Giant Supratentorial Brain Tumors in Children: Functional Outcome and Progression-Free Survival Analysis.

INTRODUCTION: This study aimed to identify factors affecting progression-free survival (PFS) in pediatric patients with giant supratentorial brain tumors (GSBTs) treated with surgical excision. The secondary aim was to analyze how these same factors affected the functional outcome in the long term. METHODS: We performed a retrospective, analytical, single-center cohort study. We included all pediatric patients with GSBT between January 2014 and June 2018. Patients were followed for a minimum of 24 months for the PFS and overall survival (OS) analysis. Functional status score (FSS) was used to assess the functional outcome. RESULTS: We included 27 patients with GSBT, the median age was six (range 2-12), and eleven patients had a grade IV tumor. The 24-month PFS and OS were 51.85% and 74.04%, respectively. A PFS-ending event or treatment failure occurred in 13 patients. We found that patients with postoperative FFS >16 have a worse PFS than patients with a postoperative FSS <15 (HR 4.51; p = 0.03). Patients with more than three surgeries had worse PFS than patients with one or two procedures (HR 11.39; p = 0.004). High-grade tumors were associated with worse PFS than low-grade tumors (HR 1.55; p = 0.04). Finally, patients with CNS infections had worse PFS than patients without that complication (HR 2.70; p = 0.04). CONCLUSIONS: GSBTs in pediatric patients are complex lesions that require multidisciplinary management. Surgical management and quality of life should be considered when choosing the best treatment. Factors influencing long-term PFS were high-grade histopathology, the need for three or more surgeries, postoperative FSS >16, and CNS infections.

Management evaluation of metastasis in the brain (MEMBRAIN)-a United Kingdom and Ireland prospective, multicenter observational study.

BACKGROUND: In recent years an increasing number of patients with cerebral metastasis (CM) have been referred to the neuro-oncology multidisciplinary team (NMDT). Our aim was to obtain a national picture of CM referrals to assess referral volume and quality and factors affecting NMDT decision making. METHODS: A prospective multicenter cohort study including all adult patients referred to NMDT with 1 or more CM was conducted. Data were collected in neurosurgical units from November 2017 to February 2018. Demographics, primary disease, KPS, imaging, and treatment recommendation were entered into an online database. RESULTS: A total of 1048 patients were analyzed from 24 neurosurgical units. Median age was 65 years (range, 21-93 years) with a median number of 3 referrals (range, 1-17 referrals) per NMDT. The most common primary malignancies were lung (36.5%, n = 383), breast (18.4%, n = 193), and melanoma (12.0%, n = 126). A total of 51.6% (n = 541) of the referrals were for a solitary metastasis and resulted in specialist intervention being offered in 67.5% (n = 365) of cases. A total of 38.2% (n = 186) of patients being referred with multiple CMs were offered specialist treatment. NMDT decision making was associated with number of CMs, age, KPS, primary disease status, and extent of extracranial disease (univariate logistic regression, P < .001) as well as sentinel location and tumor histology (P < .05). A delay in reaching an NMDT decision was identified in 18.6% (n = 195) of cases. CONCLUSIONS: This study demonstrates a changing landscape of metastasis management in the United Kingdom and Ireland, including a trend away from adjuvant whole-brain radiotherapy and specialist intervention being offered to a significant proportion of patients with multiple CMs. Poor quality or incomplete referrals cause delay in NMDT decision making.

Prostate cancer tumour features on template prostate-mapping biopsies: implications for focal therapy.

BACKGROUND: Focal therapy is being offered as a viable alternative for men with localised prostate cancer (PCa), but it is unclear which men may be suitable. OBJECTIVE: To determine the proportion of men with localised PCa who are potentially suitable for focal therapy. DESIGN, SETTING, AND PARTICIPANTS: Our institutional transperineal template prostate-mapping (TTPM) biopsy registry of 377 men from 2006 to 2010 identified 291 consecutive men with no prior treatment. INTERVENTION: TTPM biopsies using a 5-mm sampling frame. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Suitability for focal therapy required the cancer to be (1) unifocal, (2) unilateral, (3) bilateral/bifocal with at least one neurovascular bundle avoided, or (4) bilateral/multifocal with one dominant index lesion and secondary lesions with Gleason ≤3 + 3 and cancer core involvement ≤3 mm. Binary logistic regression modelling was used to determine variables predictive for focal therapy suitability. RESULTS AND LIMITATIONS: The median age was 61 yr, and the median prostate-specific antigen was 6.8 ng/ml. The median total was 29 cores, with a median of 8 positive cores. Of 239 of 291 men with cancer, 29% (70 men), 60% (144 men), and 8% (20 men) had low-, intermediate-, and high-risk PCa, respectively. Ninety-two percent (220 men) were suitable for one form of focal therapy: hemiablation (22%, 53 men), unifocal ablation (31%, 73 men), bilateral/bifocal ablation (14%, 33 men), and index lesion ablation (26%, 61 men). Binary logistic regression modelling incorporating transrectal biopsy parameters showed no statistically significant predictive variable. When incorporating TTPM parameters, only T stage was a significant negative predictor for suitability (p=0.001) (odds ratio: 0.001 [95% confidence interval, 0.000-0.048]). Limitations of the study include potential selection bias caused by tertiary referral practise and lack of long-term results on focal therapy efficacy. CONCLUSIONS: Focal therapy requires an accurate tool to localise individual cancer lesions. When such a test, TTPM biopsy, was applied to men with low- and intermediate-risk PCa, most of the men were suitable for a tissue preservation strategy.

Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes.

Lithium (Li(+)) is a common treatment for bipolar mood disorder, a major psychiatric illness with a lifetime prevalence of more than 1%. Risk of bipolar disorder is heavily influenced by genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li(+) sensitivity. Using the social amoeba Dictyostelium, we previously identified prolyl oligopeptidase (PO) as a modulator of Li(+) sensitivity. In a link to the clinic, PO enzyme activity is altered in bipolar disorder patients. Further studies demonstrated that PO is a negative regulator of inositol(1,4,5)trisphosphate (IP(3)) synthesis, a Li(+) sensitive intracellular signal. However, it was unclear how PO could influence either Li(+) sensitivity or risk of bipolar disorder. Here we show that in both Dictyostelium and cultured human cells PO acts via Multiple Inositol Polyphosphate Phosphatase (Mipp1) to control gene expression. This reveals a novel, gene regulatory network that modulates inositol metabolism and Li(+) sensitivity. Among its targets is the inositol monophosphatase gene IMPA2, which has also been associated with risk of bipolar disorder in some family studies, and our observations offer a cellular signalling pathway in which PO activity and IMPA2 gene expression converge.

PtdIns(3,4,5)P(3) and inositol depletion as a cellular target of mood stabilizers.

Lithium (Li(+)) is the mood stabilizer most frequently used in the treatment of bipolar mood disorder; however, its therapeutic mechanism is unknown. In the 1980s, Berridge and colleagues proposed that Li(+) treatment acts via inhibition of IMPase (inositol monophosphatase) to deplete the cellular concentration of myo-inositol. Inositol depletion is also seen with the alternative mood stabilizers VPA (valproic acid) and CBZ (carbamazepine), suggesting a common therapeutic action. All three drugs cause changes in neuronal cell morphology and cell chemotaxis; however, it is unclear how reduced cellular inositol modulates these changes in cell behaviour. It is often assumed that reduced inositol suppresses Ins(1,4,5)P(3), a major intracellular signal molecule, but there are other important phosphoinostide-based signal molecules in the cell. In the present paper, we discuss evidence that Li(+) has a substantial effect on PtdIns(3,4,5)P(3), an important signal molecule within the nervous system. As seen for Ins(1,4,5)P(3) signalling, suppression of PtdIns(3,4,5)P(3) signalling also occurs via an inositol-depletion mechanism. This has implications for the cellular mechanisms controlling phosphoinositide signalling, and offers insight into the genetics underlying risk of bipolar mood disorder.

CD8alpha/alpha homodimers fail to function as co-receptor for a CD8-dependent TCR.

In this study, we have started to dissect the molecular basis of CD8 dependence of a high and low avidity CTL clone specific for the same peptide epitope. Using anti-CD8alpha and anti-CD8beta antibodies, we found that cytotoxicity and IFN-gamma production by high but not by low avidity CTL was strongly CD8 dependent. We isolated the TCR genes of both types of CTL clones and used retroviral gene transfer to analyse the function of these TCR in primary T cells of wild-type and CD8beta-deficient mice. Both TCR triggered antigen-specific killing in wild-type T cells, and blocking experiments showed that CD8 dependence/independence co-transferred with the TCR into primary T cells, indicating that it was dictated by the TCR itself. Gene transfer experiments into CD8beta-deficient T cells revealed that only the TCR derived from the CD8-independent CTL clone elicited antigen-specific cytotoxicity, while the CD8-dependent TCR was non-functional in the absence of the CD8beta-chain. These data indicate a striking difference between CD8alpha/beta heterodimers and CD8alpha/alpha homodimers as only the former were able to provide co-receptor function for the CD8-dependent TCR.

Proteomic and microarray analyses of the Dictyostelium Zak1-GSK-3 signaling pathway reveal a role in early development.

GskA, the Dictyostelium GSK-3 orthologue, is modified and activated by the dual-specificity tyrosine kinase Zak1, and the two kinases form part of a signaling pathway that responds to extracellular cyclic AMP. We identify potential cellular effectors for the two kinases by analyzing the corresponding null mutants. There are proteins and mRNAs that are altered in abundance in only one or the other of the two mutants, indicating that each kinase has some unique functions. However, proteomic and microarray analyses identified a number of proteins and genes, respectively, that are similarly misregulated in both mutant strains. The positive correlation between the array data and the proteomic data is consistent with the Zak1-GskA signaling pathway's functioning by directly or indirectly regulating gene expression. The discoidin 1 genes are positively regulated by the pathway, while the abundance of the H5 protein is negatively regulated. Two of the targets, H5 and discoidin 1, are well-characterized markers for early development, indicating that the Zak1-GskA pathway plays a role in development earlier than previously observed.