Pretreatment ADC is not a prognostic factor for local recurrences in head and neck squamous cell carcinoma when clinical T-stage is known.

OBJECTIVES: Pretreatment identification of radio-insensitive head and neck squamous cell carcinomas (HNSCC) would affect treatment modality selection. The apparent diffusion coefficient (ADC) of a tumor could be a predictor of local recurrence. However, little is known about its prognostic value next to known factors such as clinical T-stage. The aim of the present study is to determine the added value of pretreatment ADC to clinical T-stage as a prognostic factor for local recurrence. METHODS: This retrospective cohort study included 217 patients with HNSCC treated with (chemo)radiotherapy between April 2009 and December 2015. All patients underwent diffusion-weighted MRI prior to treatment. Median ADC values of all tumors were obtained using a semi-automatic delineation method. Univariate models containing ADC and T-stage were compared with a multivariable model containing both variables. RESULTS: Fifty-eight patients experienced a local recurrence within 3 years. On average, the ADC value in the group of patients with a recurrence was 1.01 versus 1.00 (10-3 mm2/s) in the group without a recurrence. Univariate analysis showed no significant association between tumor ADC and local recurrence within 3 years after (chemo)radiotherapy (p = 0.09). Cox regression showed that clinical T-stage was an independent predictor of local recurrence and adding ADC to the model did not increase its performance. CONCLUSION: Pretreatment ADC has no added value as a prognostic factor for local recurrence to clinical T-stage. KEY POINTS: • Pretreatment identification of head and neck squamous cell carcinoma patients who do not benefit from (chemo)radiotherapy could improve personalized cancer care. • The apparent diffusion coefficient (ADC) obtained from diffusion-weighted MRI has been reported to be a prognostic factor for local recurrence. • In this study, ADC has no added value as a prognostic factor compared with clinical T-stage.

Outcome prediction of head and neck squamous cell carcinoma by MRI radiomic signatures.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer. MATERIALS AND METHODS: Native T1-weighted images of four independent, retrospective (2005-2013), patient cohorts (n = 102, n = 76, n = 89, and n = 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC). RESULTS: In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (p < 0.001). CONCLUSIONS: MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters. KEY POINTS: • MRI radiomics can predict overall survival and relapse-free survival in oral and HPV-negative oropharyngeal cancer. • MRI radiomics provides additional prognostic information to known clinical variables, with the best performance of the combined models. • Variation in MRI vendors and acquisition protocols did not influence performance of radiomic prognostic models.

Prediction of ultrasound guided fine needle aspiration cytology results by FDG PET-CT for lymph node metastases in head and neck squamous cell carcinoma patients.

INTRODUCTION: Accurate assessment of cervical lymph node status is essential in patients with head and neck squamous cell carcinoma (HNSCC) as it influences prognosis and treatment decisions. During patient workup, lymph node status is often examined by ultrasound guided fine needle aspiration cytology (USgFNAC). 18F-Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is frequently used to assess primary tumor and distant metastases but provides information on lymph node status as well. It is possible that FDG PET-CT (if already made for abovementioned indications) can predict the results of USgFNAC in subgroups of lymph nodes based on FDG-uptake and size. The objective of this study is to identify maximum standardized uptake (SUVmax) and short axis diameter cutoff values of lymph nodes at which FDG PET-CT can reliably predict USgFNAC results. METHODS: One hundred and seventeen patients with HNSCC were retrospectively analyzed. Patients were included when FDG PET-CT and USgFNAC were available. SUVmax measurements were performed and compared to the USgFNAC results. RESULTS: Using USgFNAC as a reference standard, the area under the curve of the receiver operating curve was 0.91. At an SUVmax cutoff value of 4.9, the accuracy of FDG PET-CT was the highest (85%). Lymph nodes with short axis diameter ≥1.0 cm and SUVmax ≥4.9 were in 91% positive on USgFNAC. If SUVmax was below 2.2, no nodes were positive on USgFNAC. Of all lymph nodes 52% either had a short axis diameter ≥1.0 cm and SUVmax ≥4.9 or an SUVmax <2.2. FDG PET-CT and USgFNAC results were very similar in these nodes. CONCLUSIONS: By measuring SUVmax values and minimal axial diameters of lymph nodes and using appropriate cutoff values, FDG PET-CT can predict the results of USgFNAC examinations in half of the examined lymph nodes. This information may lead to a reduction of USgFNAC examinations in HNSCC patients if FDG PET-CT is already performed for other indications.

Accurate detection of circulating tumor DNA using nanopore consensus sequencing.

Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ~60×, enabling accurate detection of TP53 mutations at frequencies down to 0.02%. We demonstrate that a TP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in clinical workflows.

Prospective comparative study of MRI including diffusion-weighted images versus FDG PET-CT for the detection of recurrent head and neck squamous cell carcinomas after (chemo)radiotherapy.

OBJECTIVE: This prospective study aims to test if MRI including diffusion weighted images can replace FDG PET-CT in the diagnosis of patients with suspicion of local recurrent head and neck squamous cell carcinomas after (chemo)radiation. METHODS: Seventy-five patients suspected of local recurrence underwent a MRI and a FDG PET-CT. Qualitative assessment of the images was performed. Reference standard was the results of biopsy or the absence of a recurrence during follow up. RESULTS: Seventy patients were included. Fifty percent had local recurrence. FDG PET-CT had accuracy of 71% compared to 73% for MRI. The sensitivity and specificity were 97% compared to 69% and 46% compared to 77% for FDG PET-CT and MRI respectively. CONCLUSIONS: MRI showed similar diagnostic accuracy, superior specificity but inferior sensitivity compared to FDG PET-CT. Based on current results, we consider MRI including diffusion weighted sequences unable to replace FDG PET-CT as a single imaging modality when local recurrent disease of HNSCC after (C)RT is suspected.

Evaluation of diffusion weighted imaging for tumor delineation in head-and-neck radiotherapy by comparison with automatically segmented 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND AND PURPOSE: Diffusion weighted (DW) MRI may facilitate target volume delineation for head-and-neck (HN) radiation treatment planning. In this study we assessed the use of a dedicated, geometrically accurate, DW-MRI sequence for target volume delineation. The delineations were compared with semi-automatic segmentations on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images and evaluated for interobserver variation. METHODS AND MATERIALS: Fifteen HN cancer patients underwent both DW-MRI and FDG-PET for RT treatment planning. Target delineation on DW-MRI was performed by three observers, while for PET a semi-automatic segmentation was performed using a Gaussian mixture model. For interobserver variation and intermodality variation, volumes, overlap metrics and Hausdorff distances were calculated from the delineations. RESULTS: The median volumes delineated by the three observers on DW-MRI were 10.8, 10.5 and 9.0 cm3 respectively, and was larger than the median PET volume (8.0 cm3). The median conformity index of DW-MRI for interobserver variation was 0.73 (range 0.38-0.80). Compared to PET, the delineations on DW-MRI by the three observers showed a median dice similarity coefficient of 0.71, 0.69 and 0.72 respectively. The mean Hausdorff distance was small with median (range) distances between PET and DW-MRI of 2.3 (1.5-6.8), 2.5 (1.6-6.9) and 2.0 (1.35-7.6) mm respectively. Over all patients, the median 95th percentile distances were 6.0 (3.0-13.4), 6.6 (4.0-24.0) and 5.3 (3.4-26.0) mm. CONCLUSION: Using a dedicated DW-MRI sequence, target volumes could be defined with good interobserver agreement and a good overlap with PET. Target volume delineation using DW-MRI is promising in head-and-neck radiotherapy, combined with other modalities, it can lead to more precise target volume delineation.

Target Volume Delineation Using Diffusion-weighted Imaging for MR-guided Radiotherapy: A Case Series of Laryngeal Cancer Validated by Pathology.

In radiotherapy treatment planning, tumor delineation based on diffusion-weighted imaging (DWI) by magnetic resonance imaging (MRI) is a promising technique. MR-only-based target definition becomes important with the recent development of MRI integrated radiotherapy treatment modalities. In this case series, DWI-based gross tumor volume (GTV) was validated using pathology and compared with a clinical GTV based on computed tomography (CT) imaging and MRI. This case series includes three patients with a laryngeal tumor. Prior to total laryngectomy (TLE), imaging was performed on CT and MRI, including a DWI scan. After TLE, the surgical specimen was processed and cut into 3-mm thick slices. The tumor was delineated on hematoxylin-eosin (HE) stained sections by a pathologist (tumorHE). This pathological imaging, including the tumorHE delineation, was three-dimensionally reconstructed and registered to the imaging. The GTV was delineated by a radiation oncologist based on CT and MR imaging (GTVclinical) and semi-automatically delineated based on DWI (GTVDWI). The microscopic tumor extent outside the GTVDWI contour was 3.0 mm, 2.7 mm, and 11.3 mm for cases I, II, and III, respectively. The microscopic tumor extent outside the GTVclinical was 7.5 mm, 2.1 mm, and 1.5 mm for cases I, II, and III, respectively. The tumor, on histology, was covered by the GTVs for 80%, 74%, and 31% (GTVDWI) and 73%, 72%, and 89% (GTVclinical) for the three subsequent cases, respectively. The GTVDWI resembled the tumorHE more than the GTVclinical in case I and case II. In case III, GTVDWI missed the caudal part of the tumor that was included in the clinical delineation due to a lack of contrast and the heterogeneous signal intensity of the tumor in DWI. In this case series, we showed the potential of DWI for MR-guided radiotherapy treatment if a clear contrast is visible. DWI-based GTV delineation might be a fast alternative to manual delineation, which could speed up the on-table target definition using an MRI-linac system. A larger case series is needed to verify these results.

The interobserver agreement in the detection of recurrent HNSCC using MRI including diffusion weighted MRI.

INTRODUCTION: For the detection of local recurrences of head and neck squamous cell carcinomas (HNSCC) after (chemo)radiation, diagnostic imaging is generally performed. Diffusion weighted magnetic resonance imaging (DW-MRI) has been proven to be able to adequately diagnose the presence of cancer. However evaluation of DW-MR images for recurrences is difficult and could be subject to individual interpretation. AIM: To determine the interobserver agreement, intraobserver agreement and influence of experience of radiologists in the assessment of DW-MRI in patients clinically suspected of local recurrent HNSCC after (chemo)radiation. METHODS: Ten experienced head and neck radiologists assessed follow-up MRI including DW-MRI series of 10 patients for the existence of local recurrence on a two point decision scale (local recurrence or local control). Patients were clinically suspected for a recurrence of laryngeal (n = 3), hypopharyngeal (n = 3) or oropharyngeal (n = 4) cancer after (chemo)radiation with curative intent. Fleiss' and Cohen's Kappa were used to determine interobserver agreement and intraobserver agreement, respectively. RESULTS: Interobserver agreement was κ = 0.55. Intraobserver agreement was κ = 0.80. Prior experience within the field of radiology and with DW-MRI had no significant influence on the scoring. CONCLUSION: For the assessment of HNSCC recurrence after (chemo)radiation by DW-MRI, moderate interobserver agreement and substantial intraobserver agreement was found.

Cerebrovascular reactivity and white matter integrity.

OBJECTIVE: To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR). METHODS: Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level-dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons. RESULTS: Areas of NAWM with negative CVR showed a significant reduction in fractional anisotropy by a mean (SD) of 3.7% (2.4), cerebral blood flow by 22.1% (8.2), regional cerebral blood volume by 22.2% (7.0), and a significant increase in mean diffusivity by 3.9% (3.1) and time to maximum by 10.9% (13.2) (p < 0.01), compared to areas with positive CVR. CONCLUSIONS: Impaired CVR is associated with subtle changes in the tissue integrity of NAWM, as evaluated using several quantitative diffusion and perfusion MRI metrics. These findings suggest that impaired CVR may contribute to the progression of white matter disease.