Biomarkers for site-specific response to neoadjuvant chemotherapy in epithelial ovarian cancer: relating MRI changes to tumour cell load and necrosis.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) potentially interrogates site-specific response to neoadjuvant chemotherapy (NAC) in epithelial ovarian cancer (EOC). METHODS: Participants with newly diagnosed EOC due for platinum-based chemotherapy and interval debulking surgery were recruited prospectively in a multicentre study (n = 47 participants). Apparent diffusion coefficient (ADC) and solid tumour volume (up to 10 lesions per participant) were obtained from DW-MRI before and after NAC (including double-baseline for repeatability assessment in n = 19). Anatomically matched lesions were analysed after surgical excision (65 lesions obtained from 25 participants). A trained algorithm determined tumour cell fraction, percentage tumour and percentage necrosis on histology. Whole-lesion post-NAC ADC and pre/post-NAC ADC changes were compared with histological metrics (residual tumour/necrosis) for each tumour site (ovarian, omental, peritoneal, lymph node). RESULTS: Tumour volume reduced at all sites after NAC. ADC increased between pre- and post-NAC measurements. Post-NAC ADC correlated negatively with tumour cell fraction. Pre/post-NAC changes in ADC correlated positively with percentage necrosis. Significant correlations were driven by peritoneal lesions. CONCLUSIONS: Following NAC in EOC, the ADC (measured using DW-MRI) increases differentially at disease sites despite similar tumour shrinkage, making its utility site-specific. After NAC, ADC correlates negatively with tumour cell fraction; change in ADC correlates positively with percentage necrosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01505829.

Aminoethyl substitution enhances the self-assembly properties of an aminocellulose as a potential archaeological wood consolidant.

The 6-deoxy-6-aminocelluloses-or "aminocelluloses"-are a class of synthetic natural cellulose derivatives which are mostly aqueous soluble and have excellent film-forming properties. Recent studies have connected these properties at the molecular level with protein-like self-associative behaviour for a range of aminocelluloses including a 6-deoxy-6-(ω-aminoethyl) aminocellulose AEA-1 with the association being a two-stage process-a reversible oligomerisation followed by further (semi-reversible) aggregation into larger structures. Here, we synthesise and compare a new 6-deoxy-6-(ω-aminoethyl) aminocellulose AEA-1' with different degree of substitution with one with further alkyl derivatisation, namely 6-deoxy-6-(ω-hydroxyethyl) aminocellulose HEA-1'. As with AEA-1, sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge still show a two-stage process for both AEA-1' and HEA-1', with the latter giving higher molar masses. The consequences of these properties for use as consolidants for archaeological wood are considered.

Tert-butyldimethylsilyl chitosan synthesis and characterization by analytical ultracentrifugation, for archaeological wood conservation.

The Oseberg ship is one of the most important archaeological testimonies of the Vikings. After excavation in 1904, the wooden gravegoods were conserved using alum salts. This resulted in extreme degradation of a number of the objects a hundred years later through acid depolymerisation of cellulose and lignin. The fragile condition of the artefacts requires a reconsolidation which has to be done avoiding water as solvent. We synthesized tert-butyldimethylsilyl (TBDMS) chitosan which is soluble in a 50:50 solution of ethyl acetate and toluene. Measurement of its molecular weight, to anticipate its penetration, provided a challenge as the density difference of the polymer and solvent was too small to provide adequate solute redistribution under a centrifugal field, so a two-stage process was implemented (i) determination of the weight-average molar mass of the aqueous soluble activated precursor, chitosan mesylate, Mw,mc using sedimentation equilibrium with the SEDFIT-MSTAR algorithm, and determination of the degree of polymerisation DP; (ii) measurement of the average degree of substitution DSTBDMS of the TBDMS group on each chitosan monosaccharide monomer unit using NMR, to augment the Mw,mc value to give the molar mass of the TBDMS-chitosan. For the preparation, we find Mw = 9.8 kg·mol-1, which is within the acceptable limit for penetration and consolidation of degraded wood. Future work will test this on archaeological wood from different sources.

Diffusion-weighted MRI in Advanced Epithelial Ovarian Cancer: Apparent Diffusion Coefficient as a Response Marker.

Background Treatment of advanced epithelial ovarian cancer results in a relapse rate of 75%. Early markers of response would enable optimization of management and improved outcome in both primary and recurrent disease. Purpose To assess the apparent diffusion coefficient (ADC), derived from diffusion-weighted MRI, as an indicator of response, progression-free survival (PFS), and overall survival. Materials and Methods This prospective multicenter trial (from 2012-2016) recruited participants with stage III or IV ovarian, primary peritoneal, or fallopian tube cancer (newly diagnosed, cohort one; relapsed, cohort two) scheduled for platinum-based chemotherapy, with interval debulking surgery in cohort one. Cohort one underwent two baseline MRI examinations separated by 0-7 days to assess ADC repeatability; an additional MRI was performed after three treatment cycles. Cohort two underwent imaging at baseline and after one and three treatment cycles. ADC changes in responders and nonresponders were compared (Wilcoxon rank sum tests). PFS and overall survival were assessed by using a multivariable Cox model. Results A total of 125 participants (median age, 63.3 years [interquartile range, 57.0-70.7 years]; 125 women; cohort one, n = 47; cohort two, n = 78) were included. Baseline ADC (range, 77-258 × 10-5mm2s-1) was repeatable (upper and lower 95% limits of agreement of 12 × 10-5mm2s-1 [95% confidence interval {CI}: 6 × 10-5mm2s-1 to 18 × 10-5mm2s-1] and -15 × 10-5mm2s-1 [95% CI: -21 × 10-5mm2s-1 to -9 × 10-5mm2s-1]). ADC increased in 47% of cohort two after one treatment cycle, and in 58% and 53% of cohorts one and two, respectively, after three cycles. Percentage change from baseline differed between responders and nonresponders after three cycles (16.6% vs 3.9%; P = .02 [biochemical response definition]; 19.0% vs 6.2%; P = .04 [radiologic definition]). ADC increase after one cycle was associated with longer PFS in cohort two (adjusted hazard ratio, 0.86; 95% CI: 0.75, 0.98; P = .03). ADC change was not indicative of overall survival for either cohort. Conclusion After three cycles of platinum-based chemotherapy, apparent diffusion coefficient (ADC) changes are indicative of response. After one treatment cycle, increased ADC is indicative of improved progression-free survival in relapsed disease. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Controlled depolymerisation assessed by analytical ultracentrifugation of low molecular weight chitosan for use in archaeological conservation.

The heterogeneity and molecular weight of a chitosan of low molecular weight (molar mass) and low degree of acetylation (0.1) for potential use as a consolidant for decayed archaeological wood were examined by sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge before and after depolymerisation. Sedimentation velocity before depolymerisation revealed a uniform distribution of sedimentation coefficient with little concentration dependence. SEDFIT-MSTAR analysis revealed a weight average molecular weight Mw of (14.2 ± 1.2) kDa, and polydispersity index of ~ 1.2. Further analysis using MULTISIG revealed a distribution of material between 2 and 20 kDa and consistent with the weight average Mw. Controlled depolymerisation using hydrogen peroxide and ultra-violet radiation in an acetic acid medium reduced this to (4.9 ± 0.7) kDa, with a similar polydispersity. The depolymerised material appears to be within the range that has been predicted to fully penetrate into archaeological wood. The consequences for this finding and the use of the analytical ultracentrifuge in wood conservation strategies are considered.

Dual Induction of New Microbial Secondary Metabolites by Fungal Bacterial Co-cultivation.

The frequent re-isolation of known compounds is one of the major challenges in drug discovery. Many biosynthetic genes are not expressed under standard culture conditions, thus limiting the chemical diversity of microbial compounds that can be obtained through fermentation. On the other hand, the competition during co-cultivation of two or more different microorganisms in most cases leads to an enhanced production of constitutively present compounds or an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain under different fermentation conditions. Herein, we report the dual induction of newly detected bacterial and fungal metabolites by the co-cultivation of the marine-derived fungal isolate Aspergillus fumigatus MR2012 and two hyper-arid desert bacterial isolates Streptomyces leeuwenhoekii strain C34 and strain C58. Co-cultivation of the fungal isolate MR2012 with the bacterial strain C34 led to the production of luteoride D, a new luteoride derivative and pseurotin G, a new pseurotin derivative in addition to the production of terezine D and 11-O-methylpseurotin A which were not traced before from this fungal strain under different fermentation conditions. In addition to the previously detected metabolites in strain C34, the lasso peptide chaxapeptin was isolated under co-culture conditions. The gene cluster for the latter compound had been identified through genome scanning, but it had never been detected before in the axenic culture of strain C34. Furthermore, when the fungus MR2012 was co-cultivated with the bacterial strain C58, the main producer of chaxapeptin, the titre of this metabolite was doubled, while additionally the bacterial metabolite pentalenic acid was detected and isolated for the first time from this strain, whereas the major fungal metabolites that were produced under axenic culture were suppressed. Finally, fermentation of the MR2012 by itself led to the isolation of the new diketopiperazine metabolite named brevianamide X.

Modelling DW-MRI data from primary and metastatic ovarian tumours.

OBJECTIVES: To assess goodness-of-fit and repeatability of mono-exponential, stretched exponential and bi-exponential models of diffusion-weighted MRI (DW-MRI) data in primary and metastatic ovarian cancer. METHODS: Thirty-nine primary and metastatic lesions from thirty-one patients with stage III or IV ovarian cancer were examined before and after chemotherapy using DW-MRI with ten diffusion-weightings. The data were fitted with (a) a mono-exponential model to give the apparent diffusion coefficient (ADC), (b) a stretched exponential model to give the distributed diffusion coefficient (DDC) and stretching parameter (α), and (c) a bi-exponential model to give the diffusion coefficient (D), perfusion fraction (f) and pseudodiffusion coefficient (D*). RESULTS: Coefficients of variation, established from repeated baseline measurements, were: ADC 3.1%, DDC 4.3%, α 7.0%, D 13.2%, f 44.0%, D* 165.1%. The bi-exponential model was unsuitable in these data owing to poor repeatability. After excluding the bi-exponential model, analysis using Akaike Information Criteria showed that the stretched exponential model provided the better fit to the majority of pixels in 64% of lesions. CONCLUSIONS: The stretched exponential model provides the optimal fit to DW-MRI data from ovarian, omental and peritoneal lesions and lymph nodes in pre-treatment and post-treatment measurements with good repeatability. KEY POINTS: • DW-MRI data in ovarian cancer show deviation from mono-exponential behaviour • Parameters derived from the stretched exponential model showed good repeatability (CV 7%) • The bi-exponential model was unsuitable because of poor parameter repeatability • The stretched exponential model showed comparable repeatability to the mono-exponential model • The extra parameter (α) provides scope for investigation of heterogeneity or response.

Ethnic Minority Status, Depression, and Cognitive Failures in Relation to Marital Adjustment in Ethnically Diverse Older Women.

The authors investigated the relationship between marital adjustment and ethnic minority status, depressive symptomatology, and cognitive failures among 78 married, community-dwelling, and predominantly non-European-American older women (ages 57-89). Respondents were screened to rule out dementia. Level of depressive symptoms, self-report of cognitive failures, and marital adjustment were obtained. As hypothesized, higher depressive symptomatology and cognitive failures were associated with worse marital adjustment (p < .05 for both). The same was true for membership in a non-dominant ethnic group, albeit only when ethnic status was considered outside the context of the other two independent variables. These results have clinical implications and fit within the theoretical framework of the socioemotional selectivity theory (Carstensen, 1992) applied to marriage in older age, a conceptualization formulated by Bookwala and Jacobs in 2004.

Validity of 13C octanoic acid breath test for measurement of solid meal gastric emptying time in children.

BACKGROUND/PURPOSE: It is important to establish a physiologic range of gastric emptying (GE) in children. Gastric emptying time measured with (99)Tc-labeled solid meal (GE(Tc)) is the gold standard. Large-scale studies with GE(Tc) are ideal but not feasible because of radiation exposure. The (13)C-labeled octanoic acid breath test (GE(13C)) does not involve radiation and is suitable for large studies. The aim of this study was to validate GE(13C) with GE(Tc) and to explore whether GE(13C) could be used to establish a physiologic range of GE in children. METHOD: Twenty-five healthy children underwent simultaneous GE(Tc) and GE(13C) using a standardized solid test meal. The time taken for the stomach to empty half its content (T(1/2)(13C)) and solid lag phase (lag(13C)) for GE(13C) were computed from the fractional excretion of (13)C in expired air. T(1/2)(13C) and lag(13C) were compared with corresponding values obtained by GE(Tc). RESULT: Correlation coefficient between T(1/2)(13C) and T(1/2)(Tc) was 0.69 (P < .01; r = 0.92 if 3 outliers were omitted). Correlation coefficient between lag(13C) and lag(Tc) was 0.39 (P < .05). There was good agreement between the methods by the Bland Altman method. CONCLUSION: There is good agreement between GE(13C) and GE(Tc). GE(13C) can be safely used to establish the reference range of GE in healthy children.

Gastric emptying of solids in normal children--a preliminary report.

OBJECTIVE: The physiological range of gastric emptying in healthy children has not previously been documented. The aim of this study was to establish the range of normal gastric emptying in children aged between 5 and 10 years with a Tc 99m-labelled solid meal acceptable to most of the children. METHODS: A list of 7 child-friendly foods was compiled. Thirty-one children aged 5 to 10 years completed a questionnaire, ranking their favourite food choices. A volume survey, to decide the weight of solid meal for the study, was carried out in 20 children. After ethical approval, gastric emptying was monitored in healthy children aged 5 to 10 years with a 99mTc-labelled solid meal selected by the methodology given hereinabove. Geometric mean counts were obtained from anterior and posterior gamma camera images, and data were used to produce normal emptying curves. In each case, a T1/2 gastric emptying time (time taken to empty half the stomach contents) was calculated. RESULTS: The overall preference was a chocolate Technecrispy cake, and the volume survey suggested a 30-g weight for the study. Twenty-four subjects consumed the meal and completed the study. The mean T1/2 gastric emptying time was 107.2 minutes (2 SD; range, 54.6-159.8 minutes). CONCLUSIONS: Chocolate Technecrispy cake was acceptable to most healthy children between 5 and 10 years of age and gave mean T1/2 gastric emptying time of 107.2 minutes. This meal can now be used for paediatric patients with transit problems.