The Value of PET/CT in Particle Therapy Planning of Various Tumors with SSTR2 Receptor Expression: Comparative Interobserver Study.

The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation.

Normofractionated and moderately hypofractionated proton therapy: comparison of acute toxicity and early quality of life outcomes.

Aim: Data on the safety of moderately hypofractionated proton beam therapy (PBT) are limited. The aim of this study is to compare the acute toxicity and early quality of life (QoL) outcomes of normofractionated (nPBT) and hypofractionated PBT (hPBT). Material and methods: We prospectively compared acute toxicity and QoL between patients treated with nPBT (dose per fraction 1.8-2.3 Gy, n = 90) and hPBT (dose per fraction 2.5-3.1 Gy, n = 49) in following locations: head and neck (H&N, n = 85), abdomen and pelvis (A&P, n = 43), and other soft tissue (ST, n = 11). The toxicities were grouped into categories-mucosal, skin, and other sites-and evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at baseline, treatment completion, and 3 months after PBT completion. QoL was evaluated with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scale for all locations and additionally with EORTC QLQ-HN35 for H&N patients. Results: Overall, the highest toxicity grades of G0, G1, G2, and G3 were observed in 7 (5%), 40 (28.8%), 78 (56.1%), and 15 (10.8%) patients, respectively. According to organ and site, no statistically significant differences were detected in the majority of toxicity comparisons (66.7%). For A&P, hPBT showed a more favorable toxicity profile as compared to nPBT with a higher frequency of G0 and G1 and a lower frequency of G2 and G3 events (p = 0.04), more patients with improvement (95.7% vs 70%, p = 0.023), and full resolution of toxicities (87% vs 50%, p = 0.008). Skin toxicity was unanimously milder for hPBT compared to nPBT in A&P and ST locations (p = 0.018 and p = 0.025, respectively). No significant differences in QoL were observed in 97% of comparisons for QLQ-C30 scale except for loss of appetite in H&N patients (+33.3 for nPBT and 0 for hPBT, p = 0.02) and role functioning for A&P patients (0 for nPBT vs +16.7 hPBT, p = 0.003). For QLQ-HN35, 97.9% of comparisons did not reveal significant differences, with pain as the only scale varying between the groups (-8.33 vs -25, p = 0.016). Conclusion: Hypofractionated proton therapy offers non-inferior early safety and QoL as compared to normofractionated irradiation and warrants further clinical investigation.

The Value of SSTR2 Receptor-Targeted PET/CT in Proton Irradiation of Grade I Meningioma.

Grade I meningioma is the most common intracranial tumor in adults. The standard imaging for its radiation treatment planning is MRI, and [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated PET/CT can further improve delineation. We investigated the impact of PET/CT on interobserver variability in identifying the tumor in 30 anonymized patients. Four radiation oncologists independently contoured residual tumor volume, first using only MRI and subsequently with the addition of PET/CT. Conformity indices (CIs) were calculated between common volumes, observer pairs and compared to the volumes previously used. Overall, 29/30 tumors (96.6%) showed [68Ga]Ga-DOTA avidity. With help of PET/CT, the participants identified six cases with new lesions not recognized in MRI, including two where new findings would critically alter the target volume used for radiation. The PET/CT-aided series demonstrated superior conformity, as compared to MRI-only between observer pairs (median CI = 0.58 vs. 0.49; p = 0.002), common volumes (CI = 0.34; vs. 0.29; p = 0.002) and matched better the reference volumes actually used for patient treatment (CI = 0.55 vs. 0.39; p = 0.008). Cis in the PET/CT-aided series were lower for meningiomas outside of the skull base (0.2 vs. 0.44; p = 0.03). We conclude that SSTR2 receptor-targeted PET/CT is a valuable tool for planning particle therapy of incompletely resected meningioma. It serves both as a workup procedure and an aid for delineation process that reduces the likelihood of marginal misses.

The application of 18F-FDG-PET/CT in gastric cancerstaging and factors affecting its sensitivity.

OBJECTIVE: To evaluate the accuracy offluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), to correctly determine initial tumor stage in treatment-naive gastric cancer patients and to analyze the factors influencing the risk of false negative results. SUBJECTS AND METHODS: The baseline 18F-FDG PET/CT scans of 111 previously untreated gastric cancer patients were retrospectively assessed. Sensitivity, specificity, positive (PPV) and negative prediction value (NPV) were evaluated. An array of clinical, pathological and metabolic variables was analyzed to identify factors contributing to the risk of a false positive (FP) and false negative (FN) PET/CT result in detecting primary and metastatic tumor sites. RESULTS: The sensitivity, specificity, PPV and NPV of PET/CT to visualize distant metastases were 76.4%; 86.7%; 83% and 81.2%, respectively. In 13 (11.7%) patients the PET/CT exam was able to identify metastatic sites not recognized in radiographic staging, significantly altering the initially planned management. Of 64 PET/CT studies negative for distant metastases, 12 (18.75%) were clinically confirmed to be false negative. The risk of acquiring a FN result for primary tumor was 10.8% (12/111) and the overall risk of any FN readout for either primary and metastatic sites was 18.9% (21/111). The factors that contributed to increased probability of a FN result for primary tumor detection were early primary tumor stage T1-T2 (+16.2%; χ2=5.0, P=0.025), female sex (+10.1%; χ2=5.71, P=0.017) and neutrophil count below 4.2k/µL (9.7%; χ2=6.1, P=0.014). Patients with non-intestinal Lauren histologic type (+18.7%; χ2=8.9, P=0.003) or signet-ring/mucinous carcinoma (+9.6%; χ2=7.7, P=0.005) had increased probability of PET/CT being unable to identify their distant metastases. Women and patients with low neutrophil count featured borderline insignificantly increased percentage of non-intestinal tumor histology (P=0.07 and P=0.057, respectively). CONCLUSION: Fluorine-18-FDG PET/CT is a valuable diagnostic method in gastric cancer patients which significantly contributes to determining the TNM stage and thus helps choose correct patient management. Histology and primary tumor stage as well as patient cohorts in which these factors may vary should be considered when evaluating results to decrease a chance of a false negative readout.

Clinical outcomes of head and neck adenoid cystic carcinoma patients treated with pencil beam-scanning proton therapy.

OBJECTIVE: The aim of this study was to evaluate the outcome of patients with head and neck adenoid cystic carcinoma (ACC) treated using pencil beam scanning proton therapy (PBS PT) at our institution. MATERIALS AND METHODS: Thirty-five patients who underwent treatment with PBS PT for ACC between 2001 and 2017 were included. Local control (LC), distant control (DC), progression-free survival (PFS), overall survival (OS) and their prognostic factors were evaluated. Adverse effects were prospectively assessed. RESULTS: The median patient follow-up was 30 months. Prior to PT, 26 patients (74.3%) underwent surgery with R0/R1/R2 outcome in 5, 13 and 8 cases, respectively. Nine patients (25.7%) presented with inoperable disease. The 2-year LC, DC, PFS and OS was 92.2%, 77.8%, 74.3% and 88.8%, respectively. LC was influenced by patient age (p = 0.002) with a significant difference between local and distant failure (median 61.3 vs. 42.3 years, p = 0.005). Tumor T stage was a significant risk factor for PFS (p = 0.045) and tumor prognostic group affected OS (p = 0.049). No significant survival advantage for operable vs. inoperable disease could be identified. The acute and late grade 3 toxicity rates were 14.3% and 6.1%, respectively. No acute or late grade 4/5 toxicities were observed. CONCLUSIONS: PBS PT is an effective and safe treatment for patients with head & neck ACC in both definitive and adjuvant setting. Distant metastases are the main pattern of failure. Age, tumor stage and clinical stage had a significant negative impact on LC, OS and PFS.

The Prognostic Value of Pretreatment Gallium-68 DOTATATE Positron Emission Tomography/Computed Tomography in Irradiated Non-benign Meningioma.

PURPOSE OF THE STUDY: The purpose of this study was to evaluate the potential value of gallium-68 (Ga-68)-DOTATATE positron emission tomography/computed tomography (PET/CT) in predicting the risk of progression in nonbenign meningioma after definite irradiation. We retrospectively reviewed our patients with meningiomas who had the highest risk of progression: WHO histological Grade II and III tumors and with macroscopic disease as identified in Ga-68-DOTATATE PET/CT. MATERIALS AND METHODS: Thirteen patients were included in this study. For each tumor, the following quantifiers were measured: maximum and mean standardized uptake volume (SUV), standard deviation, metabolic tumor volume (MTV), total lesion activity, and coefficient of variation. Each of the quantifiers except for maximum SUV was obtained with three different SUV thresholds: muscle based (ms), liver based (liv), and gradient based (gb). The quantifiers were analyzed in univariate Cox model for their prognostic value for progression-free survival (PFS) and overall survival (OS). RESULTS: Mean follow-up of the patients was 28.2 months. The 2-year PFS and OS was 28.1% and 76.9%, respectively. The MTVgb was a significant predictor for PFS (risk of progression of disease above vs. below the 34 cm3 threshold: 100% vs. 28.3%, P = 0.0003). Clinically, the male sex also influenced PFS (Hazard ratio =13.06; 95% confidence interval: 1.56-109.25; P = 0.018). The mean SUVms(P = 0.041) and SUVgb(P = 0.048) had a prognostic value for predicting the risk of death. CONCLUSION: Ga-68-DOTATATE PET/CT has potential to predict disease progression in nonbenign meningioma patients. Further prospective studies for validating and standardizing these findings are indicated.

The prognostic significance of indoleamine-2,3-dioxygenase and the receptors for transforming growth factor ß and interferon γ in metastatic lymph nodes in malignant melanoma.

We analyzed the prognostic significance of indoleamine-2,3-dioxygenase (IDO) and type 1 receptors for transforming growth factor beta (TGF-ßR1) and interferon gamma (IFN-γR1) in resected nodal metastases of 48 malignant melanoma patients. In 32 cases the corresponding skin tumors were available. We used immunohistochemical (IHC) staining which was assessed by pathologists and by a computer-aided algorithm that yielded quantitative results, both absolute and relative. We correlated the results with the patient outcome. We identified absolute computer-assessed IDO levels as positively correlated with increased risk of death in a multivariate model (HR = 1.02; 95% CI: 1.002-1.04; p = 0.03). In univariate analysis, patients with IDO levels below the median had a better overall survival time (30.3 vs. 17.5 months; p = 0.03). TGF-ßR1 and IFN-γR1 expression was modestly correlated (R = 0.34; p lt; 0.05) and TGF-ßR1 expression was lower in lymph nodes than in matched primary skin tumors (Z = 2.87; p = 0.004). The pathologists' and computer-aided IHC assessment demonstrated high correlation levels (R = 0.61, R = 0.74 and R = 0.88 for IDO, TGF-ßR1 and IFN-γR1, respectively). Indoleamine-2,3-dioxygenase is prognostic for the patient outcome in melanoma with nodal involvement and should be investigated prospectively for its predictive significance. IHC assessment by computer-aided methods is recommended as its gives IHC more objectivity and reproducibility. ecting mismatch repair deficiency. Association of CDX2 and PMS2 in the present study is necessary to conduct further genetic and pathological studies focusing on these two markers together.

The presence and clinical implications of α-2,6-galactose-linked sialic acids in non-small-cell lung cancer brain metastases--preliminary study.

Brain metastases (BM) in non-small-cell lung cancer (NSCLC) patients present an increasing clinical challenge. Identifying biomarkers which specifically identify patients at high risk of BM may improve their early diagnosis, which is crucial for surgical and radiotherapeutic treatment outcome. Alpha-2,6-sialyltransferase (α-2,6-ST) and the primary product of its activity, alpha-2,6-galactose-linked sialic acids (α-2,6-GalSA) have been found responsible for the adhesion of tumor cells to the brain vessels' endothelium and enabling their transmigration through the blood-brain barrier in brain metastatic tumors. The aim of the study was to investigate by histochemical method the presence and possible role of α-2,6-GalSA in the formation of brain metastasis in NSCLC. In the screening phase 76 metastatic brain tumors were stained for α-2,6-GalSA and the second phase involved an identical staining of 20 primary tumors of patients who had their primary tumors treated with surgery or definite radiochemotherapy yet who later developed BM. The results were compared to a control group of 22 patients treated with surgery for NSCLC and who survived 5 years without the recurrence of disease. Alpha-2,6-GalSA presence was found to be down-regulated in poorly differentiated tumor types, whereas majority of differentiated tumors overexpressed it. This was statistically significant for both BM and the primary tumors. The expression of α-2,6-GalSA remained stable in primary and metastatic tumor pairs, however, no statistically significant differences were observed between study and control groups. Within the study group, a higher α-2,6-GalSA expression was associated with better overall survival, but not all statistical models found this result significant. Further studies are recommended to validate these findings.