Peter Kappert

Diffusion-weighted imaging of normal fibroglandular breast tissue: influence of microperfusion and fat suppression technique on the apparent diffusion coefficient.

The influence of microperfusion and fat suppression technique on the apparent diffusion coefficient (ADC) values obtained with diffusion weighted imaging (DWI) of normal fibroglandular breast tissue was investigated. Seven volunteers (14 breasts) were scanned using diffusion weighting factors (b values) up to 1600 s/mm2 and the four different fat suppression techniques: STIR, fat saturation, SPAIR, and Water Excitation. The relationship between the logarithmic DW attenuation curves and b was linear for b values up to 600 s/mm2 (R2 > 0.999). Small differences were noted between the ADC values obtained with the various fat suppression methods, especially at the higher b values. Water Excitation had the highest mean SNR, exceeding STIR (p = 0.03) though not significantly different from fat saturation and SPAIR. In conclusion, the ADC of fibroglandular breast tissue is not influenced by microperfusion and Water Excitation is recommended because it yielded the best SNR values. These factors may be crucial in the differentiation between benign and malignant lesions. Copyright

Rationale and design of the DIPAK 1 study: A randomized controlled clinical trial assessing the efficacy of lanreotide to halt disease progression in autosomal dominant polycystic kidney disease

BACKGROUND There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. STUDY DESIGN The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. SETTING & PARTICIPANTS We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. INTERVENTION Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. OUTCOMES Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. MEASUREMENTS Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. RESULTS Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts. LIMITATIONS The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. CONCLUSIONS The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD.

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

BACKGROUND A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS Limited sample size, no control group. CONCLUSIONS In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.

Decreased energy and phosphorylation status in the liver of lung cancer patients with weight loss.

BACKGROUND/AIMS Altered energy status has been reported in the liver of tumour-bearing animals, but data on energy status in humans are scarce. Therefore, bioenergetics in tumour-free liver of lung cancer patients were monitored using 31P magnetic resonance spectroscopy (MRS) with infusion of L-alanine as a gluconeogenic challenge. METHODS Twenty-one overnight-fasted lung cancer patients without liver metastases, with (CaWL) or without weight loss (CaWS), and 12 healthy control subjects (C) were studied. Hepatic energy status was monitored before and during an i.v. L-alanine infusion of 1.4-2.8 mmol/kg + 2.8 mmol x kg(-1) x h(-1) for 90 min by 31p MR spectroscopy. RESULTS Baseline levels of ATP in WL lung cancer patients, expressed relative to total MR-detectable phosphate, were reduced (CaWL, 9.5+/-0.9% vs. CaWS, 12.6+/-0.8% and C, 12.4+/-0.8%; p<0.05) and inversely correlated with the degree of weight loss in lung cancer patients (r=-0.46, p=0.03). Pi/ATP ratios were increased (p<0.05), indicating reduced liver phosphorylation status. During L-alanine infusion, ATP levels decreased in all groups (p<0.05); in CaWL, ATP levels were lower at all time-points between 0-90 min as compared to both CaWS and C (p<0.05). Pi/ATP ratios were significantly higher after 70-90 min of L-alanine infusion in CaWL compared to CaWS and C (p<0.05). CONCLUSIONS Hepatic ATP and phosphorylation status are reduced in WL lung cancer patients, in contrast to WS patients and healthy subjects, and continue to decrease during infusion of a gluconeogenic substrate, suggesting impaired energy regenerating capacity in these patients.

Determination of Choline Concentration in Breast Lesions: Quantitative Multivoxel Proton MR Spectroscopy as a Promising Noninvasive Assessment Tool to Exclude Benign Lesions

PURPOSE To determine the optimal cutoff of choline (Cho) concentration in quantitative multivoxel magnetic resonance (MR) spectroscopic data to safely prove benignancy in breast lesions. MATERIALS AND METHODS The study was institutional review board approved, and informed consent was obtained from each patient. Between July 2009 and July 2010, multivoxel MR spectroscopy was performed in 24 consecutive patients with 25 breast lesions assessed as Breast Imaging Reporting and Data System 3 or 4 and larger than 1 cm in diameter at mammography. Two-dimensional point-resolved spatially localized spectroscopy chemical shift imaging was first performed without signal suppression (repetition time msec/echo time msec, 1500/30) as reference measurement and was performed subsequently with suppression of water and fat signals (1500/135) to detect Cho. Differences in mean and highest Cho concentration in the breast lesions were tested for significance by using the independent sample t test. The final diagnosis was confirmed with pathologic findings. RESULTS Fourteen of 25 breast lesions were malignant. The mean Cho concentration varied between 0.3 and 1.3 mmol/L (0.84 mmol/L ± 0.32 [standard deviation]) in benign lesions and between 1.3 and 9.5 mmol/L (3.10 mmol/L ± 2.21) in malignant lesions. The highest Cho concentrations in benign and malignant lesions were 0.4-1.5 mmol/L (1.19 mmol/L ± 0.33) and 1.7-11.8 mmol/L (4.08 mmol/L ± 2.81), respectively. Mean and highest Cho concentrations in benign and malignant breast lesions differed significantly (P = .02 for both). CONCLUSION The study, in a relatively small patient population, shows that quantitative multivoxel MR spectroscopy can be applied to exclude benign breast lesions from further invasive diagnostic work-up with the implementation of a Cho concentration of 1.5 mmol/L or lower as a cutoff. Further larger studies will be needed to confirm these results.

Detection of lymph node metastases with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging in oesophageal cancer : a feasibility study

Abstract Aim: In this feasibility study we investigated whether magnetic resonance imaging (MRI) with ultrasmall superparamagnetic iron oxide (USPIO) can be used to identify regional and distant lymph nodes, including mediastinal and celiac lymph node metastases in patients with oesophageal cancer. Patients and methods: Ten patients with a potentially curative resectable cancer of the oesophagus were eligible for this study. All patients included in the study had positive lymph nodes on conventional staging (including endoscopic ultrasound, computed tomography and fluorodeoxyglucose-positron emission tomography). Nine patients underwent MRI + USPIO before surgery. Results were restricted to those patients who had both MRI + USPIO and histological examination. Results were compared with conventional staging and histopathologic findings. Results: One patient was excluded due to expired study time. Five out of 9 patients underwent an exploration; in 1 patient prior to surgery MRI + USPIO diagnosed liver metastases and in 3 patients an oesophageal resection was performed. USPIO uptake in mediastinal lymph nodes was seen in 6 out of 9 patients; in 3 patients non-malignant nodes were not visible. In total, 9 lymph node stations (of 6 patients) were separately analysed; 7 lymph node stations were assessed as positive (N1) on MRI+USPIO compared with 9 by conventional staging. According to histology findings, there was one false-positive and one false-negative result in MRI + USPIO. Also, conventional staging modalities had one false-positive and one false-negative result. MRI + USPIO had surplus value in one patient. Not all lymph node stations could be compared due to unforeseen explorations. No adverse effects occurred after USPIO infusion. Conclusion: MRI+USPIO identified the majority of mediastinal and celiac (suspect) lymph nodes in 9 patients with oesophageal cancer. MRI+USPIO could have an additional value in loco-regional staging; however, more supplementary research is needed.

Non-invasive liver iron concentration measurement by MRI : Comparison of two validated protocols

In the non-invasive determination of the liver iron concentration several validated MRI methods are available, two of which are compared in this study. Twenty-eight patients were examined by MRI and evaluated by the methods of Kreeftenberg et al. [Kreeftenberg Jr HG, Mooyaart EL, Huizenga JR, Sluiter WJ, Kreeftenberg Sr HG. Quantification of liver iron concentration with magnetic resonance imaging by combining T1-, T2-weighted spin echo sequences and a gradient echo sequence. Neth J Med 2000;56:133-7] and Gandon et al. [Gandon Y, Olivie D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004;363:357-62]. It is concluded that the latter shows a better inter- and intra-observer correlation and is more accurate because of the automated preselection of one of five sequences most sensitive in the estimated liver iron concentration range. In the Kreeftenberg method combining the results of three suboptimal sequences, leads to underestimation of the liver iron concentration.

Quantitative multivoxel proton chemical shift imaging of the breast

The study of focal pathology by single-voxel magnetic resonance spectroscopy (MRS) is hampered by the impossibility to study tissue heterogeneity or compare the metabolite signals in breast lesion directly to those in unaffected tissue. Multivoxel MRS studies, while potentially allowing for truly quantitative tissue characterization, have up to now also been far from quantitative with, for example, the signal-to-noise ratio of the choline (Cho) signal serving as measure of tumor activity. Shown in this study is that in a standard clinical setting with a regular 1.5-T magnetic resonance scanner, it is possible to perform quantitative multivoxel MRS. With the use of literature values for the T1 and T2 relaxation times of Cho and water in fibroglandular breast tissue and tumors, one can determine the concentrations of Cho in different tumor compartments and surrounding tissues in two brief multivoxel MRS measurements. This opens excellent perspectives to quantitative diagnostic and follow-up studies of focal pathology such as lesions suspected of breast cancer.

Assessment of the link between quantitative biexponential diffusion-weighted imaging and contrast-enhanced MRI in the liver

PURPOSE To investigate if intravoxel incoherent motion (IVIM) modeled diffusion-weighted imaging (DWI) can be linked to contrast-enhanced (CE-)MRI in liver parenchyma and liver lesions. METHODS Twenty-five patients underwent IVIM-DWI followed by multiphase CE-MRI using Gd-EOB-DTPA (n=20) or Gd-DOTA (n=5) concluded with IVIM-DWI. Diffusion (Dslow), microperfusion (Dfast), its fraction (ffast), wash-in-rate (Rearly) and late-enhancement-rate (Rlate) of Gd-EOB-DTPA were calculated voxel-wise for the liver. Parenchyma and lesions were segmented. Pre-contrast IVIM was compared 1) between low, medium and high Rearly for parenchyma 2) to post-contrast IVIM substantiated with simulations 3) between low and high Rlate per lesion type. RESULTS Dfast and ffast increased (P<0.001) with 25.6% and 33.8% between low and high Rearly of Gd-EOB-DTPA. Dslow decreased (-15.0%; P<0.001) with increasing Rearly. Gd-DOTA demonstrated similar observations. ffast (+10%; P<0.001) and Dfast (+6.6%; P<0.001) increased after Gd-EOB-DTPA, while decreasing after Gd-DOTA (-4.2% and -5.7%, P<0.001) and were confirmed by simulations. For focal nodular hyperplasia lesions (n=5) Dfast and ffast increased (P<0.001) with increasing Rlate, whereas for hepatocellular carcinoma (n=4) and adenoma (n=7) no differences were found. CONCLUSION Microperfusion measured by IVIM reflects perfusion in a way resembling CE-MRI. Also IVIM separated intra- and extracellular MR contrast media. This underlines the potential of IVIM in quantitative liver imaging.

Clinical Implications of Non-Steatotic Hepatic Fat Fractions on Quantitative Diffusion-Weighted Imaging of the Liver

Diffusion-weighted imaging (DWI) is an important diagnostic tool in the assessment of focal liver lesions and diffuse liver diseases such as cirrhosis and fibrosis. Quantitative DWI parameters such as molecular diffusion, microperfusion and their fractions, are known to be affected when hepatic fat fractions (HFF) are higher than 5.5% (steatosis). However, less is known about the effect on DWI for HFF in the normal non-steatotic range below 5.5%, which can be found in a large part of the population. The aim of this study was therefore to evaluate the diagnostic implications of non-steatotic HFF on quantitative DWI parameters in eight liver segments. For this purpose, eleven healthy volunteers (2 men, mean-age 31.0) were prospectively examined with DWI and three series of in-/out-of-phase dual-echo spoiled gradient-recalled MRI sequences to obtain the HFF and T2*. DWI data were analyzed using the intravoxel incoherent motion (IVIM) model. Four circular regions (ø22.3 mm) were drawn in each of eight liver segments and averaged. Measurements were divided in group 1 (HFF≤2.75%), group 2 (2.75< HFF ≤5.5%) and group 3 (HFF>5.5%). DWI parameters and T2* were compared between the three groups and between the segments. It was observed that the molecular diffusion (0.85, 0.72 and 0.49 ×10−3 mm2/s) and T2* (32.2, 27.2 and 21.0 ms) differed significantly between the three groups of increasing HFF (2.18, 3.50 and 19.91%). Microperfusion and its fraction remained similar for different HFF. Correlations with HFF were observed for the molecular diffusion (r = −0.514, p<0.001) and T2* (−0.714, p<0.001). Similar results were obtained for the majority of individual liver segments. It was concluded that fat significantly decreases molecular diffusion in the liver, also in absence of steatosis (HFF≤5.5%). Also, it was confirmed that fat influences T2*. Determination of HFF prior to quantitative DWI is therefore crucial.