Longitudinal correlations between intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced (DCE) MRI during radiotherapy in prostate cancer patients

Purpose: Intravoxel incoherent motion (IVIM) is a promising technique that can acquire perfusion information without the use of contrast agent, contrary to the more established dynamic contrast-enhanced (DCE) technique. This is of interest for treatment response monitoring, where patients can be imaged on each treatment fraction. In this study, longitudinal correlations between IVIM- and DCE parameters were assessed in prostate cancer patients receiving radiation treatment.Materials and Methods: 20 prostate cancer patients were treated on a 1.5 T MR-linac with 20 x 3 or 3.1 Gy. Weekly IVIM and DCE scans were acquired. Tumors, the peripheral zone (PZ), and the transition zone (TZ) were delineated on a T2-weighted scan acquired on the first fraction. IVIM and DCE scans were registered to this scan and the delineations were propagated. Median values from these delineations were used for further analysis. The IVIM parameters D, f, D* and the product fD* were calculated. The Tofts model was used to calculate the DCE parameters Ktrans, kep and ve. Pearson correlations were calculated for the IVIM and DCE parameters on values from the first fraction for each region of interest (ROI). For longitudinal analysis, the repeated measures correlation coefficient was used to determine correlations between IVIM and DCE parameters in each ROI.Results: When averaging over patients, an increase during treatment in all IVIM and DCE parameters was observed in all ROIs, except for D in the PZ and TZ. No significant Pearson correlations were found between any pair of IVIM and DCE parameters measured on the first fraction. Significant but low longitudinal correlations were found for some combinations of IVIM and DCE parameters in the PZ and TZ, while no significant longitudinal correlations were found in the tumor. Notably in the TZ, for both f and fD*, significant longitudinal correlations with all DCE parameters were found.Conclusions: The increase in IVIM- and DCE parameters when averaging over patients indicates a measurable response to radiation treatment with both techniques. Although low, significant longitudinal correlations were found which suggests that IVIM could potentially be used as an alternative to DCE for treatment response monitoring.</p

Daily Intravoxel Incoherent Motion (IVIM) in prostate cancer patients during MR-guided radiotherapy: a multicenter study

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

ADC measurements on the Unity MR-linac - A recommendation on behalf of the Elekta Unity MR-linac consortium

Background and purpose: Diffusion-weighted imaging (DWI) for treatment response monitoring is feasibleon hybrid magnetic resonance linear accelerator (MR-linac) systems. The MRI scanner of the ElektaUnity system has an adjusted design compared to diagnostic scanners. We investigated its impact onmeasuring the DWI-derived apparent diffusion coefficient (ADC) regarding three aspects: the choice ofb-values, the spatial variation of the ADC, and scanning during radiation treatment. The aim of this studyis to give recommendations for accurate ADC measurements on Unity systems.Materials and methods: Signal-to-noise ratio (SNR) measurements with increasing b-values were done todetermine the highest bvalue that can be measured reliably. The spatial variation of the ADC wasassessed on six Unity systems with a cylindrical phantom of 40 cm diameter. The influence of gantry rotationand irradiation was investigated by acquiring DWI images before and during treatment of 11 prostatecancer patients.Results: On the Unity system, a maximum b-value of 500 s/mm2 should be used for ADC quantification, asa trade-off between SNR and diffusion weighting. Accurate ADC values were obtained within 7 cm fromthe iso-center, while outside this region ADC values deviated more than 5%. The ADC was not influencedby the rotating linac or irradiation during treatment.Conclusion: We provide Unity system specific recommendations for measuring the ADC. This willincrease the consistency of ADC values acquired in different centers on the Unity system, enabling largecohort studies for biomarker discovery and treatment response monitoring.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

PORTEC-4a: International randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer

Background Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with highintermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics. Primary objectives To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecularintegrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy Study hypothesis Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant t

Molecular pathogenesis of serous Fallopian tube and ovarian carcinoma

Serous type Fallopian tube carcinoma (FTC) and ovarian carcinoma (OVCA) are gynaecological malignancies with a poor prognosis. Although most of the encountered tumours are sporadic, a positive family history is an important risk factor. Both tumour types have been linked to mutations in the BRCA1 and BRCA2 genes and share several cellular, molecular and clinical features. However, a detailed and unbiased comparison at the molecular level had been lacking. In this thesis the molecular pathogenesis of serous FTC and serous OVCA was further studied. After an introduction in Chapter 1, we describe a genome-wide array comparative genomic hybridization (array CGH) study of 14 serous FTCs (Chapter 2). All FTCs showed a high frequency of copy number aberrations, while these were remarkably homogeneous. Recurrent regions of amplification suggested known oncogenes MYC, CCNE1 and AKT2 to be driver genes. In Chapter 3 we describe the immunohistochemical analysis of p53, HER-2/neu and p27Kip1 on 28 serous FTCs and we correlated expression levels with DNA copy number. The studies suggested that p53 accumulation and p27Kip1 down-regulation are early events, whereas HER-2/neu overexpression may be involved in progression. Furthermore, overexpression of HER-2/neu may be caused partly by amplification. In Chapter 4 we were the first to report on a direct comparison with array CGH of serous FTCs and OVCAs. The analysis suggested that these display (quantitative) differences in their genomic profiles, besides shared features. Multiplex ligation-dependent probe amplification (MLPA) directly identified EIF2C2 as a new possible driver gene. Gains/amplifications of CCNE1 and MYC, often in conjunction with changes of EVI1 and PTK2, seemed to be common in earlier stages, whereas changes of HER2 were associated with advanced stages (see Chapter 3). In Chapter 5 we report on the development of dedicated MLPA gain-probe-sets, specifically tailored at high-grade serous FTC and OVCA and primarily based on our previous array CGH (see Chapter 4). We identified, besides known genes PIK3CA, AKT2, FGFR1 and PDGFB, new putative genes MYCBP, LIMK1, SOCS1, SMARCA4, DPF1, BCL2L1, NCOA3, PTPN1, NFATC2 and KCNQ2. As an application, we performed logistic regression, resulting in a model that could discriminate 76% of the FTCs and 80% of the OVCAs on basis of 3 markers. Since serous endometrial carcinomas (ECs) share their aggressive clinical behaviour and their histological appearance with serous OVCA and FTC, it could be hypothesized that these serous cancers share common denominators. In Chapter 6, we examined 9 serous ECs with the same array as before and compared the profiles with those described in Chapter 4. We could show that serous ECs can be discriminated from serous OVCAs. In Chapter 7 the results of the studies are discussed. We conclude that despite their histomorphological and clinical resemblance, high-grade serous FTC and OVCA show differences in their genomic profiles, besides also shared features, and should be regarded as distinct entities. We have identified new candidate genes for carcinogenesis and validated certain known genes, which has resulted in a more detailed knowledge on the pathogenesis of this class of tumours

MRI basics for radiation oncologists

MRI is increasingly used in radiation oncology to facilitate tumor and organ-at-risk delineation and image guidance. In this review, we address issues of MRI that are relevant for radiation oncologists when interpreting MR images offered for radiotherapy. Whether MRI is used in combination with CT or in an MRI-only workflow, it is generally necessary to ensure that MR images are acquired in treatment position, using the positioning and fixation devices that are commonly applied in radiotherapy. For target delineation, often a series of separate image sets are used with distinct image contrasts, acquired within a single exam. MR images can suffer from image distortions. While this can be avoided with dedicated scan protocols, in a diagnostic setting geometrical fidelity is less relevant and is therefore less accounted for. Since geometrical fidelity is of utmost importance in radiation oncology, it requires dedicated scan protocols. The strong magnetic field of an MRI scanner and the use of radiofrequency radiation can cause safety hazards if not properly addressed. Safety screening is crucial for every patient and every operator prior to entering the MRI room. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Pre-treatment prediction of early response to chemoradiotherapy by quantitative analysis of baseline staging FDG-PET/CT and MRI in locally advanced cervical cancer

Background Early prediction of response to concurrent chemoradiotherapy (cCRT) could aid to further optimize treatment regimens for locally advanced cervical cancer (LACC) in the future. Purpose To explore whether quantitative parameters from baseline (pre-therapy) magnetic resonance imaging (MRI) and FDG-PET/computed tomography (CT) have potential as predictors of early response to cCRT. Material and Methods Forty-six patients with LACC undergoing cCRT after staging with FDG-PET/CT and MRI were retrospectively analyzed. Primary tumor volumes were delineated on FDG-PET/CT, T2-weighted (T2W)-MRI and diffusion-weighted MRI (DWI) to extract the following quantitative parameters: T2W volume; T2W signal(mean); DWI volume; ADC(mean); ADC(SD); MTV42%; and SUVmax. Outcome was the early treatment response, defined as the residual tumor volume on MRI 3-4 weeks after start of external beam radiotherapy with chemotherapy (before the start of brachytherapy): patients with a residual tumor volume <10 cm(3)were classified as early responders. Imaging parameters were analyzed together with FIGO stage to assess their performance to predict early response, using multivariable logistic regression analysis with bi-directional variable selection. Leave-one-out cross-validation with bootstrapping was used to simulate performance in a new, independent dataset. Results T2W volume (OR 0.94,P = 0.003) and SUVmax(OR 1.15,P = 0.18) were identified as independent predictors in multivariable analysis, rendering a model with an AUC of 0.82 in the original dataset, and AUC of 0.68 (95% CI 0.41-0.81) from cross-validation. Conclusion Although the predictive performance achieved in this small exploratory dataset was limited, these preliminary data suggest that parameters from baseline MRI and FDG-PET/CT (in particular pre-therapy tumor volume) may contribute to prediction of early response to cCRT in cervical cancer

Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma.

Fallopian tube carcinoma (FTC) is a rare, poorly studied and aggressive cancer, associated with poor survival. Since tumorigenesis is related to the acquisition of genetic changes, we used genome-wide array comparative genomic hybridization to analyse copy number aberrations occurring in FTC in order to obtain a better understanding of FTC carcinogenesis and to identify prognostic events and targets for therapy. We used arrays of 2464 genomic clones, providing approximately 1.4 Mb resolution across the genome to map genomic DNA copy number aberrations quantitatively from 14 FTC onto the human genome sequence. All tumors showed a high frequency of copy number aberrations with recurrent gains on 3q, 6p, 7q, 8q, 12p, 17q, 19 and 20q, and losses involving chromosomes 4, 5q, 8p, 16q, 17p, 18q and X. Recurrent regions of amplification included 1p34, 8p11-q11, 8q24, 12p, 17p13, 17q12-q21, 19p13, 19q12-q13 and 19q13. Candidate, known oncogenes mapping to these amplicons included CMYC (8q24), CCNE1 (19q12-q21) and AKT2 (19q13), whereas PIK3CA and KRAS, previously suggested to be candidate driver genes for amplification, mapped outside copy number maxima on 3q and 12p, respectively. The FTC were remarkably homogeneous, with some recurrent aberrations occurring in more than 70% of samples, which suggests a stereotyped pattern of tumor evolution

Applied Research In Endodontic Morphology.

BACKGROUND: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intima-media thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). METHODS: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. RESULTS: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and follow-up was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P = .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. CONCLUSIONS: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes