Tumor hypoxia may play a fundamental role in determining the radiotherapy outcome for several cancer types. Functional imaging with hypoxia specific radiotracers offers a way to visualize and quantify regions of increased radio-resistance, which may benefit from dose escalation strategies. Conversion of the uptake in positron emission tomography (PET) images into oxygenation maps offers a way to quantitatively characterize the microenvironment. However, normalization of the uptake with respect to a well-oxygenated reference volume (WOV), which should be properly selected, is necessary when using conversion functions. This study aims at assessing the sensitivity of quantifying tumor oxygenation based on F-18-fluoromisonidazole (FMISO) PET with respect to the choice of the location and the oxygenation level of the WOV in head and neck cancer patients. WOVs varying not only in shape and location but also with respect to the assigned pO(2) level were considered. pO(2) values other than the standard 60 mmHg were selected according to the specific tissue type included in the volume. For comparison, the volume which would be considered as hypoxic based on a tissue-to-muscle ratio equal to 1.4 was also delineated, as conventionally done in clinical practice. Hypoxia mapping strategies are found highly sensitive to selection of the location of well-oxygenated region, but also on its assigned oxygenation level, which is crucial for hypoxia-guided adaptive dose escalation strategies.

The aim of this study was to investigate whether textural features of tumour hypoxia, assessed with serial [18F]fluoromisonidazole (FMISO)-PET, were able to predict clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC, T1-4, N+, M0) during chemoradiotherapy (CRT). In a preliminary evaluation of a prospective trial, tumour hypoxia was evaluated in 29 patients via serial FMISO-PET before and during CRT. All patients received an initial [18F]fluorodeoxyglucose (FDG)-PET before CRT, and tumour regions were defined on this FDG-PET. The first-order metrics tumour-to-background ratio (TBRmean, TBRmax, TBRpeak), coefficient of variation, total lesion uptake and integral non-uniformity were calculated for all scans. Further, 3 second-order (textural) features from two grey-level matrices were calculated, as well as differential non-uniformity (udiff). Prognostic value was examined by median split for group separation (GS) in Kaplan-Meier estimates and correlated with overall survival (OS), quantified via log-rank tests (p ≤ 0.05) and group-relative hazard ratios (HR). Within a median follow-up of 29.6 months (95% CI: 16.8–48.0 months), no first-order metrics predicted OS with a significant GS (all p > 0.05) on any FMISO-PET scan. Only udiff before and in week 2 during CRT (p = 0.03, HR = 10.8 and p = 0.05, HR = 5.2) and non-uniformity from grey-level run length matrix in week 2 separated prognostic groups (p = 0.05, HR = 5.3); lower values were correlated with better OS. Further, the decrease in udiff from before CRT to week 2 was correlated with better OS (p = 0.04, HR = 9.4). FDG-PET before CRT did not predict outcome in any measure. Textural features on FMISO-PET scans before CRT, in week 2 and, to a limited degree, the change of features during CRT, were able to identify head and neck squamous cell carcinoma patients with better OS, suggesting that a higher homogeneity of the degree of hypoxia in tumours could correlate with a better outcome after CRT.

Insulinomas are predominantly benign neuroendocrine tumors originating from beta cells within islets of Langerhans of the endocrine pancreas. Autonomous insulin secretion by insulinomas is the most prevalent cause for endogenous hyperinsulinaemic hypoglycaemia. Since surgical resection represents the only curative therapy for these patients, exact tumor localization and discrimination of insulinomas from focal or diffuse manifestations of nesidioblastosis is crucial for optimal treatment strategies. We investigated the diagnostic value of PET imaging of the glucagon-like peptide-1 (GLP-1) receptor, which is overexpressed in high density in insulinomas.

To prospectively assess in HNSCC patients the effect of chemoradiotherapy (CRT) on tumor hypoxia and tissue properties with [18F]FMISO PET/CT (FMISO PET) and multiparametric (mp) MRI at baseline and at an early (week 2) and late (week 5) time point during treatment and to analyze whether mpMRI and PET parameters are related with outcome. Patients with stage III to IVb HNSCC undergoing definitive CRT (total dose 70 Gy, 3 cycles of cisplatin over 7 weeks) were included. Patients were prospectively imaged with [18F]FDG PET/CT at baseline and with serial FMISO PET and serial 3 Tesla mpMRI for T1w-, T2w- as well as contrast-enhanced perfusion and diffusion-weighted measurements (ktrans, ve and apparent diffusion coefficient (ADC) maps) in weeks 0, 2 and 5. Patients were identified as responders or non-responders during follow-up regarding loco-regional control (LRC) and overall survival (OS). Tumor volumes were contoured and SUVmax FMISO PET and mean values for mpMRI parameters were compared between responders and non-responders with the t-test and Log Rank test at a significance level of p≤0.05. A complete set of serial FMISO PET data and 3 T MRI was available in 21 patients. Of those, 12 patients were diagnosed with local recurrence. Baseline tumor volume and FMISO-PET-derived tumor hypoxia (SUVmax FMISO) were higher among patients with local recurrence as compared to locally controlled patients (p=n.s.). On Kaplan-Meier analysis stratified at median change in SUVmax FMISO between weeks 0 to 5 (ΔFMISOwk0-5), LRC was higher for ΔFMISOwk0-5 > median (p=n.s.). For ADC, an increase was found from week 0 to 5 (responders > non-responders). LRC was significantly higher for patients with ΔADCwk0-5 and %ΔADCwk0-5 > median (Log Rank, p=0.04 and p=0.005). In perfusion MRI, ktrans increased from week 0 to 5 for both non-responders and responders (p=n.s.). For non-responders, ktrans reached a maximum at week 2, while for responders, ktrans showed a steady increase until week 5. Interstitial space volume fraction ve did not differ significantly between responders and non-responders and increased between week 0 and 5 (p=n.s.). Baseline ADC below median was significantly (p=0.013) correlated with improved OS. ADCweek2 below median was associated with improved OS (p=n.s.). Baseline ve below median was significantly correlated with improved OS (p=0.043) and associated with increased LRC (p=n.s.). Multiparametric MRI parameters ADC and interstitial space volume fraction ve obtained at baseline were significantly correlated with improved OS and an increase of ADC between week 0 to 5 was significantly correlated with improved LRC. FMISO-PET-derived tumor hypoxia and mean values of MRI parameters ktrans and ve differed between relapsing and non-relapsing patients, however without reaching statistical significance in this cohort. The correlations found for ve and ADC may suggest predictive power for OS and LRC depending on baseline imaging and the dynamics of ADC.

Ziel dieser Studie war es den prädiktiven Wert von Texturanalysen der Tumor-Hypoxie mittels [18F]Fluoromisonidazol-PET (FMISO-PET) unter Radiochemotherapie (RCT, 2 Gy Fraktionen, geplant bis 70 Gy) für das Überleben von Patienten mit lokal fortgeschrittenen Kopf-Hals-Tumoren zu untersuchen.

Previous studies using hypoxia PET have shown significant reduction of tumor hypoxia (reoxygenation) during primary radiochemotherapy (RCT) of HNSCC and a significant correlation between reoxygenation on hypoxia PET and local control. Assessment of tumor hypoxia using MRI would offer independence from hypoxia PET tracer availability. The apparent MRI transverse relaxation time T2* has been proposed as an imaging biomarker and as a potential surrogate for hypoxia PET. The aim of this study was to assess the effect of primary RCT on T2* at an early (week 2) and late (week 5) time point during RCT and to analyse the relation between T2* and established hypoxia PET tracer 18F-misonidazole PET/CT (FMISO PET) and standard 18F-FDG PET/CT (FDG PET). In 10 T2-4N+ HNSCC patients, FDG PET was obtained at baseline and repeat FMISO PET and 3 Tesla MRI T2* in weeks 0, 2 and 5. MRI gross tumor volumes for tumor and lymph nodes (GTV-T, GTV-LN) were contoured and FMISO PET derived hypoxic tumor/lymph node subvolumes (HSV-T, HSV-LN) and complementary non-hypoxic subvolumes (nonHSV-T, nonHSV-LN) were generated using a threshold level of 1.4 times the mean SUV FMISO within muscle. Volumes were contoured for all time points (week 0, 2 and 5) individually and mean values for T2* and SUVmean FDG PET were obtained. Within GTVs (T, LN), r2 (FMISO to T2*) was calculated for [FMISO SUVmax GTV/SUVmean muscle] to [T2* mean GTV] and r2 (FMISO to FDG) was calculated for [FMISO SUVmax GTV/SUVmean muscle] to [FDG SUVmax GTV/SUVmean muscle]. From week 0 to 5 GTV-T and GTV-LN decreased by -56% and -63%, respectively and HSV-T and HSV-LN nearly completely resolved (n = 10). Mean T2* signal showed no significant change for GTV-T or GTV-LN. Within HSV-T mean T2* values were smaller compared to nonHSV-T: 15.0+/-4.6 vs. 18.3+/-2.9 (p = 0.051), whereas FDG SUVmean was significantly higher within hypoxic as compared to non-hypoxic regions: HSV-T 12.1+/-5.5 vs. nonHSV-T 6.1+/-2.6 and HSV-LN 10.2+/-3.9 vs. nonHSV-LN 4.7+/-1.9 (week 0, p≤0.026 and p≤0.011). Correlation between FMISO PET and FDG PET was higher than between FMSIO PET and T2*: r2 for GTV-T (FMISO/FDG)=0.81, r2 for GTV-T (FMISO/T2*)=0.32. Marked reduction of tumor hypoxia between week 0, 2 and 5 found on FMISO PET was not accompanied by a significant T2*change within GTVs over time. At baseline, smaller T2* values and significantly larger FDG SUVmean were found within HSV-T as compared to nonHSV-T. These results suggest a relation between tumor oxygenation status and T2* at baseline, however with the correlation coefficient r2 FMISO/T2* being lower than r2 FMISO/FDG. Overall, T2* quantitation was feasible and the findings on T2* imaging warrant further investigations but do not indicate a simple surrogate role for T2* as hypoxia imaging marker due to lack of correlation to established hypoxia marker FMISO PET. Our findings on reduction of FMISO uptake during RCT were in line with previous reports.

Material and Methods: The study cohort comprised 40 patients who underwent neoadjuvant radiochemotherapy (NRCT) for rectal cancer (28x1.8 Gy, 5 times weekly, concomitant with two cycles 5-FU-based chemotherapy). From each of those patients dermal fibroblasts were cultured from skin specimen gained outside of the radiotherapy planning target volume at occasion of surgery conducted about six weeks upon N-RCT completion. Acute radiotoxicity was thoroughly monitored throughout the N-RCT series and documented according to CTC classification. Maximal acute toxicity (MAT) was defined by the highest CTC grade of the four items “cystitis”, “proctitis”, “enteritis”, and “dermatitis”. MAT was grouped into grades 0/1 (n=16), 2 (n=16), and 3/4 (n=8). N-RCT was simulated in the cultured fibroblasts for five consecutive days (1.8 Gy each at d1-d5 with addiation of 5-FU at a concentration reflecting clinical steady-state levels) followed by a 7-day wash-out period. Gene expression of nine candidate genes (CAT, CDKN1A, CTGF, SMAD2/3/4/7, TGFB1, TGFBR1) supposed to mediate early radiation-induced toxicity was ascertained by quantitative real time PCR. Samples for these RNA analyses were harvested at d2 and d5 (each 4 hours upon application of the radiation fraction) as well as at day 12 upon the washout period. GAPDH and HPRT1 transcript levels served as reference.

Tumor hypoxia in squamous cell carcinoma of the head and neck (HNSCC) is associated with poor prognosis. Reoxygenation as a result of treatment leads to increased radiosensitivity. Early adaptive radiation therapy planning may allow for a more individualized treatment. Therefore, in the following study, the dynamics of hypoxia during chemoradiation (RCTx) is detected with FMISO PET/CT and correlated to perfusion MRI parameters. Perfusion-weighted MRI parameters can be correlated with tumor hypoxia. In particular, the volume transfer constant between plasma and interstitial space Ktrans is an indirect measure of the capillary permeability and blood flow. High skewness of Ktrans is associated with good treatment response, whereas primary tumors with lower Ktrans values have a poor prognosis. A subsequent rise of Ktrans, ve (fractional volume of the extracellular, extravascular space) during RCTx is associated with a good response to treatment. A prospective serial imaging study was conducted in patients undergoing definitive RCTx (70 Gy, concomitant cisplatin) for HNSCC: in weeks 0, 2 and 5 3T-MRI and FMISO PET were acquired. Tumor hypoxia was assessed in FMISO PET 2.5 h P.i. Gross tumor volume in MRI (GTVMRI) was defined as the area of high signal on T2-weighted images using the T1-weighted images for anatomic cross reference. Perfusion parameters Ktrans and ve were calculated from a dynamic T1-weighted study after Gadolinium injection. MRI and PET scans were matched using a contouring tool. Hypoxic subvolume (HSV) of GTVMRI was defined after normalization to the FMISO background in the contralateral sternocleidomastoid muscle, thresholded by 1.4. Volumetric parameters between weeks 0, 2 and 5 were compared and related to treatment response in terms of local recurrence (LR) and stable disease (SD). Statistical analysis was done with Spearman correlation. Before t-test analysis, normal sample distribution was confirmed with Shapiro–Wilk test. Between 2014 and 2015 10 male patients (mean 59 years), treated for HNSCC with RCTx, were included. All patients received a total dose of 70 Gy. In total, 30 FMISO-PET/CT data sets and 27 MRI data sets were obtained. Mean follow up (FU) was 6 months (2-16 months). In weeks 0-5, patients with LR showed a mean Ktrans-decrease of 19%, whereas in weeks 0-2 an increase of SUVmax (57%) was shown. Patients with SD showed Ktrans-increase (25%) and SUVmax-decrease (-61%). HSV diminished in all patients. The correlation analysis was significant between Δ GTVMRI and Δ Ktrans in week 0-2 (p = 0.037) and between Δ SUVmax (week 0-2) and Δ Ktrans (week 0-2, week 0-5), p = 0.001 and p = 0.02, respectively. We conclude that changes in SUVmax are crucial in week 2. In our limited patient cohort and the short FU, we found that a decrease in Ktrans might indicate a poorer outcome. Finding markers in bioimaging may allow individualization of treatment by dose painting and adaptive radiation therapy.

Tumor hypoxia, a common feature of locally advanced head and neck cancer (HNSCC), is associated with higher malignancy and increased radioresistance.The decrease of tumor hypoxia during