function in both cytosolic and nuclear signaling pathways in mesangial cells.