###### Abstract  
Gamma Knife treatment is an alternative to traditional brain surgery and whole-brain radiation therapy for treating cancers that are inaccessible via conventional treatments. To assess the effectiveness of Gamma Knife treatments, functional imaging can play a crucial role. The aim of this study is to evaluate new prognostic indices to perform an early assessment of treatment response to therapy using positron emission tomography imaging. The parameters currently used in nuclear medicine assessments can be affected by statistical fluctuation errors and/or cannot provide information on tumor extension and heterogeneity. To overcome these limitations, the Cumulative standardized uptake value (SUV) Histogram (CSH) and Area Under the Curve (AUC) indices were evaluated to obtain additional information on treatment response. For this purpose, the absolute level of [11C]-Methionine (MET) uptake was measured and its heterogeneity distribution within lesions was evaluated by calculating the CSH and AUC indices. CSH and AUC parameters show good agreement with patient outcomes after Gamma Knife treatments. Furthermore, no relevant correlations were found between CSH and AUC indices and those usually used in the nuclear medicine environment. CSH and AUC indices could be a useful tool for assessing patient responses to therapy.  
gamma knife; imaging quantification; [11C]-methionine positron emission tomography; cancer 2021 with excellent soft-tissue contrast [3; 4; 5; 6]. With the aim of adding another layer of sophistication during radiosurgery, the integration of positron emission tomography (PET) images in the treatment planning phase was evaluated [7; 8; 9]. Functional information improves lesion knowledge, as demonstrated by [PERSON] et al. [10]. The biological tumor volume (BTV) identified by PET can be used to treat the cancer region more precisely [11]. Furthermore, PET imaging has become a standard component of diagnosis and staging in oncology [12; 13; 14; 15; 16]. Functional changes are often faster and more indicative of the effects caused by therapy than anatomical imaging, providing a faster method of detecting the treatment response [17; 18]. [PERSON] et al. [19] found that PET conveys complementary information to information derived from computerized tomography (CT) or MR imaging in brain disorders. Historically, the first parameter introduced for the evaluation of PET studies is the maximum standardized uptake value (SUVmax), which provides punctual information of the voxel showing the highest uptake value within the tumor. Nevertheless, this parameter can be affected by statistical fluctuation errors and cannot provide information on the extent of the tumor [20]. For this reason, other quantitative indices have been introduced, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) [21]. These parameters provide information on the extent of the tumor but no information on the uptake heterogeneity.  
To overcome these limitations and considering that the dose distribution is not uniform in GK treatments, sixteen patients underwent [11C]-Methionine (MET) PET scans and GK treatments were considered in this study to calculate new PET indices, such as the Cumulative SUV Histogram (CSH) and Area Under the Curve (AUC), in order to obtain additional PET information, such as the functional heterogeneity [22]. In other words, we focus on the [11C]-MET uptake heterogeneity in pre- and post-treatment PET examinations by calculating CSH and AUC for each patient. Methionine is an amino acid that exhibits increased transport within active cancer cells. It has been reported that the extent of tumor cell invasion can be more clearly detected by [11C]-MET PET than by CT or MR [23]. The correlation between CSH and AUC results with medical reports evaluated by three physicians was also considered in our study. The proposed methodology could represent a useful tool for assessing patient response to GK treatments.