The impact of cancer and chemotherapy during pregnancy on child neurodevelopment: A multimodal neuroimaging analysis.

BACKGROUND: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. METHODS: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state blood-oxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-by-GA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. FINDINGS: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR ≤ 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. INTERPRETATION: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. FUNDING: This project has received funding from the European Union's Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014-152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N).

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

Monitoring and optimising cognitive function in cancer patients: Present knowledge and future directions.

The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence. We review the state of knowledge on the cognitive functioning of patients with primary and secondary brain tumours at diagnosis, during and after therapy, and discuss current initiatives to diminish cognitive decline in these patients. Similarly, attention is paid to the cognitive sequelae of cancer and cancer therapies in patients without CNS disease. Disease and treatment effects on cognition are discussed, as well as current insights into the neural substrates and the mechanisms underlying cognitive dysfunction in these patients. In addition, rehabilitation strategies for patients with non-CNS disease confronted with cognitive dysfunction are described. Special attention is given to knowledge gaps in the area of cancer and cognition, in CNS and non-CNS diseases. Finally, we point to the important role for cooperative groups to include cognitive endpoints in clinical trials in order to accelerate our understanding and treatment of cognitive dysfunction related to cancer and cancer therapies.

Integrating imaging findings in evaluating the post-chemotherapy brain.

Cognitive complaints following cancer and cancer therapy are common. Many studies have investigated the effects of chemotherapy on the brain. However, the mechanisms for the associated cognitive impairment are not well understood. Some studies have also included brain imaging to investigate potential neurological substrates of cognitive changes. This review examines recent neuroimaging studies on cancer- and chemotherapy-related cognitive dysfunction in non-central nervous system cancers and compares findings across imaging modalities. Grey matter volume reductions and decreases in white matter integrity are seen after exposure to adjuvant chemotherapy for breast cancer, and functional studies have illuminated both hypo- and hyperactivations in many of the same regions months to years following therapy. These comparisons can assist in further characterizing the dysfunction reported by patients and contribute to a better understanding of the mechanisms involved.

Role of proline and hydroxyproline in N-nitrosamine formation during heating in cured meat.

N-Nitrosamines are formed in a multi-step reaction of nitrite with free amino acids and amines in the meat products. The aim of this study was to determine the role of proline and hydroxyproline in N-nitrosamines formation during heating of cured meat. A lean meat model was used with different nitrite concentrations (0, 120, and 480mg/kg), and addition of proline and hydroxyproline (1000mg/kg), followed by heating at different temperatures. Volatile nitrosamines were analyzed with GC-TEA. The nitrosamine content never exceeded 10µg/kg and stayed 120°C.

Intranasal absorption of sumatriptan and naratriptan: no evidence of local transfer from the nasal cavities to the brain arterial blood in male rats.

Nasal administration to rats of small molecules (tritiated water, tyrosine, and propanol) results in a higher concentration in the brain arterial blood than in other arteries. The preferential distribution is based on a counter current transfer, which takes place between nasal vein blood and brain arterial blood in the cavernous sinus-carotid artery complex. This model was used to investigate whether the antimigraine 5HT(1B/1D) receptor agonists sumatriptan and naratriptan may also be transferred by the system. The ratio of 'head':'heart' plasma concentrations obtained from two carotid catheters after intranasal administration was not different from 1.00 for either compound, and thus, there was no experimental evidence of a preferential local transfer of drug from the nose to the carotid artery circulation. However, plasma concentrations increased from the first minute after intranasal dosing suggesting that sumatriptan and naratriptan are absorbed into the general systemic circulation from the nasal cavity in rats in a first-order fashion with no lag time. This is consistent with the clinical onset of efficacy of sumatriptan after an intranasal dose which occurs as early as 15 min post dose.

Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells.

The gut absorption of proanthocyanidins (PAs) and of the related (+)-catechin monomer was investigated with colonic carcinoma (Caco-2) cells of a human origin, grown in monolayers on permeable filters. Permeability of various radiolabeled PAs differing in their molecular weight was compared with that of the radiolabeled (+)-catechin. No toxicity was observed at PA concentrations up to the physiological concentration of 1 mM. (+)-Catechin and PA dimer and trimer had similar permeability coefficients (P(app) = 0.9-2.0 x 10(-6) cm s(-1)) close to that of mannitol, a marker of paracellular transport. Paracellular transport was also indicated by the increase of absorption after reduction of the transepithelial electric resistance through calcium ion removal. In contrast, permeability of a PA polymer with an average polymerization degree of 6 (molecular weight 1,740) was approximately 10 times lower (P(app) = 0.10 +/- 0.04 x 10(-6) cm s(-1)). PAs, particularly the most astringent PA polymer, were also adsorbed on the epithelial cells. These results suggest that PA dimers and trimers could be absorbed in vivo and that polymer bioavailability is limited to the gut lumen.

Characterization of methylation site of monomethylflavan-3-ols by liquid chromatography/electrospray ionization tandem mass spectrometry.

Liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was used for the structural characterization and differentiation of four isomeric O-monomethylated catechins (on phenolic positions) by the analysis of the fragmentation behaviour of catechin. The catechin fragmentation routes were rationalized and it is shown that several diagnostic ions such as (1,3)A(+), (1,2)B(+), and (1,4)B(+) allow the unambiguous identification of the methylated ring. The precise position of the methyl group on each ring is determined by the difference in the relative intensities of the diagnostic ions. Isomeric O-methylepicatechins were also differentiated using this methodology.

Polymeric proanthocyanidins are catabolized by human colonic microflora into low-molecular-weight phenolic acids.

Polymeric proanthocyanidins are common constituents of many foods and beverages. Their fate in the human body remains largely unknown. Their metabolism by human colonic microflora incubated in vitro in anoxic conditions has been investigated using nonlabeled and (14)C-labeled purified proanthocyanidin polymers. Polymers were almost totally degraded after 48 h of incubation. Phenylacetic, phenylpropionic and phenylvaleric acids, monohydroxylated mainly in the meta or para position, were identified as metabolites by gas chromatography coupled to mass spectrometry (GC-MS). Yields were similar to those previously reported for flavonoid monomers. These results provide the first evidence of degradation of dietary phenolic polymers into low-molecular-weight aromatic compounds. To understand the nutritional properties of proanthocyanidins, it is therefore essential to consider the biological properties of these metabolites.

Proanthocyanidins and human health: systemic effects and local effects in the gut.

Proanthocyanidins share common properties with other polyphenols, in particular their reducing capacity and ability to chelate metal ions. However, their polymeric nature clearly makes them different. They have a high affinity for proteins and their absorption through the gut barrier is likely limited to the molecules of low polymerization degree and to the metabolites formed by the colonic microflora, as suggested by in vitro experiments. The nutritional significance of proanthocyanidins is discussed in relation to their physico-chemical properties and bioavailability.

Carbon-14 biolabeling of (+)-catechin and proanthocyanidin oligomers in willow tree cuttings.

Proanthocyanidin polymers, oligomers, and the structurally related monomer (+)-catechin were labeled by incorporation of radioactive precursors in shoots of willow tree (Salix caprea L.). [1-(14)C]-Acetate and [U-(14)C]-phenylalanine precursors were fed through the cut stems or petioles of leaves. Optimization of several parameters such as the nature and origin of the plant material, leaf maturity, nature, and quantity of radioactive precursor applied and the duration of metabolism led to incorporation yields of 3.2% and to specific activities of 500 microCi/g. Detailed characterization of the products (polymerization degree, procyanidin/prodelphinidin ratio, specific activities) and purification by chromatography are reported. Some sugars bound to radiolabeled proanthocyanidin polymers were removed by enzymic treatment with a mixture of glycosidases. A radioactive purity close to 100% and specific activities suitable for bioavailability studies were obtained.

Epithelioid sarcoma of the vulva.

We report a case of a 23-year-old woman diagnosed as having an epithelioid sarcoma of the vulva. She was treated by a clitoris-sparing hemivulvectomy and lymph node sampling of the ipsilateral groin. Vulvar reconstruction was performed with a rectus abdominis myocutaneous flap. Four years after the operation there is no evidence of disease and the patient has a normal sex life. The English literature on this subject is reviewed with special attention to the biological behavior and therapeutic approach.

Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features.

We report on 22 patients with myelodysplastic syndrome (MDS), all of whom showed striking marrow fibrosis. Variable blood counts, often with teardrop poikilocytosis and a leukoerythroblastic picture, were present at diagnosis. Visceral enlargement was detected in 17 patients with a distinct splenomegaly in seven cases. All cases demonstrated dysplasia in at least two cell lineages. No specific cytogenetic abnormality seems to characterize this group of patients. Southern blot analysis showed no breakpoint cluster region rearrangement as observed in classical chronic myeloid leukemia. Ferrokinetic studies revealed quantitatively deficient erythropoiesis in all except two cases and an abnormally high fraction of ineffective erythropoiesis in all. Splenic erythropoiesis was present in eight patients. The median survival was 18 months. At the time of this report, 12 patients had died. The causes of death were disease progression (7 patients) and infection (5 patients). One might speculate that the present series of cases represents a transition between MDS and myeloproliferative disease, thereby displaying characteristics of both groups of diseases.