Diffusion-weighted MR imaging including bi-exponential fitting for the detection of recurrent or residual tumour after (chemo)radiotherapy for laryngeal and hypopharyngeal cancers

Objectives: To assess whether diffusion-weighted magnetic resonance imaging (DW-MRI) including bi-exponential fitting helps to detect residual/recurrent tumours after (chemo)radiotherapy of laryngeal and hypopharyngeal carcinoma. Methods: Forty-six patients with newly-developed/worsening symptoms after (chemo)radiotherapy for laryngeal/hypopharyngeal cancers were prospectively imaged using conventional MRI and axial DW-MRI. Qualitative (visual assessment) and quantitative analysis (mono-exponentially: total apparent diffusion coefficient [ADCT], and bi-exponentially: perfusion fraction [FP] and true diffusion coefficient [ADCD]) were performed. Diffusion parameters of tumour versus post-therapeutic changes were compared, with final diagnosis based on histopathology and follow-up. Mann-Whitney U test was used for statistical analysis. Results: Qualitative DW-MRI combined with morphological images allowed the detection of tumour with a sensitivity of 94% and specificity 100%. ADCT and ADCD values were lower in tumour with values 120 ± 49 × 10−5mm2/s and 113 ± 50 × 10−5mm2/s, respectively, compared with post-therapeutic changes with values 182 ± 41 × 10−5mm2/s (P < 0.0002) and 160 ± 47 × 10−5mm2/s (P < 0.003), respectively. FP values were significantly lower in tumours than in non-tumours (13 ± 9% versus 31 ± 16%, P < 0.0002), with FP being the best quantitative parameter for differentiation between post-therapeutic changes and recurrence. Conclusions: DW-MRI in combination with conventional MRI substantially improves detection and exclusion of tumour in patients with laryngeal and hypopharyngeal cancers after treatment with (chemo)radiotherapy on both qualitative and quantitative analysis, with FP being the best quantitative parameter in this context. Key Points : • DW-MRI is increasingly used to detect tumour recurrence. • DW-MRI allows accurate post-treatment recurrence detection in laryngeal or hypopharyngeal cancer • ADC values in recurrent tumour are lower than in benign tissue alterations • Both qualitative and quantitative DW-MRI approaches allow detection of recurrence • DW-MRI can easily be added to daily clinical routine imagin

Influence of Immunosuppressive Regimen on Diffusivity and Oxygenation of Kidney Transplants-Analysis of Functional MRI Data from the Randomized ZEUS Trial.

The ZEUS study was a multi-center randomized controlled trial investigating the effect of early conversion from a ciclosporin-based to an everolimus-based regimen on graft function twelve months post-transplantation. In this investigator-initiated sub-study, functional magnetic resonance imaging (fMRI) of kidney grafts was prospectively performed to non-invasively assess differences in graft oxygenation, diffusion and perfusion between groups and time-points using diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD)-MRI. Sixteen patients underwent DWI and BOLD-MRI at months 4.5 and 12 post-transplantation on a 3 Tesla and 1.5 Tesla (n = 3) MR scanner. After exclusion due to image quality, outlier values or missing data, DWI was analyzed for ten subjects; BOLD for eight subjects. The diffusion coefficient ADCD decreased in the CsA-treated group over time, whereas it increased in the EVE group (p = 0.046, medulla). The change in ADCD from months 4.5 to 12 significantly differed between groups in the cortex (p = 0.033) and medulla (p = 0.019). In BOLD, cortico-medullary transverse relaxation rate R2* increased (decreased tissue oxygen) in the CsA-treated and decreased in EVE-treated groups over time. Similarly, R2* values at month 12 were higher in the CsA-treated group compared to the EVE-treated group. There was no significant difference for the perfusion fraction FP. In conclusion, this prospective sub-study of the ZEUS trial suggests an impact of immunosuppressive regimen on fMRI parameters of the kidney graft

Differentiation of prostate cancer lesions with high and with low Gleason score by diffusion-weighted MRI.

OBJECTIVES To differentiate prostate cancer lesions with high and with low Gleason score by diffusion-weighted-MRI (DW-MRI). METHODS This prospective study was approved by the responsible ethics committee. DW-MRI of 84 consenting prostate and/or bladder cancer patients scheduled for radical prostatectomy were acquired and used to compute apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM: the pure diffusion coefficient D t, the pseudo-diffusion fraction F p and the pseudo-diffusion coefficient D p), and high b value (as acquired and Hessian filtered) parameters within the index lesion. These parameters (separately and combined in a logistic regression model) were used to differentiate lesions depending on whether whole-prostate histopathological analysis after prostatectomy determined a high (≥7) or low (6) Gleason score. RESULTS Mean ADC and D t differed significantly (p of independent two-sample t test < 0.01) between high- and low-grade lesions. The highest classification accuracy was achieved by the mean ADC (AUC 0.74) and D t (AUC 0.70). A logistic regression model based on mean ADC, mean F p and mean high b value image led to an AUC of 0.74 following leave-one-out cross-validation. CONCLUSIONS Classification by IVIM parameters was not superior to classification by ADC. DW-MRI parameters correlated with Gleason score but did not provide sufficient information to classify individual patients. KEY POINTS • Mean ADC and diffusion coefficient differ between high- and low-grade prostatic lesions. • Accuracy of trivariate logistic regression is not superior to using ADC alone. • DW-MRI is not a valid substitute for biopsies in clinical routine yet

Determination of Intra- and Extracellular Metabolic Adaptations of 3D Cell Cultures upon Challenges in Real-Time by NMR.

NMR flow devices provide longitudinal real-time quantitative metabolome characterisation of living cells. However, discrimination of intra- and extracellular contributions to the spectra represents a major challenge in metabolomic NMR studies. The present NMR study demonstrates the possibility to quantitatively measure both metabolic intracellular fingerprints and extracellular footprints on human control fibroblasts by using a commercially available flow tube system with a standard 5 mm NMR probe. We performed a comprehensive 3D cell culture system characterisation. Diffusion NMR was employed for intra- and extracellular metabolites separation. In addition, complementary extracellular footprints were determined. The implemented perfused NMR bioreactor system allowed the determination of 35 metabolites and intra- and extracellular separation of 19 metabolites based on diffusion rate differences. We show the reliability and sensitivity of NMR diffusion measurements to detect metabolite concentration changes in both intra- and extracellular compartments during perfusion with different selective culture media, and upon complex I inhibition with rotenone. We also demonstrate the sensitivity of extracellular footprints to determine metabolic variations at different flow rates. The current method is of potential use for the metabolomic characterisation of defect fibroblasts and for improving physiological comprehension

Evaluation of renal allograft function early after transplantation with diffusion-weighted MR imaging

Aims: To determine the inter-patient variability of apparent diffusion coefficients (ADC) and concurrent micro-circulation contributions from diffusion-weighted MR imaging (DW-MRI) in renal allografts early after transplantation, and to obtain initial information on whether these measures are altered in histologically proven acute allograft rejection (AR). Methods: DW-MRI was performed in 15 renal allograft recipients 5-19days after transplantation. Four patients presented with AR and one with acute tubular necrosis (ATN). Total ADC (ADCT) was determined, which includes diffusion and micro-circulation contributions. Furthermore, diffusion and micro-circulation contributions were separated, yielding the "perfusion fraction” (FP), and "perfusion-free” diffusion (ADCD). Results: Diffusion parameters in the ten allografts with stable function early after transplantation demonstrated low variabilities. Values for ADCT and ADCD were (×10−5mm2/s) 228 ± 14 and 203 ± 9, respectively, in cortex and 226 ± 16 and 199 ± 9, respectively, in medulla. FP values were 18 ± 5% in cortex and 19 ± 5% in medulla. FP values were strongly reduced to less than 12% in cortex and medulla of renal transplants with AR and ATN. FP values correlated with creatinine clearance. Conclusion: DW-MRI allows reliable determination of diffusion and micro-circulation contributions in renal allografts shortly after transplantation; deviations in AR indicate potential clinical utility of this method to non-invasively monitor derangements in renal allograft

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction.

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology

Combined transcriptome and metabolome analyses of metformin effects reveal novel links between metabolic networks in steroidogenic systems.

Metformin is an antidiabetic drug, which inhibits mitochondrial respiratory-chain-complex I and thereby seems to affect the cellular metabolism in many ways. It is also used for the treatment of the polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. In addition, metformin possesses antineoplastic properties. Although metformin promotes insulin-sensitivity and ameliorates reproductive abnormalities in PCOS, its exact mechanisms of action remain elusive. Therefore, we studied the transcriptome and the metabolome of metformin in human adrenal H295R cells. Microarray analysis revealed changes in 693 genes after metformin treatment. Using high resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS-NMR), we determined 38 intracellular metabolites. With bioinformatic tools we created an integrated pathway analysis to understand different intracellular processes targeted by metformin. Combined metabolomics and transcriptomics data analysis showed that metformin affects a broad range of cellular processes centered on the mitochondrium. Data confirmed several known effects of metformin on glucose and androgen metabolism, which had been identified in clinical and basic studies previously. But more importantly, novel links between the energy metabolism, sex steroid biosynthesis, the cell cycle and the immune system were identified. These omics studies shed light on a complex interplay between metabolic pathways in steroidogenic systems