Towards improved outcome in children treated surgically for spontaneous intracranial suppuration in South Wales.

INTRODUCTION: Spontaneous central nervous system (CNS) infections in children are rare. Treatment involves surgical intervention and antibiotic therapy. We describe a single centre experience of managing this condition in South Wales. METHODS: We performed a retrospective review of surgically managed cases in our unit for patients under 18 years of age between 2008 and 2018. Data were collected regarding aetiology, location, microbiology examination, treatment and outcomes. RESULTS: Twenty-six patients were identified of which 25 case notes were available. Fifteen were male and 10 were female. Median age was 12 years (age range 0.3-17 years). Seven patients (28%) had a burr-hole aspiration and 18 (72%) underwent craniotomy. A second procedure was performed in 10 (40%) and a third procedure in two (8%). Fourteen (56%) had a brain abscess, 10 (40%) had subdural empyema (one was bilateral) and one (4%) had an extradural empyema. Fifteen (60%) had a raised WCC (>11.5 × 109/L) and 22 (88%) had a CRP of >10 mg/L at presentation. Three (12%) patients had a normal WCC and CRP at presentation. Overall, 12 (48%) were secondary to sinus infection, with the most common organism being Streptococcus. Seven (28%) were due to otitis media or mastoiditis, six (24%) had no cause identified. The mean number of CT/MRI scans was 6.7 (range 3-13). The mean follow-up period was 16.7 months (range 1-117 months). At last follow up, 19 (76%) had a GOS of 5, five (20%) had a GOS of 4 and one (12%) had GOS of 3. There were no deaths. CONCLUSIONS: In Wales, outcomes have improved over time in keeping with other paediatric neurosurgical units in England. Increased availability of imaging resources in our hospital and use of neuro-navigation for all cases in our unit as well as earlier identification of sepsis, communication with microbiologists with dedicated ward rounds and, enhanced identification of causative organisms and contemporary anti-microbials have also contributed towards the improved management of this condition.

Trends in peri-operative performance status following resection of high grade glioma and brain metastases: The impact on survival.

OBJECTIVES: Maximal surgical resection of high grade brain tumours is associated with improved overall survival (OS). It carries the risk of neurological deterioration leading to worsening performance status (PS), which may affect overall survival and preclude patients from adjuvant therapy. We aim to review the changes in performance status of patients undergoing resection of high grade tumours and metastases and the impact of changes on overall survival. PATIENTS AND METHODS: A prospective study of the perioperative performance status of 75 patients who underwent primary resection of malignant primary brain tumour or solitary metastasis in a single centre. Data on patients' demographics, tumour histology and overall survival were also collected. WHO performance status was recorded pre-operatively and at intervals following surgery. RESULTS: Of the 75 patients (35 males, 40 females, median age 61 years at diagnosis), 50 had primary malignant brain tumours, 25 had metastasis. Although PS dropped at postoperative day 1 in 14 patients (18.7%), 28% improved by day 5 and there was significant improvement by day 14 (41%, p=0.02). The number of patients with PS 3 or worse changed from 4% pre-operatively (n=3) to 8% (n=6). Overall survival is better in those whose PS remained improved or unchanged at 2 weeks after surgery compared to those whose PS deteriorated; high grade glioma median survival 15.67 vs. 2.4 months (p=0.005) and metastasis median survival 8.53 vs.2.33 months (p=0.001). CONCLUSION: Our data demonstrates that although PS may deteriorate immediately after surgery, the majority of patients regain their baseline PS or improve by 2 weeks postoperatively; decisions on fitness for adjuvant treatment should therefore be delayed until then. In those patients whose PS declines following surgery overall survival is poor.

Recurrence or re-emergence of keratoconus--what is the evidence telling us? Literature review and two case reports.

Keratoconus may recur following penetrating or lamellar keratoplasty, but latency is considerably longer in the former. Since keratoplasty involves only partial excision of the cornea, and recent research strongly indicates the presence of the pathology in the peripheral host cornea, the reappearance of the pathology after a latency period is most likely due to migration of the disease from host to donor cornea. This notion is further corroborated by the shorter latency period in partial thickness keratoplasty, where more of the diseased host cornea remains in place. Other proposed causes for the recurrence of keratoconus, such as eye rubbing and contact lens wear, were reportedly not associated with a significant number of cases, and, therefore, are not the primary factor. Based on existing literature, it is concluded that, in post-keratoplasty keratoconus, the etiology stems from re-emergence of the disease rather than recurrence. Keratoconus patients in need of keratoplasty should be counseled on the possibility of the disease re-emerging.

Inhibition of estrone sulfatase (ES) by alkyl and cycloalkyl ester derivatives of 4-[(aminosulfonyl)oxy] benzoic acid.

In our search for potent inhibitors of the enzyme estrone sulfatase (ES), we have undertaken the synthesis and biochemical evaluation of a range of esters of 4-[(aminosulfonyl)oxy] benzoic acid. The results of the study show that the synthesised compounds possess potent inhibitory activity, indeed the cyclooctyl derivative was found to be more potent than 667-COUMATE, which is currently undergoing clinical trials.

The design, synthesis, and in vitro biochemical evaluation of a series of esters of 4-[(aminosulfonyl)oxy]benzoate as novel and highly potent inhibitors of estrone sulfatase.

We report the initial results of our study into the use of a potential transition-state (TS) of the reaction catalysed by the enzyme estrone sulfatase (ES) in the design of a series of cyclic esters of 4-[(aminosulfonyl)oxy]benzoate as novel inhibitors of ES. The results of the study show that these compounds are some of the most potent inhibitors known todate, possessing greater inhibitory activity than the three standard compounds: 4-methylcoumarin-7-O-sulfamate (COUMATE); the tricyclic derivative of COUMATE, namely 667-COUMATE (which is in Phase I of clinical trials) and; the steroidal inhibitor estrone-3-O-sulfamate (EMATE).

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase.

The enzyme oestrone sulfatase (ES) is responsible for the conversion of the stored (sulfated) form of oestrogens to the active form, namely oestrone. In our continuing quest to synthesize potent inhibitors of oestrone sulfatase and to determine the structural requirements for such inhibition, we have synthesized and evaluated several derivatives of phenyl sulfamate. We report the results of the synthesis and biochemical evaluation of a series of 3- and 4-aminosulfonated derivatives of phenol in an effort to investigate the role of the acid dissociation constant (pK(a)), and therefore the stability of the phenoxide ion, on the inhibitory activity of compounds against this enzyme. The results showed that there was a strong correlation between the observed pK(a) and inhibitory activity within the aminosulfonated compounds considered. This suggested that in the inhibition of oestrone sulfatase by these compounds, pK(a) was an important physicochemical property, and as such, the stability of the O(-) ion was a crucial factor in the inhibition, and therefore the drug design process.

Design, synthesis and biochemical evaluation of AC ring mimics as novel inhibitors of the enzyme estrone sulfatase (ES).

We report the initial results of our study into a series of simple 4'-O-sulfamoyl-4-biphenyl based compounds as novel inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that these compounds are potent inhibitors, possessing greater inhibitory activity than COUMATE, but weaker inhibitory activity than EMATE or the tricyclic derivative of COUMATE, namely 667-COUMATE. Furthermore, the compounds are observed to be irreversible inhibitors.

Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES).

In an effort to investigate the structural requirements for the inhibition of the enzyme oestrone sulphatase (ES), we have previously undertaken extensive structure-activity relationship studies. Using the data from molecular modelling and structure-activity relationship determination studies, we have designed a number of compounds based upon 4-sulphamated phenyl ketones. Here, we report the results of our study into a series of these compounds as potential inhibitors of ES. The results of the study show that these compounds are potent inhibitors the possessing greater inhibitory activity than 4-methylcoumarin-7-O-sulphamate derivative (COUMATE) (a potent non-steroidal inhibitor), but are weaker than oestrone-3-sulphamate (EMATE) and the recently reported 667- and 669-COUMATE, however, they provide good lead compounds in the search for potent inhibitors of ES. Furthermore, the compounds are observed to be irreversible inhibitors. From the consideration of the structure-activity relationship of these novel compounds, we have attempted to rationalise the significance of the log P factor in the inhibition of ES and suggest that a log P requirement of approximately 3.5 aids the inhibition through the rapid expulsion of the carbon backbone from the active site. We also propose that the same factor is responsible for the hydrolysis of oestrone sulphate reaction, appearing to be an irreversible process.

Evidence for the mechanism of the irreversible inhibition of oestrone sulphatase (ES) by aminosulphonate based compounds.

In our search for the mechanism of the enzyme oestrone sulphatase (ES) we have synthesised and evaluated a number of compounds that were predicted to possess some inhibitory activity. Some of these compounds were indeed found to be inhibitors of ES, whilst other compounds were not. From a consideration of the structure-activity relationship (SAR) of the inhibitors and non-inhibitors of this enzyme, we discovered a factor which we now believe is the main inhibitory moiety within the aminosulphonated inhibitors. We therefore report the results of our study into a series of phenyl and alkyl sulphamated compounds as inhibitors of ES. The results of the study show that the substituted phenyl sulphamates are potent inhibitors, whereas the alkyl compounds are, in general, non-inhibitors. Using the results of our SAR study, we postulate the probable mechanism for the irreversible and reversible inhibition of ES, and rationalise the role of the different physicochemical factors in the inhibition of this crucial enzyme.

The mechanism of the irreversible inhibition of estrone sulfatase (ES) through the consideration of a range of methane- and amino-sulfonate-based compounds.

We report the results of our study into a series of simple phenyl and alkyl sulfamates and alkyl methanesulfonates as potential inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that the substituted phenyl sulfamates are good irreversible inhibitors; the alkyl sulfamate compounds were found to lack inhibitory activity; whilst the large alkyl chain containing methanesulfonate-based compounds were found to possess weak reversible inhibitory activity. Using the results of the inhibition study, we postulate the probable mechanism for ES and suggest that an attack by the gem-diol is a major requirement prior to the hydrolysis of the sulfamate group, following which, attack on the active site C=O occurs and which therefore leads to the production of an imine type functionality, resulting in irreversible inhibition.

Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer.

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3 beta,17 beta-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid/estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken to date, as well as possible future development with respect to dual inhibitors of both estrone sulfatase and AR.