S-100 and MATH-1 Protein Expressions Can Be Useful for the Prediction of Clinical Outcome in Neuroblastoma Patients.

Neuroblastoma (NB) is the most frequent extracranial solid tumor of childhood, remarkable for its broad spectrum of clinical behavior. This diversity in behavior correlates closely with defined clinical and biological features and combinations of prognostic variables are used for risk-group assignment. S-100 proteins have roles in differentiation and were shown to be frequently dysregulated in NB. MATH-1 protein plays role in neuronal cell differentiation through development. However, up to date, there are no studies evaluating the relationship between MATH-1 and NB. Grb2-associated binding (Gab) proteins have roles in the regulation of cell growth and differentiation. Gab1 was reported to be related to poor survival of high-risk NB patients. The aim of this study was to investigate the relationship between differentiation-related S-100, MATH-1, and Gab1 proteins and risk group and/or stages of NB. A significant relation was found between S-100 and early stages of NB. This study also revealed a significant association between MATH-1 and low-risk groups. S-100 and MATH-1 were also shown to provide survival advantages among stages and risk groups. The findings of this study support the assumption that S-100 and MATH-1 can be potential prognostic biomarkers for staging and risk-group assignment of NB patients. These proteins can be useful tools for clinicians to guide through treatment options, especially for the evaluation of tumor differentiation.

Genomic Alterations of Signaling and DNA Damage Repair Pathways in Non-Muscle Invasive Bladder Cancer.

The aim of the study was to demonstrate the most common genetic alterations and evaluate possible targets involving phosphatidylinositol-3-OH kinase (PIK3)/AKT/mammalian target of rapamycin (mTOR) signaling and DNA damage repair (DDR) pathways for personalized treatment in patients with non-muscle invasive bladder cancer (NMIBC). Alterations of these pathways were observed in 89.5% and 100% of patients, respectively. Among them, BARD1 was more frequently altered in low/intermediate-risk cases, but PARP4 was more frequently affected in intermediate/high-risk patients. The possible target feasibility of BARD1 and PARP4 alterations should be evaluated for personalized treatment using PARP-inhibitors in NMIBC. It is important to detect high tumor mutation burden (TMB) in patients in terms of immunotherapy.

The prognostic role of epidermal growth factor receptor mutation in completely resected ampullary adenocarcinoma.

The aim of this study is to make a differential diagnosis and prognosis of the ampullary adenocarcinoma subtypes. We also investigated the role of prognostic markers PD-1 and PD-L1, and epidermal growth factor receptor (EGFR). Local or locally advanced stage ampullary adenocarcinoma patients who had undergone pancreaticoduodenectomy at the time of diagnosis were included. MUC1, MUC2, MUC5AC, CDX2, CK7, CK20, PD-1, and PDL-1 were analysed immunohistochemically, and EGFR was analysed by real-time polymerase chain reaction. According to histopathological and immunohistochemical evaluation, we found 27 patients as pancreatobiliary type and 56 patients as intestinal type adenocarcinoma. The median survival of patients with intestinal and pancreatobiliary type adenocarcinoma was 23 months and 76 months ( p = 0.201), respectively. When the survival of PD1-positive ( n = 23) and PD-L1-positive ( n = 18) patients were compared with the patients with negative staining ( n = 60, n = 65), no significant difference was found. Epidermal growth factor receptor mutation was detected in a total of 6 patients, and 5 of these 6 mutations were shown in intestinal type tumours and one in a pancreatobiliary type tumour. A significant difference was determined in terms of overall survival for the patients with EGFR mutations compared to those without ( p = 0.008). In conclusion, we could reveal the prognostic significance of EGFR mutation, which is also a target molecule.

Safety of Eicosapentaenoic Acid in Cancer Treatment: Effect on Cancer Cells and Chemotherapy in Vitro.

Eicosapentaenoic acid (EPA) is a long-chain polyunsaturated fatty acid that has been used to treat cachectic cancer. However, its efficacy and safety with regard to cancer cells remain unclear. The present study comprised an In Vitro investigation of the effects of EPA on cancers. The effects of 0.01-300 µg/mL of EPA on the proliferation and death of cells after 24, 48, and 72 h were explored. The study included cell lines representing neuroblastoma (Kelly, SH-SY5Y, C1300); acute lymphoblastic leukemia (ALL); Burkitt's lymphoma; acute myeloid leukemia (AML); adult cancer cell lines of the pancreas, colon, and prostate; and a fibroblast cell line. EPA caused 4.4%-7% proliferation of fibroblasts, but did not protect them from the toxic effect of cisplatin. It did not induce proliferation in the neuroblastoma cells, and did not reduce the cytotoxic effect of cisplatin. EPA also did not cause proliferation in ALL, Burkitt's lymphoma, and AML cells, and did not alter the cytotoxic effects of L-asparaginase, cyclophosphamide, and cytosine arabinoside, respectively. Our results were similar in the adult cancer cell lines. EPA is safe because it has no effects on the proliferation of cancer cells or on chemotherapy In Vitro.

A Novel Biomarker in Diabetic Macular Edema with Serous Retinal Detachment: Serum Chitinase-3-Like Protein 1.

PURPOSE: To determine whether serum chitinase-3-like protein 1 (CHI3L1) and interleukin-6 (IL-6) levels correlate with serous retinal detachment (SRD) in diabetic macular edema (DME) using spectral-domain optical coherence tomography (SD-OCT). METHODS: In this cross-sectional case-control study, 394 patients (treatment-naive DME patients, n = 218; diabetic patients without DME, n = 96; nondiabetic controls, n = 80) were included in the study. Eyes were classified according to SD-OCT features of DME: SRD, cystoid macular edema (CMO), and diffuse retinal thickness (DRT). Serum concentrations of CHI3L1 and IL-6 were analyzed using enzyme-linked immunosorbent assay. RESULTS: Serum CHI3L1 and IL-6 levels were significantly higher in DME with SRD compared to patients with CMO and DRT (p < 0.001 for all groups). Multivariate regression analysis showed that CHI3L1 and IL-6 had a stronger influence on the presence of SRD in DME (r = 1.162, p = 0.026, and r = 1.242, p = 0.016, respectively). Serum concentration of CHI3L1 was significantly correlated with that of IL-6 (r = 0.386, p = 0.0015). CONCLUSIONS: Our data suggest that serum concentrations of CHI3L1 and IL-6 are involved in the process of SRD in DME. CHI3L1 can be investigated further as a new diagnostic biomarker for DME with SRD.

The efficacy of systemic and intravitreal infliximab treatments in an endotoxin-induced uveitis model.

Purpose: To compare the efficacy of systemic and intravitreal infliximab treatments in an experimental endotoxin-induced uveitis (EIU) model. Methods: Twenty-eight white New Zealand rabbits were equally divided into 4 groups. Group 1 received an intravitreal injection of 0.1 cc saline, group 2 received an intravitreal injection of 2 µg/0.1 cc lipopolysaccharide (LPS), group 3 received an intravitreal injection of 2 µg/0.1 cc LPS and 2 mg/0.1 cc infliximab, and group 4 received intravitreal injection of 2 µg/0.1 cc LPS and intravenous injection of 5 mg/kg infliximab. Clinical, biochemical (aqueous and vitreous humour protein levels and TNF-α concentrations), and histopathological evaluations were performed. Results: The clinical examination score was lower in group 4 than in group 2 (p = 0.006); but there was no significant difference between groups 2 and 3 (Bonferroni correction, p = 0.016). No statistically significant difference was found among groups 2, 3, and 4 for aqueous humour protein levels (p > 0.05). Significantly higher aqueous humour concentrations of TNF-α was measured in group 3 comparing to both group 1 and 4 (p = 0.003 and p = 0.002, respectively). No significant difference was found in vitreous protein levels or TNF-α concentrations among all study groups (Bonferroni correction, p = 0.026 and p = 0.101, respectively). Histopathological evaluation of the uveal tissue and anterior chamber reaction revealed the highest inflammation in group 3 (p < 0.001). In group 4, histopathological evaluation of uveal tissue was lower than in groups 2 and 3 (p < 0.001 and p = 0.001, respectively); whereas there was no difference in anterior chamber inflammation between groups 2 and 4 (p = 1.00). Conclusion: Intravitreal 2 mg/0.1 cc infliximab injection exacerbated inflammation in an EIU model; whereas systemic infliximab treatment at a dose of 5 mg/kg suppressed inflammation effectively and rapidly.

BRCA genes: BRCA 1 and BRCA 2.

BRCA1 and BRCA2 are the genes related with breast and ovarian cancer. They have function in DNA repair processes and thus they are tumor suppressor genes. There are hundreds of mutations identified in these genes. Functional deficiencies due to these mutations impair DNA repair and cause irregularities in the DNA synthesis. The standard method for the laboratory assessment of these BRCA genes includes comprehensive sequencing and testing of broad genomic rearrangements. Members of the families with BRCA mutations have an increased risk for early onset of breast cancer and ovarian cancer occurring at any age. Surveillance of patients with mutations in BRCA 1/2 is done by yearly mammography and breast MRI and by transvaginal ultrasonography and serum CA-125 levels every 6-12 months for ovarian cancer.

Which Mechanism is Effective on the Hyperamylasaemia After Coronary Artery Bypass Surgery?

BACKGROUND AND AIM: Acute pancreatitis is one of the less frequently diagnosed lethal abdominal complications of cardiac surgery. The incidence of early postoperative period hyperamylasaemia was reported to be 30-70% of patients who underwent coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). The mechanism of pancreatic enzyme elevation after cardiac surgery is not clear. Our aim was to determine the relationship between ischaemia associated temporary renal dysfunction and elevation of pancreatic enzymes after CABG. METHODS: Forty-one consecutive patients undergoing CABG under CPB were prospectively studied to determine serum total amylase, phospholipase A2, macroamylase, Cystatin C and urine NAG levels. RESULTS: Hyperamylasaemia was observed in 88% of the cases, with a distribution of 6% at the beginning of cardioplegic arrest, 5% at the 20th minute after cardioplegic arrest, 7% at the 40th minute after cardioplegic arrest, 14% when the heart was re-started, 26% at the 6th hour of intensive care and 30% at the 24th hour of intensive care. All of these patients had asymptomatic isolated hyperamylasaemia, and none of them presented with clinical pancreatitis. As indicators of renal damage; Cystatin C and NAG levels were higher compared to baseline values. CONCLUSION: Amylase began to rise during initial extracorporeal circulation and reached a maximum level postoperatively at 6 and 24hours. Decreased amylase excretion is the main reason for post CABG hyperamylasaemia.

Is there a gender-related susceptibility for cisplatin ototoxicity?

Ototoxicity is a well-known side effect of cisplatin. Some genetic and non-genetic risk factors were described for cisplatin ototoxicity. Although there are some studies which point out a sex-related difference for cisplatin nephrotoxicity and neurotoxicity, sex-related differences for cisplatin ototoxicity have not been studied. The aim of this study is to reveal whether there is any gender-related difference for susceptibility to cisplatin ototoxicity in rats. Fourteen male, 14 female Wistar albino rats were divided into four groups; a female control, a male control, a female cisplatin and a male cisplatin group. Distortion Product Otoacoustic Emission and, Auditory Brainstem Response measurements were obtained. For the cisplatin groups 16 mg/kg of cisplatin was applied. On the 4th day audiological examinations were repeated. After killing, cochleae and brainstem tissues were evaluated by light and electron microscopy. The hearing of the female rat cisplatin group was found to have deteriorated more than the hearing of the male rat cisplatin group. Histopathological evaluation revealed more serious damage in the spiral ganglion and brainstem tissues of female rats. Hearing of female rats deteriorated more than the hearing of male rats upon application of cisplatin. This difference in hearing can be attributed to the more severe damage seen in neuronal tissues such as spiral ganglion cells and brainstem neurons.

Gene expression characteristics of breast cancer stem cells.

PURPOSE: Breast cancer stem cells have been found to be responsible for tumorigenic potential and resistance to therapy. This study aimed at comparing gene expression profiles in breast cancer, based on the differences of stem cells in their biological characteristics. METHODS: Four breast cancer cell lines with different molecular and biological characteristics were used to analyze 84 breast cancer-related gene expressions. These were the ductal human epithelial breast cancer cell line T47D (HTB-133) with metastatic origin, the invasive ductal human breast carcinoma cell line MDA-MB-231 (HTB-26), the ductal human epithelial breast cancer cell line BT-474 (HTB-20) and the human metastatic breast adenocarcinoma cell line MCF-7 (HTB-22). RESULTS: There were significant differences between the breast cancer cells and the stem cells, particularly in angiogenesis, migration, proliferation and the expression of the DNA repair genes. CONCLUSION: These data indicated the absence of a general cancer stem cell in breast cancer. Our study supports the use of the term "breast cancer initiating cells" instead of breast cancer stem cells. All of these genetic differences should be taken into account in the planning of final therapeutic approach.

Dexamethasone Addition Impairs the Therapeutic Effects of Nimodipine for Subarachnoid Hemorrhage: An Experimental Animal Study.

AIM: To evaluate the effects of the combination of nimodipine and dexamethasone in subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: In this study, 35 female adult Wistar Albino rats were randomly assigned to four groups: Sham (n=8), SAH with no treatment (n=9), SAH with nimodipine (n=9, oral gavage, 12 mg/kg, BID) treatment, and SAH with combined therapy with nimodipine and dexamethasone (n=9, intraperitoneally, 1mg/kg, BID). The "cisterna magna double injection of autologous blood" model was used. The animals were euthanized 5 days after the first injection. RESULTS: Of the total, five rats died before euthanasia. The SAH+Nontreatment group showed the worst score in neurological examinations, and the most severe histopathological findings were noted in terms of vasospasm. The SAH+Nimodipine group showed the best neurological score and the closest histopathological results to those of the Sham group, whereas adding dexamethasone to nimodipine treatment (the SAH+Nimodipine+Dexamethasone group) worsened the neurological and histopathological outcomes. CONCLUSION: We thus concluded that the therapeutic effects of nimodipine were impaired when combined with dexamethasone. We thus hypothesized that dexamethasone possibly induces the CYP3A4-enzyme that metabolizes nimodipine. However, it should be noted that our results are based on laboratory findings obtained on a small sample, therefore further studies with drug-drug interaction on a larger sample size through CYP3A4-enzyme and clinical confirmation are warranted.

Investigation of YAP-1, OTX-2, and nestin protein expressions in neuroblastoma: a preliminary study.

OBJECTIVES: Neuroblastoma is the most common extracranial solid tumor in childhood. YAP (Yes-associated protein) is a highly expressed protein in NB. Nestin is an important marker of neuronal differentiation in NB. Orthodenticle homeobox (OTX) is a transcription factor and is overexpressed in blastoma-derived tumors. The aim of this study was to examine the potential roles of YAP-1, Nestin, and OTX-2 proteins in prognosis and risk stratification in neuroblastoma METHODS: Tumor sections of 56 patients with different NB risk groups were analyzed. YAP-1, Nestin, and OTX-2 protein expression levels were evaluated by immunohistochemical staining in NB patient tissue samples. RESULTS: YAP-1, Nestin, and OTX-2 protein expression levels were evaluated together with the clinical findings of NB patients. YAP-1 was expressed in 18% of all tissues, while Nestin was expressed in 20.4%. OTX-2 protein expression was found in 41.1% of the NB patients. YAP-1 was expressed in 26.9% of high-risk and 11.5% of low-risk patients. Nestin was expressed in 24.4% high-risk and 33.3% low-risk patients. OTX-2 was expressed in 68.2% high-risk and 60% low-risk patients.YAP-1 was shown to provide survival advantages among risk groups. INTERPRETATION: The findings of this study support that YAP-1 may be a potential prognostic biomarker for staging and risk-group assignment of NB patients. YAP-1 expression in neuroblastoma is associated with significantly poorer survival probabilities and should be considered as a potential therapeutic target. OTX-2 is a promising predictive biomarker candidate, but its mechanisms need further investigation in neuroblastoma, as nestin expression is not significantly linked to patient survival.

The prognostic significance of PD-1 and its ligands in non-small cell lung cancer.

Background: In this study, we aimed to investigate the prognostic value of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and programmed cell death ligand 2 (PD-L2) expressions on immune and cancer cells in terms of survival in patients with lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Methods: Between January 2000 and December 2012, a total of 191 patients (172 males, 19 females; mean age: 60.3±8.4 years; range, 38 to 78 years) who were diagnosed with non-small cell lung cancer and underwent anatomic resection and mediastinal lymph node dissection were retrospectively analyzed. The patients were evaluated in three groups including lung squamous cell carcinoma (n=61), adenocarcinoma (n=66), and large-cell carcinoma (n=64). The survival rates of all three groups were compared in terms of immunohistochemical expression levels of PD-1, PD-L1, and PD-L2. Results: The mean follow-up was 71.8±47.9 months. In all histological subtypes, PD-1 expressions on tumor and immune cells were observed in 33% (61/191) and in 53.1% (102/191) of the patients, respectively. Higher expression levels of PD-L1 and PD-L2 at any intensity on tumor and immune cells were defined only in lung adenocarcinomas, and PD-L1 and PD-L2 values were detected in 36.4% (22/64) of these patients. The PD-L1 expressions on tumor and immune cells were observed in 41.7% (10/24) and 25% (6/24) of the patients, respectively. The PD-L2 expressions on tumor and immune cells were detected in 16.7% (4/24) and 8.4% (2/24) of the patients, respectively. Univariate and multivariate analyses revealed that PD-1 expression in tumor cells was an independent prognostic factor in all histological subtypes. Conclusion: Our study results suggest that PD-1 expression is a poor prognostic factor for overall survival in patients with completely resected adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

Whole-exome sequencing reveals genetic variants in low-risk and high-risk neuroblastoma.

This study aimed to investigate the genetic aberrations in neuroblastoma (NB) by comparing high and low-risk NB patients by whole-exome sequencing (WES) and to reveal the heterogeneity and association between somatic variants and clinical features. Seven NB patients with available clinical data were included in the study (4 in the low-risk group and 3 in the high-risk group). WES was performed and somatic variants associated with NB genes in the COSMIC database were selected through bioinformatics pipeline analysis. Variants were determined using the Integrative Genomics Viewer (IGV). Some gene variations were found in both groups, including variations in oncogene and tumor suppressor genes. In general, candidate gene variations were associated with chromatin remodeling complexes, the RAS pathway, cell proliferation, and DNA repair mechanism. Some variations in CSF1R, MSH6, PTPN11, SOX9, RET, TSC1, and DNMT1 genes were detected only in high-risk patients, while EP300, TET2, MYCN, PRDM1, and ARID2 gene variations were detected only in low-risk patients. When high-risk gene variants were compared with the cBioportal cancer genomic database, two common gene variants (ARID1A and NCOR2) were identified. However, when low-risk gene variants were compared with the cBioportal cancer genomic database, no common genes were found. GO/KEGG enrichment analysis was performed to find relevant biological processes and molecular pathways related to gene variants, which will help to decipher the molecular mechanisms of NB tumorigenesis and the phenotypic differences between high-risk and low-risk patients.

Comparing Tribbles Homolog 3 (TRIB3) Protein Expression Levels with Clinicopathological Characteristics and Survival Among Neuroblastoma Patients.

Background: Tribbles Homolog 3 (TRIB3) is a member of the pseudokinase family of tribbles and acts as an adaptor protein to regulate different cellular processes. Upregulation of TRIB3 expression was shown either as a favorable or an adverse prognostic factor in various adult malignancies. However, TRIB3 expression has not been examined in pediatric cancers. Neuroblastoma is the most common malignant solid tumor of childhood, which affects mostly children under 5 years old. Risk stratification of patients defined by International Neuroblastoma Risk Group was used to determine prognosis and treatment of the disease. This study aimed to examine the relationship between TRIB3 protein expression levels and clinicopathological features and survival of patients. Methods: TRIB3 protein expression was analyzed using immunohistochemical staining on formalin-fixed paraffin-embedded tissue samples of neuroblastoma patients (n = 56). Survival analyses were performed with Kaplan-Meier method and log-rank tests. Association between TRIB3 expression and clinicopathological characteristics were analyzed with Spearman's correlation. Results: Of the patients, 32.1% were in the low-risk group, 21.4% in the medium-risk group, and 46.4% in the high-risk group. Survival analysis was performed in the entire neuroblastoma patient group and sub-risk groups of neuroblastoma patients. In the entire patient group, there was no significant difference in overall survival (P = .202) and event-free survival (P = .172) between TRIB3-positive and -negative patients. However, when survival analyses were performed in each risk group, TRIB3 expression was significantly associated with higher overall survival (P = .034) and event-free survival (P = .032) in low-risk group neuroblastoma patients. Nevertheless, no association was found between TRIB3 expression and overall survival (P = .799) and event-free survival (P = .448) in high-risk neuroblastoma patients. Furthermore, a significant correlation was identified between 1p36 loss-of-heterozygosity and TRIB3 expression (P = .030). However, TRIB3 expression did not correlate with other clinicopathological features. Conclusion: TRIB3 expression is a potential predictive biomarker for low-risk neuroblastoma patients.

Investigation of the effectiveness of hyperthermic intraperitoneal chemotherapy in experimental colorectal peritoneal metastasis model.

Objectives: In our study, we aimed to (1) create a peritoneal metastasis (PM) model in nude mice, administer intraperitoneal chemotherapy using the peritoneal infusion pump we developed in this model, and (2) compare the efficacy of intraperitoneal chemotherapy using various drugs at different temperatures. Methods: The peritoneal metastasis model was established in nude mice using the CC531 colon carcinoma cell line. Models with peritoneal metastasis (PM) were randomized into four groups of seven animals each: Group 1, control group (n=7); Group 2, normothermic intraperitoneal chemotherapy (NIPEC) with mitomycin C(MMC) (n=7); Group 3, hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (n=7), and Group 4, NIPEC with 5-fluorouracil (5-FU). Results: Tumor development was achieved in all animals. While the tumor burden decreased significantly in the treatment Group 3 (p=0.034), no significant difference was found in the other groups. In the PM mouse model, hyperthermic intraperitoneal administration of MMC had the highest tumoricidal effect. Conclusions: Our PM model provided a good opportunity to examine the efficacy of HIPEC and intraperitoneal infusion pump (IPIP). In future studies, we plan to evaluate efficacies of different drugs in the PM models we have created.

Identification of ALK Mutation in Neuroblastoma on the Point of Molecular Heterogeneity.

BACKGROUND AND AIM: In neuroblastoma, anaplastic lymphoma kinase mutations have recently received attention as molecular targets for the treatment of neuroblastoma, as 6% to 10% of patients with neuroblastoma have anaplastic lymphoma kinase mutations. There are little data from the cases in Turkey. We aimed to detect anaplastic lymphoma kinase mutations and molecular heterogeneity in neuroblastoma using next-generation sequencing. This study is the first one with this many cases in Turkey. METHODS: Next-generation sequencing analysis was performed using an Illumina MiniSeq custom gene panel. Clinically important mutations were selected for the analysis. We also gathered clinical data of the patients from Turkish Pediatric Oncology Group cohorts to associate them with anaplastic lymphoma kinase mutations. This study is a retrospective cross-sectional study. We followed STROBE guideline (https://www.equator-network.org/reporting-guidelines/strobe/) on this study. RESULTS: We analyzed anaplastic lymphoma kinase in 108 patients with neuroblastoma, with a mean age of 43.76 months. Pathogenic anaplastic lymphoma kinase mutations were detected in 13 patients (12.04%). We noted that anaplastic lymphoma kinase mutations were primarily observed in intermediate- and high-risk patients (P = .028). R1275Q and F1174-related mutations were predominant; I1171T, L1226F, S1189F, V1135A, and G1125S mutations were rare. Duplicate samples did not exhibit any heterogeneity. CONCLUSIONS: We found that F1174 and R1275Q-related anaplastic lymphoma kinase mutations are the most common pathogenic mutations in neuroblastoma. Anaplastic lymphoma kinase mutation status did not show any heterogeneity, and the mutations were correlated with intermediate- or high-risk groups.

Anna Karenina principle in personalized treatment of bladder cancer according to oncogram: which drug for which patient?

Aim: To evaluate the ex vivo efficacy of chemotherapy, immunotherapy and targeted agents with the oncogram method in patients with bladder cancer and determine the most appropriate personalized treatment agent using immune markers. Materials & methods: Bladder cancer tissues were obtained from each patient. After cultivation, cell cultures were divided into 12 groups for each patient and 11 drugs were administered. Cell viability and immunohistochemistry expression were examined. Results: A good response rate was determined to be a 23% viability drop. The nivolumab good response rate was slightly better in PD-L1-positive patients and the ipilimumab good response rate was slightly better in tumoral CTLA-4-positive cases. Interestingly, the cetuximab response was worse in EGFR-positive cases. Conclusion: Although good responses of drug groups after their ex vivo application by using oncogram were found to be higher than control group, this outcome differed on a per patient basis.

Bladder cancer primary cell cultures were shown to be effective for drug sensitivity and also able to be used ex vivo in the process of determining personalized treatment. The ex vivo efficacy of 11 different agents was evaluated with oncogram in bladder cancer cell cultures obtained from patients. Together with clinicopathological features, evaluation of drug responses detected by oncogram can provide important information for pretreatment drug selection when deciding on individualized treatment.

Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies.

BACKGROUND: There is considerable interest in the molecular evaluation of solid tumors in pediatric cases. Although clinical trials are in progress for targeted therapies against neuroblastoma (NB), novel therapeutic strategies are needed for high-risk cases that are resistant to therapy. The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). METHODS: The study included 57 NB patients from amongst 1965 neuroblastic cases in Turkey who experienced a recurrence after multi-model therapy. The cases were diagnosed, risk-stratified, and treated according to the classification system from the International Neuroblastoma Risk Group. Single nucleotide variations in 60 genes were investigated using the Pillar Onco/Reveal Multicancer v4 panel and Pillar RNA fusion panel on the Illumina Miniseq platform. RESULTS: ERBB2 I655V was the most frequent mutation and was found in 39.65% of cases. Anaplastic Lymphoma Kinase (ALK) mutations (F1174L, R1275Q, and rare mutations in the tyrosine kinase domain) were detected in 29.3% of cases. Fusion mutations in NTRK1, NTRK3, ROS1, RET, FGFR3, ALK and BRAF were observed in 19.6% of cases. CONCLUSIONS: This study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.

Resveratrol reduces matrix metalloproteinase-2 activity induced by oxygen-glucose deprivation and reoxygenation in human cerebral microvascular endothelial cells.

The main pathophysiology in cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Among the human matrix metalloproteinases (MMPs), MMP-2 and -9, known as gelatinases, are the key enzymes for degrading type IV collagen, which is the major component of the basal membrane that surrounds the cerebral blood vessel. In the present study, we investigated the effects of resveratrol on cytotoxicity, reactive oxygen species (ROS), and gelatinases (MMP-2 and -9) in human cerebral microvascular endothelial cells exposed to 6 hours of oxygen-glucose deprivation and a subsequent 24 hours of reoxygenation with glucose (OGD/R), to mimic ischemia/reperfusion in vivo. Lactate dehydrogenase increased significantly, in comparison to that in the normoxia group. ROS was markedly increased in the OGD/R group, compared to normoxia. Correspondingly, ROS was significantly reduced with 50 µM of resveratrol. The proMMP-2 activity in the OGD/R group showed a statistically significant increase from the control cells. Resveratrol preconditioning decreased significantly the proMMP-2 in the cells exposed to OGD/R in comparison to that in the OGD/R group. Our results indicate that resveratrol regulates MMP-2 activity induced by OGD/R via its antioxidant effect, implying a possible mechanism related to the neuroprotective effect of resveratrol.