Dynamic interplay between corticosteroid treatment and the role of SRC-1 gene dysregulation in the progression of WHO-Grade 4 Astrocytoma.

BACKGROUND: Corticosteroid is commonly used before surgery to control cerebral oedema in brain tumours and is frequently continued throughout treatment. Its long-term effect of on the recurrence of WHO-Grade 4 astrocytoma remains controversial. The interaction between corticosteroid, SRC-1 gene and cytotoxic T-cells has never been investigated. METHODS: A retrospective cohort of 36 patients with WHO-Grade 4 astrocytoma were examined for CD8 + T-cell and SRC-1 gene expressions through IHC and qRT-PCR. The impact of corticosteroid on CD8+T-cells infiltration, SRC-1 expression, and tumour recurrence was analyzed. RESULTS: The mean patients age was 47-years, with a male to female ratio 1.2. About 78% [n = 28] of the cases showed reduced or no CD8+T-cell expression while 22% [n = 8] of cases have showed medium to high CD8+T-cell expression. SRC-1 gene was upregulated in 5 cases [14%] and 31 cases [86%] showed SRC-1 downregulation. The average of total days and doses of administered corticosteroid from the preoperative period to the postoperative period was at range of 14-106 days and 41-5028 mg, respectively. There was no significant statistical difference in RFI among tumours expressing high or low CD8+T-cells when corticosteroid was administered in recommended or exceeded doses [p-value = 0.640]. There was a significant statistical difference in RFI between CD8+T-Cell expression and SRC-1 gene dysregulation [p-value = 002]. Tumours with high CD8+T T-cell expression and SRC-1 gene downregulation had late recurrence. CONCLUSIONS: Corticosteroid treatment can directly affect the SRC-1 gene regulation but does not directly influence cytotoxic T-cells infiltration or tumor progression. However, SRC-1 gene downregulation can facilitate late tumor recurrence.

Management of Sciatic Nerve Defects: Lessons Learned and Proposal for a New Strategy.

Management of sciatic nerve injuries can be difficult for surgeons without a special interest in nerve surgery as they would only treat a handful of such cases for many years. Sciatic nerve defects pose the greatest repair challenges, with nerve grafting producing mixed results because of the large size of the nerve in both diameter and length. This article first presents the peculiarities of sciatic nerve defects management, based on the authors experience and a literature review. Various issues are dealt with: When to operate depending on the injury mechanism? What are the results of nerve autografting and allografting? On which component should the repair focus in very large defects? Subsequently, alternatives to conventional nerve grafting are proposed. The authors stress the usefulness of direct nerve suture with knee flexion at 90 degrees, which permits bridging of gaps as much as 8 cm in length. For larger defects, other procedures should be considered: long vascularized nerve grafting in complete lesions, short grafting with knee flexed, or tendon transfers in partial lesions.

Major Histocompatibility Class-I (MHC-I) downregulation in glioblastoma is a poor prognostic factor but not a predictive indicator for treatment failure.

BACKGROUND: MHC-I expression is a crucial factor in cancer immunity, and its regulations can impact tumor progression and recurrence. The mechanism through which glioblastoma use MHC-I to avoid immunosurveillance has been rarely investigated. METHODS: A retrospective cohort of 35 patients with IDH-mutant WHO-Grade 4 astrocytoma and IDH-wildtype glioblastoma were examined for MHC-I using protein and gene expression assays. The association between IDH mutation, TP53 mutation, and MHC-I expression with recurrence-free interval were investigated. RESULTS: The average patients' age was 49.6 year. IDH was wildtype in 13 tumors. MHC-I protein expression was absent in 30 tumors, faint in 4 tumors, and membrane bound dense expression in single tumor. MHC-I expression was upregulated in 10 tumors and 25 tumors showed MHC-I downregulation. P53 was positively expressed in 19 cases and lost in 13 cases. A significant statistical difference was observed in the RFI between tumors with distinct MHC-I expression and IDH-mutation [p-value = 0.008]. IDH-wildtype tumors with upregulated MHC-I expression showed late tumor recurrence compared to IDH-wildtype tumors with downregulated MHC-I expression. There was insignificant statistical difference in RFI among patients with varying degree of MHC-I expression, who received TMZ or TMZ and other chemotherapies [P-value = 0.44] CONCLUSIONS: Glioblastoma with upregulated MHC-I showed a delayed tumor recurrence in comparison to those with downregulated MHC-I expression. However, downregulated MHC-I may not necessarily be an indicator of poor problems.

Association Between CD204-Expressed Tumor-Associated Macrophages and MGMT-Promoter Methylation in the Microenvironment of Grade 4 Astrocytomas.

Background: Tumor-associated macrophages (TAMs) are principal immune cells in glioma microenvironment which support tumor growth and proliferation. Our aim in this study was to assess the relationship between CD204-expressed TAMs and O6-methylguanine-DNA methyltransferase (MGMT)-promoter methylation in World Health Organization (WHO) grade 4 astrocytomas, and its impact on patient's clinical outcome. Methods: The expression of CD204 + TAMs was quantitively assessed on 45 samples of WHO grade 4 astrocytomas using immunohistochemistry. MGMT-promoter methylation was tested by methylation techniques. The relationship between TAMs, MGMT-promoter methylation, and recurrence-free interval (RFI) was statistically analyzed. Results: There were 10 cases (22.2%) with isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytoma and 35 cases (77.8%) with IDH-wildtype glioblastoma. MGMT-promotor was methylated in 18 cases (40%), unmethylated in 15 cases (33%), and the remaining 12 cases showed no MGMT status because of nucleic acid degradations. The expression of CD204+ TAMs was high in 32 cases (71.7%) and low in 13 cases (28.8%). The relationship between IDH1 mutation and CD204+ TAM expression was insignificant (P = 0.93). However, the significant difference was found between MGMT methylation and CD204+ TAMs expression (P = 0.01), in which CD204+ TAMs were diffusely expressed in MGMT-methylated cases. There was no significant difference in RFI between CD204+ TAMs expression, MGMT-promoter methylation and treatment modalities. Conclusions: Grade 4 astrocytomas with diffusely expressed CD204+ TAMs are usually associated with MGMT-promoter methylation. Although this association is unclear, CD204+ TAMs may neutralize the effect of MGMT-DNA protein to loss its function, which contributes to tumor progression. This relationship had no significant impact on the patient's clinical outcome after different treatment modalities.

The Assessment of Major Histocompatibility Complex (MHC) Class-I Expression in Different Neuromuscular Diseases.

BACKGROUND: Major histocompatibility complex (MHC) class-1 antigen is a glycoprotein expressed in all nucleated cells. The aim of this study was to assess MHC class-I expression in different neuromuscular diseases. METHODS: The authors reviewed the data of 54 patients with neuromuscular diseases. Anti MHC class-I antibody was performed on the frozen muscle tissues using immunohistochemistry. MHC class-I was scored based on its expression on muscle fibers (0: normal, 1: expression <5 fibers, 2: expression in 5-10 fibers, 3: expression in >10 fibers). The pattern was only assessed in cases with MHC class-I scored 3 as: (1: Sarcocapillary, 2: Sarcocapillary and necrotic fibers, 3: Perifascicular). The relationship between MHC class-I expression and neuromuscular diseases was statistically analyzed. RESULTS: The mean age of the patients was 39.1 ± 18.5 years. Around 50% of patients showed normal CK levels and 5% of the cases showed elevated CK levels. There was a significance difference in MHC class-I expression between cases with normal and elevated CK levels when MHC class-I score was 3 (p= 0.020). There was a significant difference in MHC class-I expression among different neuromuscular diseases (p<0.001). All cases with idiopathic inflammatory myopathies (IIMs) have expressed MHC class-I in more than 10 fibers. MHC class-I was expressed in 15 cases of non-IIMs. CONCLUSION: MHC class-I cannot be solely used as a biomarker to distinguish IIMs from non-IIMs. The presence of MHC class-I molecules in non-IIMs might be related to immunoproteasomes mechanism. Further studies, with different muscle proteins expression and genomic sequencing, must be conducted to understand the role of MHC Class-I in neuromuscular diseases.

Ulnar Neuropathy at the Elbow Associated With Focal Demyelination in the Proximal Forearm and Intraoperative Imaging Correlation.

Ulnar nerve focal demyelination (FD) in the forearm [defined as conduction block (CB) and or temporal dispersion (TD)] has been described with immune-mediated neuropathy and with compression affecting the forearm segment of the nerve. The association of FD in the forearm with entrapment ulnar neuropathy at the elbow, as well as the intraoperative imaging of the abnormal ulnar nerve at the flexor carpi ulnaris muscle level (FCU), has not been reported before. We report a 33-years-old woman presented with only sensory symptoms of the right hand suggestive of right ulnar neuropathy for the last 10 years. On clinical examination, she had reduced pinprick sensation on the little and ring fingers with no motor deficit. Nerve-conduction study showed slowing of conduction velocity across the elbow on the right when recording at the abductor digiti minimi (ADM) and first dorsal interossei (FDI). There was 63% amplitude drop when stimulating below the elbow compared to distal stimulation at the wrist. Increment inching study localized the block at 5 cm distal to the medial epicondyle. During surgical transposition, the ulnar nerve was swollen, and edematous in the segment where the nerve enters the FCU muscle, which provides a physiological explanation for the electrophysiological findings. After the surgery, the patient reported complete resolution of the symptoms. This case demonstrate that ulnar nerve motor potential FD at the proximal forearm could be recorded and it is still compatible with ulnar-nerve entrapment at the elbow.

Skin-derived precursor cells enhance peripheral nerve regeneration following chronic denervation.

While peripheral nerves demonstrate the capacity for axonal regeneration, outcome following injury remains relatively poor, especially following prolonged denervation. Since axon-deprived Schwann cells (SCs) in the distal nerve progressively lose their ability to support axonal growth, we took the approach of using skin-derived precursor cells (SKPs) as an accessible source of replacement SCs that could be transplanted into chronically denervated peripheral nerve. In this study, we employed a delayed cross-reinnervation paradigm to assess regeneration of common peroneal nerve axons into the chronically denervated rodent tibial nerve following delivery of SKP-derived SC (SKP-SCs). SKP-SC treated animals exhibited superior axonal regeneration to media controls, with significantly higher counts of regenerated motorneurons and histological recovery similar to that of immediately repaired nerve. Improved axonal regeneration correlated with superior muscle reinnervation, as measured by compound muscle action potentials and wet muscle weights. We therefore conclude that SKPs represent an easily accessible, autologous source of stem cell-derived Schwann cells that show promise in improving regeneration through chronically injured nerves.

Nerve transfers for severe nerve injury.

Nerve transfers are becoming used increasingly for repair of severe nerve injures, especially brachial plexus injuries, where the proximal spinal nerve roots have been avulsed from the spinal cord. The procedure essentially involves the coaptation of a proximal foreign (donor) nerve to the distal denervated (recipient) nerve, so that the latter's end-organs will be reinnervated by the donated axons. Cortical plasticity appears to play an important physiologic role in the functional recovery of the reinnervated muscles. This article provides the indications for nerve transfer, principles for their use, and a comprehensive survey on various intraplexal and extraplexal nerves that have been used for transfer to repair clinical nerve injuries. Specific transfers to reanimate muscles denervated by the common patterns of brachial plexus are emphasized, including expected clinical outcomes based on the existing literature.