•5 patients with pelvic lymph node metastases received SBRT using a 1.5 T MR-linac.•Session time was <60 min for all 25 treatment fractions.•All quality assurance tests were passed (dose calculations ...& film measurements).
Online adaptive radiotherapy using the 1.5 Tesla MR-linac is feasible for SBRT (5 × 7 Gy) of pelvic lymph node oligometastases. The workflow allows full online planning based on daily anatomy. Session duration is less than 60 min. Quality assurance tests, including independent 3D dose calculations and film measurements were passed.
Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B ...evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably.
Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3
, CD4
, CD8
, CD20
, CD68
, FOXP3
) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures.
The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infiltrates were highly variable (r = 0.01-0.56). Similar observations were made for cell type-specific quantifications (r = 0.001-0.54). We observed a strong inter-method variability between the omics-derived estimations, which is further cell type dependent. Finally, we demonstrated that most methods more accurately identify highly infiltrated (sTIL ≥ 60%; area under the curve, AUC, 0.64-0.99) as compared to lowly infiltrated tumors (sTIL ≤ 10%; AUC 0.52-0.82).
There is a lower inter-pathologist concordance for cell-specific quantification as compared to overall infiltration quantification. Microscopic assessments are underestimated when considering small cores (tissue microarray) instead of whole slides. Results further highlight considerable differences between the microscopic-, transcriptomic-, and methylomic-based methods in the assessment of overall and cell-specific immune infiltration in BC. We therefore call for extreme caution when assessing immune infiltrates using current methods and emphasize the need for standardized immune characterization beyond TIL.
Since numerous miRNAs have been shown to be present in circulation, these so-called circulating miRNAs have emerged as potential biomarkers for disease. However, results of qPCR studies on ...circulating miRNA biomarkers vary greatly and many experiments cannot be reproduced. Missing data in qPCR experiments often occur due to off-target amplification, nonanalyzable qPCR curves and discordance between replicates. The low concentration of most miRNAs leads to most, but not all missing data. Therefore, failure to distinguish between missing data due to a low concentration and missing data due to randomly occurring technical errors partly explains the variation within and between otherwise similar studies. Based on qPCR kinetics, an analysis pipeline was developed to distinguish missing data due to technical errors from missing data due to a low concentration of the miRNA-equivalent cDNA in the PCR reaction. Furthermore, this pipeline incorporates a method to statistically decide whether concentrations from replicates are sufficiently concordant, which improves stability of results and avoids unnecessary data loss. By going through the pipeline's steps, the result of each measurement is categorized as "valid, invalid, or undetectable." Together with a set of imputation rules, the pipeline leads to more robust and reproducible data as was confirmed experimentally. Using two validation approaches, in two cohorts totaling 2214 heart failure patients, we showed that this pipeline increases both the accuracy and precision of qPCR measurements. In conclusion, this statistical data handling pipeline improves the performance of qPCR studies on low-expressed targets such as circulating miRNAs.
The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging ...(MRI) with that of mammography for screening in this group of high-risk women.
Women who had a cumulative lifetime risk of breast cancer of 15 percent or more were screened every six months with a clinical breast examination and once a year by mammography and MRI, with independent readings. The characteristics of the cancers that were detected were compared with the characteristics of those in two different age-matched control groups.
We screened 1909 eligible women, including 358 carriers of germ-line mutations. Within a median follow-up period of 2.9 years, 51 tumors (44 invasive cancers, 6 ductal carcinomas in situ, and 1 lymphoma) and 1 lobular carcinoma in situ were detected. The sensitivity of clinical breast examination, mammography, and MRI for detecting invasive breast cancer was 17.9 percent, 33.3 percent, and 79.5 percent, respectively, and the specificity was 98.1 percent, 95.0 percent, and 89.8 percent, respectively. The overall discriminating capacity of MRI was significantly better than that of mammography (P<0.05). The proportion of invasive tumors that were 10 mm or less in diameter was significantly greater in our surveillance group (43.2 percent) than in either control group (14.0 percent P<0.001 and 12.5 percent P=0.04, respectively). The combined incidence of positive axillary nodes and micrometastases in invasive cancers in our study was 21.4 percent, as compared with 52.4 percent (P<0.001) and 56.4 percent (P=0.001) in the two control groups.
MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.
This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), ...treated with induction systemic therapy followed by complete local treatment.
Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center.
In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008).
Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS.
•Tumor total volume (TTV) is prognostic for survival outcomes in patients with CRLM.•5-year survival is 72 % for baseline of TTV 3 mL, 7 % for a baseline TTV of 300 mL.•Change in TTV after systemic therapy is associated with survival, RECIST1.1 is not.•TTV may guide individualized therapeutic decision making in patients with CRLM.
Purpose
To develop and implement an acceptance procedure for the new Elekta Unity 1.5 T MRI‐linac.
Methods
Tests were adopted and, where necessary adapted, from AAPM TG106 and TG142, IEC 60976 and ...NCS 9 and NCS 22 guidelines. Adaptations were necessary because of the atypical maximum field size (57.4 × 22 cm), FFF beam, the non‐rotating collimator, the absence of a light field, the presence of the 1.5 T magnetic field, restricted access to equipment within the bore, fixed vertical and lateral table position, and the need for MR image to MV treatment alignment. The performance specifications were set for stereotactic body radiotherapy (SBRT).
Results
The new procedure was performed similarly to that of a conventional kilovoltage x‐ray (kV) image guided radiation therapy (IGRT) linac. Results were acquired for the first Unity system.
Conclusions
A comprehensive set of tests was developed, described and implemented for the MRI‐linac. The MRI‐linac met safety requirements for patients and operators. The system delivered radiation very accurately with, for example a gantry rotation locus of isocenter of radius 0.38 mm and an average MLC absolute positional error of 0.29 mm, consistent with use for SBRT. Specifications for clinical introduction were met.
The lack of radiation-attenuating tuning capacitors in high impedance coils (HICs) make HICs an interesting building block of receive arrays for MRI-guided radiotherapy (MRIgRT). Additionally, their ...flexibility and limited channel coupling allow for low-density support materials, which are likely to be more radiation transparent (radiolucent). In this work, we introduce the use of HICs in receive arrays for MRIgRT treatments. We discuss the design and show the dosimetric feasibility of a HIC receive array that has a high channel count and aims to improve the imaging performance of the 1.5 T MR-linac. Our on-body design comprises an anterior and posterior element, which each feature a channel layout (32 channels total). The anterior element is flexible, while the posterior element is rigid to support the patient. Mockups consisting of support materials and conductors were built, irradiated, and optimized to minimize impact on the surface dose (7% of the dose maximum) and dose at depth (0.8% under a single conductor and 1.4% under a conductor crossing). Anatomical motion and the use of multiple beam angles will ensure that these slight dose changes at depth are clinically insignificant. Subsequently, several functional, single-channel HIC imaging prototypes and a 5-channel array were built to assess the performance in terms of signal-to-noise ratio (SNR). The performance was compared to the clinical MR-linac array and showed that the 5-channel imaging prototype outperformed the clinical array in terms of SNR and channel coupling. Imaging performance was not affected by the radiation beam. In conclusion, the use of HICs allowed for the design of our flexible, on-body receive array for MRIgRT. The design was shown to be dosimetrically feasible and improved the SNR. Future research with a full array will need to show the gain in parallel imaging performance and thus acceleration.
Live donor kidneys with multiple arteries are associated with surgical complexity for removal and increased rate of recipient ureteral complications. We evaluated the outcome of vascular imaging and ...the clinical consequences of multiple arteries and veins.
From 2001 to 2005 data of 288 live kidney donations and transplantations were prospectively collected. Vascular anatomy at operation was compared with vascular anatomy as imaged by magnetic resonance imaging (MRI) or subtraction angiography, and consequences of multiple vessels were investigated.
Simple renal anatomy with a solitary artery and vein was present in 208 (72%) kidneys. Sixty (21%) transplants had multiple arteries. Thirty (10%) transplants had multiple veins. Magnetic resonance imaging failed to predict arterial anatomy in 23 of 220 donors (10%) compared with 3 of 101 (3%) after angiography. The presence of multiple veins did not influence outcomes after nephrectomy in general. Multiple arteries did not affect clinical outcomes in open donor nephrectomy (n=103). In laparoscopic donor nephrectomy (n=185) multiple arteries were associated with longer operation times (245 vs. 221 min, P=0.023) and increased blood loss (225 vs. 220 mL, P=0.029). In general, neither multiple arteries nor vascular reconstructions influenced recipient creatinine clearance or ureteral complication rate. However, accessory arteries to the lower pole correlated with an increased rate of ureteral complications (47% vs. 14%, P=0.01).
Multiple arteries may increase operation time. Accessory lower pole arteries are associated with a higher rate of recipient ureteral complications indicating the importance of arterial imaging. Currently, both magnetic resonance imaging and angiography provide suboptimal information on renal vascular anatomy.
To study the regenerative capacity of the endothelium in patients with coronary artery disease (CAD), we cultured blood outgrowth endothelial cells (BOECs) of patients with premature CAD and their ...first degree relatives (FDR). Additionally we evaluated the influence of statin treatment on circulating BOEC precursors in subjects with subclinical atherosclerosis.
Patients with premature CAD (men <51 yr, women <56 yr) and their FDRs were included. Based on coronary calcification (CAC) scores FDRs were divided in a group of healthy subjects (CAC = 0) and subjects with subclinical atherosclerosis (CAC>0). We did not observe differences in the number of BOEC colonies and proliferation between premature CAD patients and FDRs. FDRs with subclinical atherosclerosis had lower colony numbers compared with healthy FDRs, however this was not statistically significant, and BOEC proliferation was significantly impaired (OR = 0.45, 95% CI 0.21-0.96). Unexpectedly, the number of BOEC colonies and BOEC proliferation were similar for premature CAD patients and healthy FDRs. Since a considerable number of premature CAD patients used statins, we studied the number of BOEC precursors as well as their proliferative capacity in ten individuals with subclinical atherosclerosis, before and after statin therapy. Interestingly, FDRs with subclinical atherosclerosis showed a significant increase in the number of BOEC colonies after statin therapy.
BOEC proliferation of subjects with subclinical atherosclerosis is impaired compared with healthy controls. In these subjects, statin therapy significantly increased the number of circulating BOEC precursors as well as their proliferative capacity, revealing a beneficial effect of statins on endothelial regeneration.
Abstract Background and aims The risk of developing cardiovascular disease (CVD) is twice as high among smoking individuals compared to non-smokers. Monocytes are involved in smoking-related ...atherosclerotic plaque formation. In this study, we investigated whether smokers with an increased risk of developing CVD can be identified on the basis of monocyte-derived miRNA expression levels. Methods We performed a miRNA microarray experiment on isolated monocytes from smoking, former smoking and non-smoking individuals in a cohort of patients with premature CVD and healthy controls (Cohort I, n = 76). Results We found miR-124-3p to be heterogeneously expressed among all smoking individuals, whereas expression was low in non-smokers. Subsequently, RT-qPCR measurements on whole blood showed that among smoking individuals an increase in miR-124-3p is associated with an increased risk for advanced atherosclerotic disease (cohort II, n = 24) (OR 11.72 95% CI 1.09–126.53) and subclinical atherosclerosis (coronary artery calcium score ≥ 80th percentile, cohort III n = 138) (OR 2.71, 95% CI 1.05–7.01). This was not observed among former smokers or non-smoking individuals. Flow cytometric analysis demonstrated that high miR-124-3p expression was associated with upregulation of the monocyte surface markers CD45RA, CD29 and CD206, indicating an altered monocyte phenotype. Finally, overexpression of miR-124-3p resulted in an upregulation of CD206 surface expression on monocytes. Conclusions High miR-124-3p expression is associated with an increased risk of subclinical atherosclerosis in smoking individuals and with an altered monocyte phenotype. This may suggest that miR-124-3p identifies which smoking individuals are susceptible for the atherogenic effects of smoking.
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