Predictive and Prognostic Role of Metabolic Response in Patients With Stage III NSCLC Treated With Neoadjuvant Chemotherapy.

INTRODUCTION: The purpose of this study was to assess the predictive and prognostic role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in candidates with stage III non-small-cell lung cancer (NSCLC) to neoadjuvant chemotherapy. PATIENTS AND METHODS: Sixty-six patients with stage III NSCLC treated with induction chemotherapy from March 2013 to December 2017 were retrospectively identified. Response assessment were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. 18F-FDG PET/CT metabolic parameters were analyzed as absolute values as well as percentage changes (Δ) between 2 consecutive scans, for primary tumor (T) and for regional lymph nodes (N). All clinical variables and metabolic parameters were compared with treatment response and correlated with progression-free survival (PFS) and overall survival (OS), based on a median follow-up of 9.4 months. RESULTS: Post-induction therapy standardized uptake value (SUV)max_T, SUVmean_T, metabolic tumor volume (MTV_T), and total lesion glycolysis of the tumor (TLG_T) varied significantly between responders and non-responders (6.6 vs. 13.8; P = .001; 4.2 vs. 8.1; P < .001; 6 vs. 17.9; P = .002; and 24.1 vs. 136.3; P < .001, respectively). Likewise, percentage changes (Δ_T) were significantly different between the 2 groups (P < .001). Along with primary tumor, also post-SUVmax_N, post-SUVmean_N, and post-TLG_N (P = .024, P = .015, and P = .024, respectively), as well as all percentage changes (Δ_N) were different between responders and non-responders. RECIST 1.1 and EORTC response classifications were discordant in 27 patients (40.9%; κ = 0.265; P = .003). On multivariate analysis, post-TLG_N was an independent predictor for both PFS and OS, whereas RECIST 1.1 was a predictor only for OS. CONCLUSIONS: Several metabolic parameters may differentiate responders from non-responders following neoadjuvant chemotherapy in stage III NSCLC. As compared with RECIST 1.1, EORTC seems to be more appropriate for evaluation therapeutic response. Finally, post-TLG_N has significant prognostic information.

Independent expression of circulating and tissue levels of PD-L1: correlation of clusters with tumor metabolism and outcome in patients with non-small cell lung cancer.

PURPOSE: To evaluate the clinical-pathological and prognostic significance of the circulating PD-L1 level in patients with surgically treated NSCLC, by combining data for PD-L1 expression with other immune-related markers and tumor metabolism. METHODS: Overall, 40 patients with resected NSCLC (stage Ia-IIIa) who had preoperative blood storage and underwent staging PET/CT were enrolled for the study. In all cases, we determined plasma levels of PD-L1 (pg/ml), immune-reactive areas (IRA %) covered by CD3, CD68, CD20, CD8, PD-1, and PD-L1 in the tumor specimen, and metabolic parameters on PET, i.e., SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Variables were statistically analyzed to establish their association with disease-free survival (DFS). RESULTS: The circulating levels of PD-L1 in the bloodstream could be determined in 38/40 (95%) samples. The mean and median expression levels were 34.86 pg/ml and 24.83 pg/ml, respectively. We did not find any statistically significant correlation between circulating PD-L1 and tissue expression of PD-L1/PD-1. Some mild degree of positive correlation was determined between tissue PD-L1 and SUVmax (ρ = 0.390; p = 0.0148). Hierarchical clustering combining circulating, tissue, and metabolic parameters identified clusters with high metabolic tumor burden or high expression of plasma PD-L1 levels (Z score ≥ 2) as having a poor DFS (p = 0.033). The multivariate analysis detected stage and metabolism (i.e., SUVmax and SUVpeak) as independent prognostic factors for DFS. CONCLUSION: Plasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical-pathological parameters, allow for the identification of clusters with different outcomes.

Computer-aided assessment of the extra-cellular matrix during pancreatic carcinogenesis: a pilot study.

BACKGROUND: A hallmark of pancreatic ductal adenocarcinoma is the desmoplastic reaction, but its impact on the tumor behavior remains controversial. Our aim was to introduce a computer -aided method to precisely quantify the amount of pancreatic collagenic extra-cellular matrix, its spatial distribution pattern, and the degradation process. METHODS: A series of normal, inflammatory and neoplastic pancreatic ductal adenocarcinoma formalin-fixed and paraffin-embedded Sirius red stained sections were automatically digitized and analyzed using a computer-aided method. RESULTS: We found a progressive increase of pancreatic collagenic extra-cellular matrix from normal to the inflammatory and pancreatic ductal adenocarcinoma. The two-dimensional fractal dimension showed a significant difference in the collagenic extra-cellular matrix spatial complexity between normal versus inflammatory and pancreatic ductal adenocarcinoma. A significant difference when comparing the number of cycles necessary to degrade the pancreatic collagenic extra-cellular matrix in normal versus inflammatory and pancreatic ductal adenocarcinoma was also found. The difference between inflammatory and pancreatic ductal adenocarcinoma was also significant. Furthermore, the mean velocity of collagenic extra-cellular matrix degradation was found to be faster in inflammatory and pancreatic ductal adenocarcinoma than in normal. CONCLUSION: These findings demonstrate that inflammatory and pancreatic ductal adenocarcinomas are characterized by an increased amount of pancreatic collagenic extra-cellular matrix and by changes in their spatial complexity and degradation. Our study defines new features about the pancreatic collagenic extra-cellular matrix, and represents a basis for further investigations into the clinical behavior of pancreatic ductal adenocarcinoma and the development of therapeutic strategies.

The Complexity and Fractal Geometry of Nuclear Medicine Images.

Irregularity in shape and behavior is the main feature of every anatomical system, including human organs, tissues, cells, and sub-cellular entities. It has been shown that this property cannot be quantified by means of the classical Euclidean geometry, which is only able to describe regular geometrical objects. In contrast, fractal geometry has been widely applied in several scientific fields. This rapid growth has also produced substantial insights in the biomedical imaging. Consequently, particular attention has been given to the identification of pathognomonic patterns of "shape" in anatomical entities and their changes from natural to pathological states. Despite the advantages of fractal mathematics and several studies demonstrating its applicability to oncological research, many researchers and clinicians remain unaware of its potential. Therefore, this review aims to summarize the complexity and fractal geometry of nuclear medicine images.

Prognostic Impact of Intratumoral Heterogeneity Based on Fractal Geometry Analysis in Operated NSCLC Patients.

PURPOSE: To determine the heterogeneity of glucose uptake applying fractal analysis on positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) images in patients with non-small cell lung carcinoma (NSCLC) before surgery, and to assess whether this heterogeneity was associated with disease-free survival (DFS). PROCEDURES: [18F]FDG PET/CT scans of 113 patients' prior surgery were retrospectively revised. PET DICOM images were analyzed for fractal geometry using a ad hoc software to automatically determine the following indexes: (a) mean intensity value (MIV), (b) standard deviation (SD), (c) relative dispersion (RD), (d) three-dimensional (3D) histogram of the fractal dimension (3D HIST FR DIM), and (e) fractal dimension in 3D (3D-FD). All the fractal indexes were subsequently compared with metabolic parameters and disease-free survival (DFS). RESULTS: We found a significant correlation between 3D-FD and SUVmax, SUVmean, MTV, and TLG. Additionally, positive correlations between MIV, SD, and all metabolic parameters were also detected. Patients with high 3D-FD tumor (≥ 1.62) showed significantly higher values of SUVmax, SUVmean, MTV, and TLG than those with lower 3D-FD. In univariate analysis, median 3D-FD and median TLG were significantly associated with DFS (p = 0.04 and p = 0.03, respectively). These findings were confirmed on log-rank test. On multivariate analysis, among age, stage disease, histotype, 3D-FD, and metabolic parameters, only 3D-FD was identified as independent prognostic factor for DFS (p = 0.032; HR 0.418, 95 % CI 0.189-0.926). 3D-FD was different between adenocarcinoma and squamous cell carcinoma (1.60 versus 1.88, p = 0.014), and 3D-FD value was found higher in advanced stage disease. CONCLUSIONS: Metabolic heterogeneity determined applying fractal principles on PET images can be considered as a novel imaging biomarker for survival in patients with NSCLC.

18F-FDG PET/CT for response assessment in Hodgkin lymphoma undergoing immunotherapy with checkpoint inhibitors.

Our aim was to evaluate Hodgkin Lymphoma (HL) response to checkpoint inhibitors with 18F-FDG PET/CT. Forty three refractory or relapsed HL patients were investigated before immunotherapy, 8 weeks and 17 weeks after administration of either nivolumab or pembrolizumab. The median follow-up was 19 months. Best clinical response was complete response (CR) in 26 patients, partial response (PR) in 5 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 4 patients. At the early assessment, Deauville Score (DS) resulted significantly different in responder group compared to nonresponders. SUVmax was significantly lower in responders, while there was no relevant modification in the tumor burden. At interim evaluation, DS well differentiated responder group. A significant decrease in glucose metabolism and tumor burden parameters was observed in responder patients, who presented with a longer progression-free survival then nonresponders. 18F-FDG PET/CT provides a reliable indication of treatment response under checkpoints inhibitors, even at an early assessment.

Celiac disease: From pathophysiology to treatment.

Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.

Correlation of metabolic information on FDG-PET with tissue expression of immune markers in patients with non-small cell lung cancer (NSCLC) who are candidates for upfront surgery.

PURPOSE: Eliciting antitumor T-cell response by targeting the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a novel therapeutic strategy in non-small cell lung cancer (NSCLC). The identification of predictors for sensitivity or resistance to these agents is, therefore, needed. Herein, we investigate the correlation of metabolic information on FDG-PET with tissue expression of immune-checkpoints and other markers of tumor-related immunity in resected NSCLC patients. MATERIALS AND METHODS: All patients referred to our institution for upfront surgical resection of NSCLC, who were investigated with FDG-PET prior to surgery, were consecutively included in the study. From January 2010 to May 2014, 55 patients (stage IA-IIIB; M:F = 42:13; mean age 68.9 years) were investigated. Sampled surgical tumor specimens were analyzed by immunohistochemistry (IHC) for CD68-TAMs (tumor-associated macrophages), CD8-TILs (tumor infiltrating lymphocytes), PD-1-TILs, and PD-L1 tumor expression. Immunoreactivity was evaluated, and scores were compared with imaging findings. FDG-PET images were analyzed to define semi-quantitative parameters: SUVmax and SUVmean. Metabolic information on FDG-PET was correlated with tissue markers expression and disease-free survival (DFS) considering a median follow-up of 16.2 months. RESULTS: Thirty-six adenocarcinomas (ADC), 18 squamous cell carcinomas (SCC), and one sarcomatoid carcinoma were analyzed. All tumors resulted positive at FDG-PET: median SUVmax 11.3 (range: 2.3-32.5) and SUVmean 6.4 (range: 1.5-13) both resulted significantly higher in SCC compared to other NSCLC histotypes (p = 0.007 and 0.048, respectively). IHC demonstrated a median immunoreactive surface covered by CD68-TAMs of 5.41 % (range: 0.84-14.01 %), CD8-TILs of 2.9 % (range: 0.11-11.92 %), PD-1 of 0.65 % (range: 0.02-5.87 %), and PD-L1 of 0.7 % (range: 0.03-10.29 %). We found a statistically significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (rho = 0.31; p = 0.027) and PD-1 (rho = 0.33; p = 0.017 and rho = 0.36; p = 0.009, respectively). The other tissue markers correlated as follows: CD8 TILs and PD-1 (rho = 0.45; p = 0.001), CD8 TILs and PD-L1 (rho = 0.41; p = 0.003), CD68-TAMs and PD-L1 (rho = 0.30; p = 0.027), PD-1 and PD-L1 (rho = 0.26; p = 0.059). With respect to patients' outcome, SUVmax, SUVmean, and disease stage showed a statistically significant correlation with DFS (p = 0.002, 0.004, and <0.001, respectively). CONCLUSIONS: The present study shows a direct association between metabolic parameters on FDG-PET and the expression of tumor-related immunity markers, suggesting a potential role for FDG-PET to characterize the tumor microenvironment and select NSCLC patients candidate to checkpoint inhibitors.