The inhibition of the lipid peroxidation, induced by iron and ascorbate in rat liver microsomes, by phenols and flavones was studied. The activity of phenol was enhanced by electron donating ...substituents, denoted by the Hammett sigma ( † ). The concentration of the substituted phenols giving 50% inhibition (IC 50 ) of lipid peroxidation gave a good correlation with the † of the substituent (ln(1/IC 50 )= m 8.92 † +5.80 ( R =0.94, p <0.05)). In flavones two pharmacophores for the protection against lipid peroxidation were pinpointed: (i) a catechol moiety as ring B and (ii) an OH-group at the 3 position with electron donating groups at the 5 and/or 7 position in the AC-ring. An example of a flavone with the latter pharmacophore is galangin (3,5,7-trihydroxyflavone) where the reactivity of the 3-OH-group is enhanced by the electron donating effect of the 5- and 7-OH-groups. This is comparable to the effect of electron donating substituents on the activity of phenol. The prooxidant activity of flavones has been related to a low half peak oxidation potential ( Ep /2). All flavones with a catechol as ring B have very low Ep /2, suggesting that they display a prominent prooxidant activity. In contrast, the Ep /2 varies within the group of flavones with a 3-OH, e.g. TUM 8436 (5,7,3',4'-tetra- O -methyl-quercetin) has a relatively high Ep /2 and is an excellent protector against lipid peroxidation. Apparently amongst the flavones with the pharmacophore in the AC-ring there are good antioxidants that are expected to display no or limited prooxidant properties.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
2.
Embryonal precursors of Wilms tumor Coorens, Tim H H; Treger, Taryn D; Al-Saadi, Reem ...
Science,
12/2019, Letnik:
366, Številka:
6470
Journal Article
Recenzirano
Odprti dostop
Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney ...cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the
locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in ...children with Wilms tumour (WT) in a United Kingdom multicentre clinical study.BACKGROUND AND AIMSTumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study.The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made.PATIENTS AND METHODSThe IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made.Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology.RESULTSTotal 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology.Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings.CONCLUSIONSRadiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings.
To review surgical management, tumour stage and clinical outcomes in children with intravascular extension of Wilms tumour (WT) registered in a national clinical study (2012–19).
WTs with ...presence/suspicion of tumour thrombus in the renal vein (RV) or beyond on radiology, surgery or pathology case report forms were identified. Only cases where thrombus was confirmed by surgeon and/or reference pathologist were included. Surgical management, disease stage, overall (OS) and event free survival (EFS) were investigated.
69/583 (11.8%) patients met the inclusion criteria. Forty-six (67%) had abdominal stage III due to thrombus-related reasons: 11 had macroscopically incomplete resection, including 8 cases where cavotomy was not performed; 20 had piecemeal complete resection of thrombus; 15 had microscopically positive resection margins at the RV. 66% of tumour thrombi contained viable tumour. There were eight relapses and five deaths. EFS, but not OS, was significantly associated with completeness of surgical resection (P<0.05). OS and EFS were also significantly associated with histological risk group (P<0.05) but not with viability of tumour thrombus (P=0.19; P=0.59).
WTs with intravascular extension have a high risk of local stage III due to thrombus-related reasons. Controlled complete removal of the thrombus should be the aim of surgery.
Level II
Objectives
To investigate the extent to which observer variability of computed tomography (CT) lung nodule assessment may affect clinical treatment stratification in Wilms tumour (WT) patients, ...according to the recent Société Internationale d'Oncologie Pédiatrique Renal Tumour Study Group (SIOP‐RTSG) UMBRELLA protocol.
Methods
I: CT thoraces of children with WT submitted for central review were used to estimate size distribution of lung metastases. II: Scans were selected for blinded review by five radiologists to determine intra‐ and inter‐observer variability. They assessed identical scans on two occasions 6 months apart. III: Monte Carlo simulation (MCMC) was used to predict the clinical impact of observer variation when applying the UMBRELLA protocol size criteria.
Results
Lung nodules were found in 84 out of 360 (23%) children with WT. For 21 identified lung nodules, inter‐observer limits of agreement (LOA) for the five readers were ±2.4 and ±1.4 mm (AP diameter), ±1.9 and ±1.8 mm (TS diameter) and ±2.0 and ±2.4 mm (LS diameter) at assessments 1 and 2. Intra‐observer LOA across the three dimensions were ±1.5, ±2.2, ±3.5, ±3.1 and ±2.6 mm (readers 1–5). MCMC demonstrated that 17% of the patients with a ‘true’ nodule size of ≥3 mm will be scored as <3 mm, and 21% of the patients with a ‘true’ nodule size of <3 mm will be scored as being ≥3 mm.
Conclusion
A significant intra–inter observer variation was found when measuring lung nodules on CT for patients with WT. This may have significant implications on treatment stratification, and thereby outcome, when applying a threshold of ≥3 mm for a lung nodule to dictate metastatic status.
Although differences exist in treatment and risk-stratification strategies for children with Wilms tumor (WT) between the European International Society of Paediatric Oncology (SIOP) and American ...Children's Oncology Group (COG) study groups, outcomes are very similar, with an overall survival of > 85%. Future strategies aim to de-intensify treatment and reduce toxicity for children with a low risk of relapse and intensify treatment for children with high-risk disease. For metastatic WT, response of lung nodules to chemotherapy is used as a marker to modify treatment intensity. For recurrent WT, a unified approach based on the use of agents that were not used for primary therapy is being introduced. Irinotecan is being explored as a new strategy in both metastatic and relapsed WT. Introduction of biology-driven approaches to risk stratification and new drug treatments has been slower in WT than in some other childhood cancers. While several new biological pathways have been identified recently in WT, their individual rarity has hampered their translation into clinical utility. Identification of robust prognostic factors requires extensive international collaborative studies because of the low proportion who relapse or die. Molecular profiling studies are in progress that should ultimately improve both risk classification and signposting to more targeted therapies for the small group for whom current therapies fail. Accrual of patients with WT to early-phase trials has been low, and the efficacy of these new agents has so far been very disappointing. Better in vitro model systems to test mechanistic dependence are needed so available new agents can be more rationally prioritized for recruitment of children with WT to early-phase trials.
Abstract
BACKGROUND: Paediatric High Grade Gliomas (HGG) have poor outcomes with conventional treatment. HGG in association with constitutional DNA mismatch repair deficiency (CMMRD) are hypermutated ...and have shown dramatic response to checkpoint inhibitors. Salvage following progression or failure to respond to check point inhibitors has rarely been reported. We describe a successful alternative therapeutic approach targeting the activated pathway (mTOR) in a hypermutated HGG. CASE SUMMARY: A 6-year-old girl presenting with seizures was diagnosed with left frontal lobe HGG with concurrent neck mass (Pilomatrixoma). Presence of synchronous tumours raised the possibility of cancer predisposition; the HGG was hypermutated with germline PMS2 mutation confirming diagnosis of CMMRD. Near total resection was undertaken followed by focal radiotherapy 54 Gy, with 1 cycle of concomitant CCNU. MRI post radiotherapy showed tumour progression. Anti-PDl inhibitor Nivolumab was commenced. CTLA-4 antibody, Ipilimumab was added after 4 cycles of Nivolumab due to poor response. Tumour response was seen, but dual therapy had to be discontinued due to toxicity. The tumour progressed following further single agent Nivolumab. In view of multiple mutations in the mTOR pathway (NF1, PIK3/PTEN, TSC1, TSC2), a mTOR inhibitor, Everolimus was commenced. There was 25% tumour reduction after 4 weeks treatment and further reduction after 6 months. Resection of residual tumour showed necrotic tissue only. There continues to be a sustained response to Everolimus for over 12 months. DISCUSSION: Approximately a third of CMMRD HGG respond to checkpoint inhibitors. For those that don’t, these hypermutated tumours offers the possibility of targeting specific molecular pathways. Response to Everolimus in HGG harbouring mTOR aberrations have been described. To our knowledge this is the first report of successful use of mTOR inhibitor in CMMRD HGG. CONCLUSION: Targeted molecular treatment for patients with CMMRD hypermutated brain tumours should be considered according to the mutated pathways.
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