New indications and controversies in arginine therapy

Arginine is an important, versatile and a conditionally essential amino acid. Besides serving as a building block for tissue proteins, arginine plays a critical role in ammonia detoxification, and nitric oxide and creatine production. Arginine supplementation is an essential component for the treatment of urea cycle defects but recently some reservations have been raised with regards to the doses used in the treatment regimens of these disorders. In recent years, arginine supplementation or restriction has been proposed and trialled in several disorders, including vascular diseases and asthma, mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), glutaric aciduria type I and disorders of creatine metabolism, both production and transportation into the central nervous system. Herein we present new therapeutic indications and controversies surrounding arginine supplementation or deprivation.     

Rhegmatogenous retinal detachment--clinical case

We present the case of a 57 years old woman which was admitted for the amputation of the infero-nasal visual field of the right eye, change observed by the pacient for 2 weeks. Clinical examination and lab exams revealed the cause of this change: a rhegmatogenous retinal detachment in the superior temporal quadrant. Surgical treatement was warranted. We did a posterior vitrectomy with trans-scleral crioapplications and injection of silicone oil 1000. We followed the patient's evolution post-operative and we observed the development of a complicated cataract which was treated in a second surgery together with the extraction of the silicone oil. The evolution was favorable.     

Neuromyelitis optica spectrum disorders and anti-myelin oligodendrocyte glycoprotein positive optic neuropathies

AIM: To describe the clinical characteristics and treatments associated with antibody positive optic neuropathies including anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4), alongside diagnostic modalities, investigations, and outcomes. METHODS: A cross-sectional single-centre retrospective case series consisting of 16 patients including 12 anti-MOG positive patients and 4 anti-AQP4 positive patients. Each of these patients had clinical signs and symptoms of optic neuritis and consisted of all patients who had a positive blood antibody result in our centre. Clinical findings including presence of a relative afferent pupillary defect, colour vision and disc assessment were recorded. Structured clinical exam and multimodal imaging was undertaken sequentially on each. Optical coherence tomography (OCT) scanning was preformed to examine the correlation between ganglion cell layer (GCL) thickness and visual acuity (VA) at presentation and as a determinant of final visual outcome in both groups. Initial and long-term treatment is also summarised. RESULTS: A total of 16 patients were included in the study consisting of 12 anti-MOG and 4 anti-AQP4 positive patients. Nine of the 16 patients were female and the average age of onset was 29.2y in the MOG group and 42y in the AQP4 group. There was no statistically significant correlation (Pearson correlation) between GCL thickness and presenting and final VA [r(10)=0.081, P=0.08 and r(10)=0.089, P=0.34 respectively]. The same statistical analysis was performed for the correlation between retinal nerve fibre layer (RNFL) and VA and similar outcomes were observed [r(10)=0.04, P=0.22 and r(10)=0.09, P=0.04]. No correlation was seen for initial RNFL thickness and final visual outcome in this group either [r(2)=0.19, P=0.38]. Visual field testing and radiological findings for each group are described. CONCLUSION: No correlation between initial VA or RNFL and final visual outcome is identified. A broad range of visual field and radiographic findings are identified, a consensus on treatment of neuromyelitis optica spectrum disorders and anti-MOG positive optic neuropathies has yet to be accepted but initial high dose immunosuppression followed by low dose maintenance therapy is favoured.     

Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas

Purposes  Here we investigate if valproic acid (VA) can enhance the efficacy of commonly used therapies for head and neck squamous cell carcinomas (HNSCC) and the molecular mechanisms that may be related to its anticancer effects. Methods  Proliferation and viability of distinct cell types subjected to VA treatment alone or in combination regimens were measured through BrdU incorporation and LDH release, respectively. Molecular markers compatible with histone deacetylase inhibitory activity of VA were assessed through western blots assays in lysates obtained from cultured cells and tumour biopsies. Results  Treatment of all cell types with VA resulted in a dose-dependent increase in histone H3 acetylation and p21 expression, as well as dose-dependent cytostasis. In contrast, the cytotoxic response to VA was variable and did not correlate with cytostasis, histone acetylation or p21 induction. The variability in response to VA was also observed in tumour biopsy samples collected from patients prior to and following a 1 week oral course of VA. In addition, we found that a combination of a clinically achievable concentration of VA plus cisplatin caused a threefold to sevenfold increase in cisplatin cytotoxicity in vitro. Conclusions  VA acts as a histone deacetylase inhibitor (HDI) in SCC cells and normal human keratinocytes (HKs), potentiates the cytotoxic effect of cisplatin in SCC cell lines and decreases the viability of SCC cells as opposed to HKs. Taken together, the results provide initial evidence that VA might be a valuable drug in the development of better therapeutic regimens for HNSCC.     

Locally advanced tonsillar squamous cell carcinoma: Treatment approach revisited

AIMS: The purpose of this study was to review the treatment policy for locally advanced stage III and IV squamous cell carcinoma (SCC) of the tonsil at the Princess Alexandra Hospital Head and Neck Unit, Brisbane, Australia. MATERIALS AND METHODS: The records of 148 patients with curable stage III and IV SCC of the tonsil were reviewed from the years 1992 to 2004 inclusive. During this period, patients were treated with surgery and postoperative radiotherapy and only offered definitive radiation if they were medically or surgically inoperable. There were 102 patients treated with surgery +/- postoperative radiotherapy (group 1) and 46 patients treated with definitive radiotherapy +/- chemotherapy (group 2). The endpoints of locoregional control (LRC), disease specific survival (DSS), and overall survival (OS) were studied and prognostic factors were investigated with univariate and multivariate analyses. RESULTS: The 5-year OS, DSS, and LRC were 57%, 69%, and 84%, respectively. Univariate analyses showed that patients in group 1 had a superior OS (69% vs. 41%, P = .007), a trend toward improvement in LRC (88% vs. 73%, P = .08), and a nonsignificant improvement in DSS (75% vs. 56%, P = .14). There was a greater percentage of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 or less in group 1, suggesting selection bias toward the surgical group. Multivariate analyses, which adjusted for known prognostic factors, showed that treatment group was significant for OS but not for LRC or DSS. CONCLUSIONS: Surgery and postoperative radiotherapy continues to provide a superior outcome in locally advanced tonsil SCC in patients with surgically resectable disease, good ECOG performance status, and medically operable.     

Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus--associated lymphoproliferative disorders and malignant lymphomas

LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral oncogene because of its ability to transform rodent fibroblasts in vivo and render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces DNA synthesis and abrogates apoptosis. LMP-1 is expressed in EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC), a subset of Hodgkin's disease (HD), and in EBV-associated lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region functionally related to the half-life to the LMP-1 protein, have been reported frequently in human immunodeficiency virus (HIV)- associated HD (100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61% respectively), but less frequently in cases of HD not associated with HIV (28%, 33%) and infectious mononucleosis (33%). To further investigate the potential relationship of del-LMP-1 to EBV- LPDs associated with immunosuppression or immunodeficiency, we studied 39 EBV-associated lymphoproliferations (10 benign, 29 malignant) from four distinct clinical settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2 reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ hybridization or by polymerase chain reaction (PCR) analysis. EBV strain type and LMP-1 deletion status were determined by PCR. EBV strain types segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV (19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive non- Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML (100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV- associated lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical by DNA sequence analysis. No correlation was identified between the presence of del-LMP-1 and the EBV strain type observed. The high incidence of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low incidence observed in reactive lymphoid proliferations (28%), suggests that the deleted form may be preferentially selected in lymphomatous processes. All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency of del-LMP-1 was observed in both HIV-associated ML (66%) and nonimmunodeficiency ML (60%), suggesting that impairment of immune function alone is not a requirement for the expansion of malignant cells infected by EBV stains containing the deleted LMP-1 gene.