Prophylactic use of dural tenting sutures in elective craniotomies in adults-is it necessary? A study protocol for a multicentre, investigator- and participant-blinded randomised, parallel-group, non-inferiority trial.

BACKGROUND: In the early days of neurosurgery, extradural haemorrhages (EDHs) contributed to a high mortality rate after craniotomies. Almost a century ago, Walter Dandy reported dural tenting sutures as an effective way to prevent postoperative EDH. Over time, his technique gained in popularity and significance to finally become a neurosurgical standard. Yet, several retrospective reports and one prospective report have questioned the ongoing need for dural tenting sutures. Dandy's explanation that the haemostasis observed under hypotensive conditions is deceiving and eventually causes EDH may be obsolete. Today, proper intra- and postoperative care, including maintenance of normovolemia and normotension and the use of modern haemostatic agents, may be sufficient for effective haemostasis. Thus, there is a fundamental need to evaluate the necessity of dural tenting sutures in a solid, unbiased, evidence-based manner. METHODS: This study is designed as a randomised, multicentre, double-blinded, controlled interventional trial with 1:1 allocation. About one half of the participants will undergo craniotomy without dural tenting sutures and will be considered an intervention group. The other half will undergo craniotomy with these sutures. Both groups will be followed clinically and radiologically. The primary outcome is reoperation due to extradural haematoma. Secondary outcomes aim to evaluate the impact of dural tenting sutures on mortality, readmission risk, postoperative headaches, size of extradural collection, cerebrospinal fluid leak risk and the presence of any new neurological deficit. The study protocol follows the SPIRIT 2013 statement. DISCUSSION: It is possible that many neurosurgeons around the globe are tenting the dura in elective craniotomies which brings no benefit and only extends the operation. Unfortunately, there is not enough data to support or reject this technique in modern neurosurgery. This is the first study that may produce strong, evidence-based recommendations on using dural tenting sutures. TRIAL REGISTRATION, ETHICS AND DISSEMINATION: The Bioethics Committee of the Medical University of Warsaw approved the study protocol (KB/106/2018). The trial is registered at http://www.clinicaltrials.gov ( NCT03658941 ) on September 6, 2018. The findings of this trial will be submitted to a peer-reviewed neurosurgical journal. Abstracts will be submitted to relevant national and international conferences. TRIAL STATUS: Protocol version and date: version 1.5, 14.01.2020 First recruitment: September 7, 2018 Estimated recruitment completion: September 1, 2021.

Epidermal Growth Factor Receptor and its Oncogenic EGFRvIII Variant in Benign and Malignant Brain Tumors.

BACKGROUND/AIM: Tumorigenesis and cancer progression might be driven by abnormal activation of growth factor receptors. Importantly, molecular changes in EGFR-dependent signaling is one of the most common characteristics of brain tumors. PATIENTS AND METHODS: HER1 and EGFRvIII variants in meningiomas and glioblastomas were evaluated at the RNA level. RESULTS: EGFRvIII was found in 18.6% of glioblastomas (GBM), whereas 25% of EGFRvIII positive tumors express wild-type EGFR as well. HER1 was over-expressed in benign meningiomas compared to glioblastomas, whereas HER1 expression in meningiomas differed significantly between sub-types of meningiomas. EGFRvIII and HER1 where positively correlated in glioblastomas. Yet, the patient overall survival did not differ between high- and low-HER1 expressing glioblastomas or between EGFRvIII positive and negative GBMs. CONCLUSION: HER1 may be considered as an independent factor for classification of benign meningiomas. The mRNA levels of HER1 or EGFRvIII should not be used as independent prognostic factors for patients with gliomas.

IFN-γ Correlations with Pain Assessment, Radiological Findings, and Clinical Intercourse in Patient after Lumbar Microdiscectomy: Preliminary Study.

OBJECTIVES: We investigated the influence of pain decrease after lumbar microdiscectomy on the interferon gamma (IFN-γ) serum level in patients with lumbar disc herniations. The study challenges the mechanism of sciatica pain and the role of IFN-γ in radicular pain development. Material and Methods. We performed clinical and immunoenzymatic assessment in a group of 27 patients with lumbar radicular pain due to disc herniations before and 3 months after surgery. Clinical status was assessed with the use of the Numeric Rating Scale (NRS), the Pain Rating Index and Pain Intensity Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. RESULTS: We observe significant correlations between the results of the pain in the back region assessment NRS back scale after the surgery with the level of IFN-γ before the procedure (r s = 0.528; p = 0.008) and after the procedure (r s = 0.455; p = 0.025). These are moderate and positive correlations-the decrease in pain is correlated with the lower IFN-γ level. Additionally, there are significant correlations between the results of the PRI scale and the IFN-γ level. The PRI score before surgery correlates positively with IFN-γ after surgery (r s = 0.462; p = 0.023), and the PRI score after surgery correlates positively with IFN before surgery (r s = 0.529; p = 0.005) and after surgery (r s = 0.549; p = 0.003). All correlations are moderate in severity-severe pain before surgery correlates with a higher level of IFN-γ after surgery and also higher IFN-γ before surgery. There were significant differences in the IFN-γ level before (Z = -2.733; p = 0.006) and after (Z = -2.391; p = 0.017) surgery in the groups of patients with and without nerve compression. In the group of patients with nerve compression, the level of IFN-γ before and after surgery was lower. CONCLUSIONS: Less pain ratio after operation correlates with the level of IFN-γ. In the group of patients without significant nerve compression confirmed by MRI scans, the level of IFN-γ before and after surgery was higher than that in the group with nerve root compression.

Examination of marketing mix performance in relation to sustainable development of the Poland's confectionery industry.

The conventional concept of marketing mix does not take into account the idea of sustainable development. The basic objective of this examination is to analyze and evaluate the performance of selected marketing mix elements from the perspective of the Poland's confectionery industry's sustainable development. The questionnaire survey was designed for this purpose. The purpose of the research questions was to evaluate a degree of development for selected elements of marketing mix from the perspective of sustainable development of the Poland's confectionery industry. Thus, a novel development ratio based on the distance from exemplary performance was proposed. Next, aseminal approach to pairwise comparisons technique was applied for the importance evaluation of each survey question in order to provide a weighted average Mean Development Ratio (MdeR) for each element of marketing mix. In this process the seminal methodology for pairwise comparisons was applied i.e. a non-heuristic approach to pairwise comparisons technique with verifiable accuracy and reliability. In consequence, assuming that all elements of marketing mix have some designated importance in the process of sustainable development, a total weighted average MdeR for performance of all elements of marketing mix was computed and evaluated. Noticeably, the total weighted average MdeR for performance of all elements of marketing mix cannot be considered as satisfactory from the perspective of sustainable development of the Poland's confectionery industry.

A Case Report of a Female Patient With Hodgkin Lymphoma Localized in the Central Nervous System and With Concomitant Pulmonary Lymphomatoid Granulomatosis.

The involvement of the central nervous system (CNS) in Hodgkin lymphoma (HL) has been rarely reported, especially in its primary isolated form. Herein, we present a case of a 33-year-old woman, who received immunosuppressive treatment due to ulcerative colitis (at the beginning azathioprine and sulfasalazine, changed to mesalazine), with repetitive episodes of loss of consciousness for a few weeks and with no other symptoms. Magnetic resonance imaging scans of the head revealed a tumor in the lateral part of the left temporal lobe and in the cerebellum. Moreover, a subsequent computed tomographic scan of the chest revealed diffuse tumorous lesions in the lungs. The brain tumor was resected and a tumorous lesion resected from the lungs was biopsied. The histopathological analysis confirmed the final diagnosis of HL localized in the CNS with concomitant pulmonary lymphomatoid granulomatosis (LYG) grade 1. After the patient underwent radiotherapy and chemotherapy, the patient showed complete regression of lesions in the CNS and lungs, which was confirmed by positron emission tomographic scan. LYG and CNS-HL are rare proliferative disease derived from lymphocytes B and associated with EBV infections. An association between LYG and other autoimmune disorders has been reported, but to the best of our knowledge, this is the first case of the CNS-HL associated with lymphatoid granulomatosis.

Treatment of very large cranial defects with individually shaped polypropylene polyester knitwear prostheses: a series of 11 cases.

BACKGROUND: Very large cranial defects are not very common in neurosurgical practice and there is not any widely acknowledged standard of their treatment. One of the useful methods in such cases is individual forming of polypropylene-polyester knitwear. Such material was used in the past but before 2008 it was available only as standardized plates. Currently, it can be also produced as individually-shaped implants. The authors give their definition of very large cranial defects and present their experience with this cranioplastic method in such defects. METHODS: The authors collected data on 11 cases of patients with very large cranial defects, from a total of 156 cases, operated on in 5 Polish neurosurgical departments. The necessary implants were prepared for individual patients according to the data provided by a computed tomography examination and with the use of computer aided machining. RESULTS: All defects were larger than 120 cm2 (129 to 178 cm2) and exceeded 1/4 of the calvaria area. Patients were operated between 2008 to 2012. In all patients, a very good aesthetic result and correct skull reconstruction was achieved. The follow-up time in all cases exceeded 1 year and reached 4 years in one case. No complications were observed. CONCLUSIONS: Individually pre-shaped polypropylene-polyester knitwear prostheses are a good alternative to the existing cranioplasty methods, particularly in very large cranial defects.

PD-L1 gene copy number and promoter polymorphisms regulate PD-L1 expression in tumor cells of non-small cell lung cancer patients.

Most drugs targeting PD-1 or PD-L1 are more effective when cancer cells of non-small cell lung cancer (NSCLC) patients express PD-L1 protein. The polymorphisms of PD-L1 gene and PD-L1 gene copy number could be responsible for PD-L1 mRNA and protein expression. We analyzed PD-L1 protein expression using two IHC assays, mRNA (PD-L1) expression by qRT-PCR, PD-L1 gene promoter region polymorphisms (rs822335 and rs822336) by qPCR and PD-L1 gene copy number by fluorescence in situ hybridization method. Patients with CC genotype in rs822335 had significantly (p = 0.043) higher percentage of tumor cells with PD-L1 expression (test with 22C3 antibody) than patients with CT or TT genotypes. PD-L1 gene copy number significantly positively correlated with percentage of tumor cells with PD-L1 expression detected in tests with 22C3 antibody (p = 0.005, R = +0.442) and with SP142 antibody (p = 0.021, R = +0.369). PD-L1 gene copy number did not correlate with PD-L1 mRNA expression. Patients with PD-L1 expression tested with 22C3 antibody had significantly higher expression of PD-L1 mRNA (p = 0.023), number of chromsosme 9 centromeres (p = 0.023) and PD-L1 gene copy number (p = 0.003) than patients without PD-L1 expression on tumor cells PD-L1 gene polymorphisms and PD-L1 gene copy number may be a predictor for PD-L1 protein expression on tumor cells.

The impact of changes in serum levels of metalloproteinase-2 and metalloproteinase-9 on pain perception in patients with disc herniation before and after surgery.

Purpose: The aim of our research was to investigate the link between serum levels of metalloproteinase-2 (MMP-2) and MMP-9, and the degree of pain experienced before and 1 and 3 months after microdiscectomy in 70 patients with disc herniation (DH). Patients and methods: The control group (group C) consisted of 70 healthy subjects and the DH group consisted of 70 patients with sciatica pain caused by lumbar DH. Before (DH0) and 1 and 3 months after surgery, the patients were assessed in terms of the following biochemical parameters: MMP-2, tissue inhibitors of metalloproteinases-2 (TIMP-2), MMP-2/TIMP-2, MMP-9, TIMP-1, and MMP-9/TIMP1, and the following clinical parameters: Numeric Rating Scale for the back (NRS-B) and the leg (NRS-L) and the Pain Rating Index (PRI) and Present Pain Intensity (PPI) of the McGill Pain Questionnaire. Results: No statistically significant correlations were observed following the biochemical and clinical assessments performed in group C and the DH group before surgery. After surgery (1 month), higher levels of TIMP-1 correlated with higher levels of NRS-B (rs =0.27; p<0.05). At 3 months after surgery higher levels of TIMP-2 and lower levels of MMP-2/TIMP-2 were correlated with higher levels of NRS-L (rs =0.27, p<0.05 and rs =-0.31, p<0.05, respectively) and higher levels of TIMP-2 were correlated with higher PRI scores (rs =0.27; p<0.005) and PPI scores (rs =0.35; p<0.01). Conclusion: The results showed that MMPs are involved in DH and play a significant role in the perception of pain after DH surgery. However, the value of MMPs as a potential therapeutic target in pain treatment should be considered cautiously.

Necessity of dural tenting sutures in modern neurosurgery: protocol for a systematic review.

INTRODUCTION: The ongoing need for dural tenting sutures in a contemporary neurosurgical practice has been questioned in the literature for over two decades. In the past, these sutures were supposed to prevent blood collecting in the potential space between the skull and the dura by elevating the latter. Theoretically, with modern haemostasis and proper postoperative care, this technique should not be necessary and the surgery time can be shortened. Unfortunately, there is no evidence-based proof to either support or reject this hypothesis. METHODS AND ANALYSIS: The systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and The Cochrane Handbook for Systematic Reviews of Interventions. Eight electronic databases of peer-reviewed journals will be searched, as well as other sources. Eligible articles will be assessed against inclusion criteria. The intervention is not tenting the dura and this will be compared with the usual dural tenting sutures. Where possible, 'summary of findings' tables will be generated. ETHICS AND DISSEMINATION: Ethical committee approval is not required for a systematic review protocol. Findings will be presented at international neurosurgical conferences and published in a peer-reviewed medical journal. PROSPERO REGISTRATION NUMBER: CRD42018097089.

The Elevated Serum Level of IFN-γ in Patients with Failed Back Surgery Syndrome Remains Unchanged after Spinal Cord Stimulation.

OBJECTIVES: We investigated the influence of spinal cord stimulation (SCS) on IFN-γ, IL-1ß, IL-6, TNF-α, IL-10, and TGF-ß serum levels in failed back surgery syndrome (FBSS) patients. The study will try to give new insights into the mechanism of SCS action and the role of IFN-γ and other cytokines in neuropathic pain (NP) development. MATERIALS AND METHODS: Clinical and biochemical assessment was conducted in four groups of patients: group 0 consisted of 24 FBSS patients qualified to SCS therapy, group 1 included 17 patients who were one month after implantation, group 2 featured 12 patients who were 3 months after the implantation, and group C (the control group) with no NP. Clinical status was assessed with the use of Numeric Rating Scale (NRS), the Pain Rating Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. RESULTS: We found a significant difference between the patients before SCS and controls' serum level of IFN-γ. Similarly, a significantly higher level of TNF-α and significantly lower level of IL-10 in FBSS patients than controls were observed. The significant differences were not observed between SCS patients 3 months after the procedure and controls' serum level of IFN-γ and other cytokines. We noticed a positive correlation between IFN-γ concentration with NRS back value before SCS and positive correlation between IFN-γ concentration after SCS with NRS leg value before SCS. Higher IFN-γ concentrations accompanied higher NRS values. Levels of TGF-ß and IL-10 may correlate with physical ability and depressive behavior. CONCLUSIONS: SCS did not influence serum cytokine levels significantly. Serum concentration of IFN-γ may be recognized as an occasional pain factor because of its significantly higher level in FBSS patients versus controls and higher IFN-γ value accompanying higher pain intensity.

Serum Level of Metalloproteinase-2 but not Metalloproteinase-9 Rises in Patients With Failed Back Surgery Syndrome After Spinal Cord Stimulation.

OBJECTIVES: The impact of spinal cord stimulation (SCS) on serum levels of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) was assessed in a group of patients with failed back surgery syndrome (FBSS). The study was to give new insights into the SCS mechanism of action and the role of MMP-2 and MMP-9 in the development of NP. MATERIAL AND METHODS: Clinical assessments were performed and biochemical markers were determined in two groups of patients: the control group (24 individuals) and the FBSS group (24 patients). Seventeen patients with the FBSS had SCS implanted and were examined before surgical procedure, one month after (17 patients), and three months after operation (12 patients). Clinical status was assessed with the use numeric rating scale, pain rating index of McGill pain questionnaire, Oswestry disability index and Beck depression inventory. MMP-2 and MMP-9 serum levels were determined using gelatin zymography. Immunoenzymatic method was employed to determine plasma concentrations of tissue inhibitors of metalloproteinases (TIMPs). RESULTS: Levels of MMP-2 and TIMP-2 were higher in the FBSS group compared to the control group. The difference was statistically significant (p < 0.001 and p = 0.004, respectively). The concentration of MMP-2 was significantly increased (p = 0.0135) one-month post-SCS and remained elevated but stable up to three months after implantation. TIMP-2, MMP-2/TIMP-2, MMP-9, TIMP-1, and MMP-9/TIMP-1 serum levels did not change significantly. CONCLUSIONS: MMPs may play a role in the development of FBSS. SCS increases the already elevated MMP-2 serum levels which are associated with neuroinflammatory processes in FBSS patients.

Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer.

Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3%-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases. We assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (P = 0.0002; χ2 = 16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Their results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, they showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations.

Size and location correlations with higher rupture risk of intracranial aneurysms.

AIM: The purpose of this study was to investigate the impact of size and location of the intracranial aneurysm on rupture probability. MATERIAL AND METHODS: 265 patients with diagnosis of intracranial aneurysms were admitted to the department from January 2012 to December 2013. The characteristic of aneurysm, such as median size, location, single and multiple aneurysms and presentation were retrospectively reviewed using cerebral angiography reports. RESULTS: There were 265 patients admitted with the diagnosis of intracranial aneurysms, 193 with single and 72 with multiple aneurysms. Among them there were 197 women (74,3%) and 68 men (25,7%). The total number of aneurysms harbored by the patients with multiple aneurysms were 184. Among all patients 96 had ruptured aneurysm, most of them located at the AComA and the minority of ruptured aneurysms were located at the ICA and MCA, In most cases the size of ruptured aneurysm was smaller than 10 mm. CONCLUSION: The location of an aneurysm is an important factor allowing to predict the rupture probability and to plan proper treatment. The size of the aneurysm is also very useful predictor especially correlated with the location but the impact on rupture probability still needs further examination.

Immunohistochemical assays incorporating SP142 and 22C3 monoclonal antibodies for detection of PD-L1 expression in NSCLC patients with known status of EGFR and ALK genes.

Different immunohistochemical (IHC) assays were approved for PD-L1 expression examination on tumor cells in qualification to immune-checkpoint inhibitors therapy in NSCLC patients. These assays have some similarities, but also very serious differences. We assessed 2 IHC tests for PD-L1 expression evaluation in NSCLC tumors with different pathological diagnoses and genetic abnormalities. We enrolled 48 NSCLC patients (median age: 65 years) with known status of EGFR and ALK genes. We compared the effectiveness of PD-L1 expression examination of two IHC assays with 22C3 (Dako) and SP142 antibodies (Ventana). IHC tests were performed in resected tissue samples and in cellblocks from bronchoscopy biopsies (formalin-fixed paraffin-embedded). IHC staining was carried out on Dako Autostainer Link 48 and Ventana Benchmark GX. The percentage of tumors with PD-L1 expression of ≥5% and ≥50% on tumor cells was significantly (p<0.05) higher in assay with 22C3 (66.7% and 45.8%) than with SP142 antibody (39.6% and 22.9%). The median percentage of tumor cells with PD-L1 expression was significantly (p<0.0001) higher in test with 22C3 than with SP142 antibody. Percentage of squamous cell carcinoma (SCC) patients with PD-L1 expression was significantly higher than of non-SCC patients. Large group of patients without PD-L1 expression on tumor cells was identified among patients with common EGFR mutations and ALK rearrangement. Our results support that the highest PD-L1 expression on tumor cells occurs in SCC patients and in adenocarcinoma patients without common, druggable genetic abnormalities. The above mentioned results were clearly visible in IHC assay with 22C3 (strong cell staining).

Primary central nervous system lymphoma as a neurosurgical problem.

Primary central nervous system lymphoma (PCNSL) comprises around 3-5% of primary central nervous system (CNS) tumours and around 1% of all non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common histological type. High effectiveness of chemo- and radiotherapy for PCNSL regrettably does not eliminate significant risks of recurrence for CNS tumours. That results in higher interest in other treatment options, including surgical procedures. PCNSL remains in the scope of interest for many specialists and neurosurgeons seem to play a more important role.

Prevalence of NRAS, PTEN and AKT1 gene mutations in the central nervous system metastases of non-small cell lung cancer.

Somatic mutations in NRAS, PTEN and AKT1 genes are rarely (~1%) reported in primary NSCLC, but their role in carcinogenesis have been proven. Therefore, we assessed the frequency of them in 145 FFPE tissue samples from CNS metastases of NSCLC using the real-time PCR technique. We identified four (two NRAS and single AKT1 and PTEN) mutations in CNS metastases of NSCLC. All mutations were observed in current male smokers (4% out of the male group; 4/100 and 4.25% out of smokers; 4/94). Three mutations have been detected in patients with SqCC (10.3% out of SqCC patients; 3/29), and only one mutation in the NRAS gene-in a patient with adenocarcinoma (1.25% out of AC patients; 1/80). The examined genes were mutually exclusive in terms of molecular background in KRAS; EGFR; DDR2; PIK3CA; HER2 and MEK1 genes that were evaluated in our previous studies. The OS of the patients who harbored NRAS, AKT1 and PTEN mutations was 10.1, 12.1, 7.3 and 4 months, respectively (vs 13.5 months of the studied group). Our results suggest that the presence of NRAS, PTEN and AKT1 gene mutations may have an influence on the occurrence of CNS metastases in patients with SqCC.

PIK3CA Mutations Detected in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC) the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene mutations have been reported in fewer than 5% of primary tumors. MATERIALS AND METHODS: We assessed PIK3CA gene mutations in 145 tissue samples from central nervous system (CNS) metastases of NSCLC using three polymerase chain reaction (PCR) techniques: high resolution melting-PCR (HRM-PCR), allele-specific-quantitative PCR (ASP-qPCR) and TaqMan PCR. RESULTS: HRM analysis allowed us to select three PIK3CA-positive specimens (2.1% of the studied group) and ASP-qPCR techniques identified them as one E542K and two H1047R substitutions, which were confirmed by TaqMan probes. The PIK3CA mutations were indicated only in males (3% of all males). One of the patients was reported to be a non-smoker with adenocarcinoma (AC; 2.5% of the AC group), however, the other two patients were smokers with squamous cell carcinoma (SCC; 3.4% of SCC group). CONCLUSION: This is the first report of the presence of PIK3CA gene mutation in CNS-metastatic lesions of NSCLC worldwide that could broaden therapeutic choices in such patients.

Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis.

BACKGROUND: A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies. METHODS: Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment. RESULTS: Median survival after BCBM excision was 18.3 months (range 0-99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm(2), respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r = 0.26 and 0.33), and so did CD68+ (r = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3, P = 0.003), CD68+ infiltration (HR = 0.2, P < 0.001), brain radiotherapy (HR = 0.1, P < 0.001), endocrine therapy (HR = 0.1, P < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6, P = 0.01), HER2 expression in BCBM (HR = 4.9, P = 0.01). CONCLUSIONS: PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM.

Analysis of KRAS and BRAF genes mutation in the central nervous system metastases of non-small cell lung cancer.

KRAS mutations are associated with tumor resistance to EGFR TKIs (erlotinib, gefitinib) and to monoclonal antibody against EGFR (cetuximab). Targeted treatment of mutated RAS patients is still considered as a challenge. Inhibitors of c-Met (onartuzumab or tiwantinib) and MEK (selumetinib-a dual inhibitor of MEK1 and MEK2) signaling pathways showed activity in patients with mutations in KRAS that can became an effective approach in carriers of such disorders. BRAF mutation is very rare in patients with NSCLC, and its presence is associated with sensitivity of tumor cells to BRAF inhibitors (vemurafenib, dabrafenib). In the present study, the frequency and type of KRAS and BRAF mutation were assessed in 145 FFPE tissue samples from CNS metastases of NSCLC. In 30 patients, material from the primary tumor was simultaneously available. Real-time PCR technique with allele-specific molecular probe (KRAS/BRAF Mutation Analysis Kit, Entrogen, USA) was used for molecular tests. KRAS mutations were detected in 21.4 % of CNS metastatic lesions and in 23.3 % of corresponding primary tumors. Five mutations were identified both in primary and in metastatic lesions, while one mutation only in primary tumor and one mutation only in the metastatic tumor. Most of mutations were observed in codon 12 of KRAS; however, an individual patient had diagnosed a rare G13D and Q61R substitutions. KRAS mutations were significantly more frequent in adenocarcinoma patients and smokers. Additional analysis indicated one patient with rare coexistence of KRAS and DDR2 mutations. BRAF mutation was not detected in the examined materials. KRAS frequency appears to be similar in primary and CNS.