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Background Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. Methods Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [ 99m Tc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. Results Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69–12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59–0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65–0.88]) or shape feature classes (c-index 0.79 [0.66–0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59–0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R 2  = 0.84–1.00), representing surrogates rather than independent predictors of pneumonitis risk. Conclusions In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Background Cardiac sarcoidosis is associated with major adverse cardiac events including cardiac arrest, for which anti-inflammatory treatment is indicated. Oral corticosteroid is the mainstay among treatment options; however, adverse effects are a major concern with long-term use. It would be beneficial for providers to predict treatment response and prognosis for proper management strategy of sarcoidosis, though it remains challenging. Fluorine (F)-18 fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography(CT) has an advantage over anatomical imaging in providing semi-quantitative functional parameters such as standard uptake value (SUV), metabolic volume, and total lesion glycolysis (TLG), which are well-established biomarkers in oncology. However, the relationship between these parameters and treatment response has not been fully investigated in cardiac sarcoidosis. Also, the prognostic value of extracardiac active inflammation noted on FDG-PET/CT in the setting of cardiac sarcoidosis is unclear. The aim of this retrospective study was to investigate the prognostic value of semi-quantitative values of both cardiac and extracardiac disease sites derived from FDG-PET/CT in predicting treatment course in cardiac sarcoidosis. Methods Sixteen consecutive patients with suspected cardiac sarcoidosis, who demonstrated abnormal myocardial activity on cardiac-inflammation FDG-PET/CT encompassing the entire chest/upper abdomen and subsequently underwent corticosteroid therapy for diagnosis of active cardiac sarcoidosis, were included. Semi-quantitative values of hypermetabolic lesions were derived from all visualized organ system and were compared to daily corticosteroid dose at 6 months. Results  Of the 16 patients, 81.3% (13/16) of the patients showed extracardiac involvement. The lesion with the greatest SUV was identified in the heart in 11 patients (68.7%), in the liver in 1 patient (6.3%), and in lymph nodes in 4 patients (25%). The maximum SUV across all visualized organ systems including the heart were 8.8 ± 3.1 for the patients with corticosteroid dose ≤ 10 mg and 12.5 ± 3.3 for those with > 10 mg ( P  = 0.04). Metabolic volume and TLG across all visualized organ systems or any values in the heart alone showed no significant statistical difference between the two groups. Conclusions Maximum SUV across all involved organ-systems of the chest and upper abdomen, not that of the heart alone, could be a predictor of treatment course of steroid therapy at 6 months in patients with active cardiac sarcoidosis.

Background Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. Methods In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. Results Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18–21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18–21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% ( p  = 0.96 and 0.85). Conclusions This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. Trial registration NCT00227539 registered September 28th, 2005.

PurposeThe purpose of the study was to correlate lung shunt fraction (LSF) calculated by intra-arterial injection of Technetium-99m (Tc-99m)-labeled macroaggregated albumin (MAA) in a hepatic artery branch with the presence of certain patterns of vascular shunts on dynamic CT or MRI of the liver.MethodsThis retrospective study was approved by the institutional review board and informed consent was waived. We reviewed 523 MAA scans in 453 patients (301 men, 152 women) performed from July 2007 to June 2015 and their correlative cross-sectional imaging. Patterns of vascular shunts on dynamic CT or MRI performed within 3 months of the MAA study and that potentially divert hepatic arterial inflow to the systemic venous return were defined as “target shunts.” Dynamic CT or MRI was classified into three groups with target shunt present, absent, or indeterminate. The mean LSF was compared across the first and second groups using paired t test.Results342 CT and MRI studies met inclusion criteria: target shunts were present in 63 studies, absent in 271 studies, and 8 studies were indeterminate. When target shunts were visualized, the mean LSF on corresponding MAA scans was 12.9 ± 10.36% (95% CI 10.29–15.15%) compared to 4.3 ± 3.17% (95% CI 3.93–4.68%) when no target shunt was visualized. The difference was statistically significant (p value < 0.001). Identified target shunts were either direct (arteriohepatic venous shunt) or indirect (arterioportal shunt combined with a portosystemic shunt).ConclusionsVisualizing certain patterns of vascular shunting on a dynamic CT or MRI scan is associated with high LSF.

Purpose To design and apply a framework for predicting symptomatic radiation pneumonitis in patients undergoing thoracic radiation, using both pretreatment anatomic and perfused lung dose–volume parameters. Materials and methods Radiation treatment planning CT scans were coregistered with pretreatment [ 99m Tc]MAA perfusion SPECT/CT scans of 20 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥ 2 (CTCAE v4 grading system). Anatomic lung dose–volume parameters were collected from the treatment planning scans. Perfusion dose–volume parameters were calculated from pretreatment SPECT/CT scans. Equivalent doses in 2 Gy per fraction were calculated in the lung to account for differences in treatment regimens and spatial variations in lung dose (EQD2 lung ). Results Anatomic lung dosimetric parameters (MLD) and functional lung dosimetric parameters (pMLD 70% ) were identified as candidate predictors of grade ≥ 2 radiation pneumonitis (AUC > 0.93, p  < 0.01). Pairing of an anatomic and functional dosimetric parameter (e. g., MLD and pMLD 70% ) may further improve prediction accuracy. Not all individuals with high anatomic lung dose (MLD > 13.6 GyEQD2 lung , 19.3 Gy for patients receiving 60 Gy in 30 fractions) developed radiation pneumonitis, but all individuals who also had high mean dose to perfused lung (pMLD 70%  > 13.3 GyEQD2) developed radiation pneumonitis. Conclusions The preliminary application of this framework revealed differences between anatomic and perfused lung dosimetry in this limited patient cohort. The addition of perfused lung parameters may help risk stratify patients for radiation pneumonitis, especially in treatment plans with high anatomic mean lung dose. Further investigations are warranted.

Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a [greater than or equai to] 20% decrease in the SUV of the primary lesion. Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy.

Background Assessment of liver function is critical in hepatocellular carcinoma (HCC) patient management. We evaluated parameters of [ 99m Tc] sulfur colloid (SC) SPECT/CT liver uptake for association with clinical measures of liver function and outcome in HCC patients. Methods Thirty patients with HCC and variable Child-Turcotte-Pugh scores (CTP A5-C10) underwent [ 99m Tc]SC SPECT/CT scans for radiotherapy planning. Gross tumor volume (GTV), anatomic liver volume (ALV), and spleen were contoured on CT. SC SPECT image parameters include threshold-based functional liver volumes (FLV) relative to ALV, mean liver-to-spleen uptake ratio (L/S mean ), and total liver function (TLF) ratio derived from the product of FLV and L/S mean . Optimal SC uptake thresholds were determined by ROC analysis for maximizing CTP classification accuracy. Image metrics were tested for rank correlation to composite scores and clinical liver function parameters. Image parameters of liver function were tested for association to overall survival with Cox proportional hazard regression. Results Optimized thresholds on SC SPECT were 58 % of maximum uptake for FLV, 38 % for L/S mean , and 58 % for TLF. TLF produced the highest CTP classification accuracy (AUC = 0.93) at threshold of 0.35 (sensitivity = 0.88, specificity = 0.86). Higher TLF was associated with lower CTP score: TLF A  = 0.6 (0.4–0.8) versus TLF B  = 0.2 (0.1–0.3), p  < 10 −4 . TLF was rank correlated to albumin and bilirubin (| R | > 0.63). Only TLF >0.30 was independently associated with overall survival when adjusting for CTP class (HR = 0.12, 95 % CI = 0.02–0.58, p  = 0.008). Conclusions SC SPECT/CT liver uptake correlated with differential liver function. TLF was associated with improved overall survival and may aid in personalized oncologic management of HCC patients.

Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results  Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.

Assessing cellular proliferation provides a direct method to measure the in vivo growth of cancer. We evaluated the application of a model of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) kinetics described in a companion report to the analysis of FLT PET image data in lung cancer patients. Compartmental model analysis was performed to estimate the overall flux constants (K(FLT)) for FLT phosphorylation in tumor, bone marrow, and muscle. Estimates of flux were compared with an in vitro assay of proliferation (Ki-67) applied to tissue derived from surgical resection. Compartmental modeling results were compared with simple model-independent methods of estimating FLT uptake. Seventeen patients with 18 tumor sites underwent up to 2 h of dynamic PET with blood sampling. Metabolite analysis of plasma samples corrected the total blood activity for labeled metabolites and provided the FLT model input function. A 2-compartment, 4-parameter model (4P) was tested and compared with a 2-compartment, 3-parameter (3P) model for estimating K(FLT). Bone marrow, a proliferative normal tissue, had the highest values of K(FLT), whereas muscle, a nonproliferating tissue, showed the lowest values. The K(FLT) for tumors estimated by compartmental analysis had a fair correlation with estimates by modified graphical analysis (r = 0.86) and a poorer correlation with the average standardized uptake value (r = 0.62) in tumor. Estimates of K(FLT) derived from 60 min of dynamic PET data using the 3P model underestimated K(FLT) compared with 90 or 120 min of dynamic data analyzed using the 4P model. Comparison of flux estimates with an independent measure of cellular proliferation showed that K(FLT) was highly correlated with Ki-67 (Spearman rho = 0.92, P < 0.001). Ignoring the metabolites of FLT in blood underestimated K(FLT) by as much as 47%. Compartmental analysis of FLT PET image data yielded robust estimates of K(FLT) that correlated with in vitro measures of tumor proliferation. This method can be applied generally to other imaging studies of different cancers after validation of parameter error. Tumor loss of phosphorylated FLT nucleotides (k(4)) is notable and leads to errors when FLT uptake is evaluated using model-independent approaches that ignore k(4), such as graphical analysis or the SUV.