Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a
hybrid imaging technique that allows the simultaneous acquisition of
quantitative PET and MR data concerning biological processes 1. A
multiparametric approach to analyze pretreatment Diffusion-weighted Imaging (DWI)
and Dynamic Contrast Enhanced (DCE) MRI of primary tumors and nodal lesions is
promising to accurately predict local treatment response to chemoradiation
therapy in Head and Neck Squamous Cell Carcinoma (HNSCC) and particularly
Ktrans has been reported as a potential noninvasive biomarker for predicting
therapeutic response in HNSCC 2,3. However, clinical thresholds as well as optimum
methods for data acquisition and analysis have yet to be established 4. Moreover,
previous studies have shown a good diagnostic accuracy of PET/computed
tomography (CT) in the assessment of treatment response after CHT/RT for HNSCC
with the potential to guide clinical decision-making 5. Thus, a combined
approach of PET and MRI may provide a better assessment of tumor
microenvironment 6. In this short report we aimed to extract metabolic and
functional PET/MR parameters of 5 patients with locally advanced HNSCC before
and after chemo (CHT) and/or radiotherapy (RT), in order to assess the response
to treatment and to possibly identify biomarkers predictive of the response.



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to our Institutional Review Board authorization and Ethical Committee, 5
consecutive patients (3 M, mean age: 49±16.7 years, range 28-76) with locally
advanced, histologically proven carcinoma of the head and neck region underwent
contrast enhanced PET/MRI of the head and neck region before and after CHT
and/or RT. Clinical and histological data of each patient are
reported in table 1.  Post-treatment PET/MRI examinations were
performed at least 3 months after treatment, while the clinical and
instrumental follow-up was conducted for at least 1 year after treatment. Written
informed consent was obtained from all subjects.


PET/MRI Acquisition

(2-(18F)FDG) PET/MRI was performed using a Biograph mMR (Siemens Healthcare,
Erlangen, Germany). All patients underwent unenhanced PET/CT scan prior to the
PET/MR examination using the same 2-(18F)FDG dose; the PET/MRI acquisition started
about 40 min after the start of PET/CT acquisition. A coronal 2-point Dixon
3-dimensional volumetric interpolated breath-hold T1-weighted MRI sequence was
acquired and used for the generation of attenuation maps and for anatomic
allocation of the PET results, as previously described 7. The PET data
acquisition occurred for the first seven minutes during MR acquisition, taking
delayed acquisition times and radioactive decay into account.

The MRI protocol was performed with a 16 channels head and neck coil,

Axial Fast Spin Echo (FSE) T2-weighted, Axial FSE T1-weighted, Axial
DWI, obtained with a single-shot echo planar 2d SPAIR sequence using three b values: 0, 500 and 800 s/mm2.
Perfusion studies were obtained during intravenous administration of
paramagnetic contrast agent (Magnevist, Bayer, Berlin, Germany) 0,2ml/kg, with a
flow rate of 3.5 ml/sec, using a Volumetric interpolated breath-hold
examination (VIBE) dynamic sequence with 50 measurements (time resolution 6 sec).
Two pre-contrast axial VIBE sequences with variable flip angles were obtained for
T1 mapping. Finally, axial isometric high-resolution VIBE and axial Fast Field
Echo (FFE) T1-weighted with fat-saturation sequences were acquired. The total MR acquisition time was
about 30-40 minutes.


Image analysis

         A radiologist with 10
years of experience in head and neck imaging and a nuclear medicine specialist
with 9 years of experience analyzed pre- and post-treatment PET/MR images in
consensus. The maximum SUV (SUVmax) and metabolic tumor volume (MTV) with a threshold
of 40% of the maximum signal intensity (MTV40) were calculated as previously performed
8. Primary tumor size, tumoral structural features and
infiltration of neighboring structures were assessed using pre-contrast and
high-resolution post-contrast images. Subsequently, the DCE-MR images were post-processed
as previously described 9,10. On the basis of the bi-compartmental model the
following parameters were calculated: transfer constant between vascular and
extravascular-extracellular space (EES) (Ktrans); the volume of EES (Ve); the transfer
constant between EES and blood plasma (kep); and the initial area under the concentration
curve (iAUC) 11. Free-hand ROI area values were following drawn in the major
diameter lesion slice and then copied and pasted on each map to automatically
extract maximum and mean values for each parameter (SUVmax and SUVmean;
ADCmean; Ktrans,
Ve, kep, and iAUC
mean values).

Response to treatment was classified as complete response (CR), partial
response (PR), stable disease (SD) or progression disease (PD), according to RECIST
and PERCIST criteria 12,13. No statistical analysis was performed, due to
the small sample size. A direct comparison of the pre-and post-treatment values
for each patient was carried out and finally integrated with clinical evaluation
and follow-up (at least 1 year after treatment).



All pre- and post-treatment PET/MR parameters are
reported in table 2. Patient 1, classified
as PR, showed a significant (>30%) reduction of tumor size, volume and SUV
max; in this patient there was also a reduction of iAUC and Kep post-treatment
values and an increase of ADC, Ktrans and Ve post-treatment values. Patient 2,
classified as PR, showed a significant (>30%) reduction of tumor size,
volume and SUVmax; in this patient, an increase of ADCmean values and reduction
of all perfusion post-treatment parameters was observed. For both patients,
clinical and instrumental follow-up documented lesion stability.

Patient 3 with a HPV- retromolar trigone carcinoma,
was classified as SD. At first PET/MR examination a large intraumoral abscess was
appreciable; so that, in addition to CHT/RT, the patient underwent drainage of
the purulent collection. Post-treatment PET/MRI examination demonstrated a
significant reduction of the intratumoral abscess while the solid portion of
the tumor showed a slight reduction of tumor volume (<30%) with substantially stable SUVmax values; multiparametric analysis demonstrated an increase of ADC and all perfusion post-treatment values except for Ve. During the clinical and instrumental follow-up progression disease was observed. In both patients 4 and 5 with nasopharynx carcinoma a CR was observed with no detectable tumor lesions on PET/MR post-treatment examinations. Of note, these two patients showed the lowest ADC and iAUC pre-treatment mean values. Examples of pre- and post-treatment multiparametric PET/MRI evaluation are illustrated in figures 1-4.   DISCUSSION   Hypopharyngeal SCC originates most frequently in the pyriform sinus, followed by the posterior pharyngeal wall, and the postcricoid area 14. The overall 5-year survival rate is 62.5% and TNM is the most significant predictor of survival 15,16. In our case series, the two patients with hypopharynx carcinoma showed a partial response after concurrent CHT/RT. In both cases there was a concordant increase of ADCmean values and a reduction of  iAUC and Kep post-treatment values; however, while in patient 2 a reduction of Ktrans and Ve values was also observed, patient 1 showed a paradoxal increase of such parameters; this difference could be explained by the different tumor grade (G3 in patient 1 and G2 in patient 2) or could be an early sign of a different prognosis even if, at present, both patients show the same stable outcome. Squamous cell carcinoma of the oropharynx is increasing in incidence, related to an increase in incidence in human papillomavirus (HPV) infections 17. Histological grade correlates poorly with patient outcome 16. In our study, patient 3 with a HPV- retromolar trigone carcinoma, treated with concurrent CHT/RT, was classified as SD. In this patient, the increase of post-treatment perfusion parameters, despite the stable lesion size, could be considered predictive of the progression disease observed during the clinical and instrumental follow-up, as often occurs in HPV- tumors. Nasopharyngeal carcinoma is a rare malignancy, near constantly associated with EBV, indicating a probable oncogenic role of the virus in the genesis of this tumour 18. In our case series, both patients 4 and 5 with nasopharynx carcinoma a complete response was observed with no detectable tumor lesions on PET/MR post-treatment examinations. Interestingly, these two patients showed the lowest ADC and iAUC pre-treatment mean values; this is in accordance with the current literature in which is reported that low pre-treatment ADC values are associated to a good response to therapy 4. In addition, the finding of low iAUC pre-treatment values in these two patients could support the hypothesis of a reduced aggressiveness of hypovascular tumors. In a previous study by King et al, who analyzed the role of DCE MRI for pre-treatment prediction and assessment of response to CHT and or RT in 49 patients with head and neck carcinoma, site control residual masses showed significantly lower Kep and iAUC compares with site failure residual masses 19. Moreover, site control residual masses showed a decrease in the iAUC while the site failure residual masses showed an increase in iAUC. Even if at present the data for pre-treatment DCE-MRI seems to be insufficient to allow translation to clinical practice, some perfusion parameters i.e. iAUC and Kep may be reliable in assessing the response to treatment in patients with HNSCC. In conclusion, multiparametric evaluation with contrast-enhanced simultaneous PET/MRI could be a useful tool to assess the response to CHT and/or RT in patients with HNSCC. Future studies in a larger cohort of patients are necessary to confirm our results and to identify possible metabolic and/or functional biomarkers that could be predictive of patient's response to therapy.

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