A number of papers have established that a high density of tumor-infiltrating lymphocytes (TILs) is highly correlated with a better prognosis for many different cancer types. More recently, some studies have shown that the spatial interplay between different subtypes of TILs (e.g. CD3, CD4, CD8) is more prognostic of disease outcome compared to just metrics related to TIL density. A challenge with TIL subtyping is that it relies on quantitative immunofluoresence or immunohistochemistry, complex and tissue-destructive technologies. In this paper we present a new approach called PhenoTIL to identify TIL sub-populations and quantify the interplay between these sub-populations and show the association of these interplay features with recurrence in early stage lung cancer. The approach comprises a Dirichlet Process Gaussian Mixture Model that clusters lymphocytes on H&E images. The approach was evaluated on a cohort of N=178 early stage non-small cell lung cancer patients, N=100 being used for model training and N=78 being used for independent validation. A Linear Discriminant Analysis classifier was trained in conjunction with 186 PhenoTIL features to predict the likelihood of recurrence in the test set. The PhenoTIL features yielded an AUC=0.84 compared to an approach involving just TIL density alone (AUC=0.58). In addition, a Kaplan-Meier analysis showed that the PhenoTIL features were able to statistically significantly distinguish early from late recurrence (p = 4 ∗ 10 −5 ).
Recently immune-checkpoint inhibitors have demonstrated promising clinical efficacy in patients with advanced non-small cell lung cancer (NSCLC). However, the response rates to immune checkpoint blockade drugs remain modest (45% in the front line setting and 20% in the second line setting). Consequently, there is an unmet need to develop accurate, validated biomarkers to predict which NSCLC patients will benefit from immunotherapy. While there has been recent interest in evaluating the role of texture and shape patterns of the nodule on CT scans to predict response to checkpoint inhibitors for NSCLC, our group has shown that nodule vessel morphology might also play a role in determining tumor aggressiveness and behavior. In this work we present a new approach using quantitative vessel tortuosity (QVT) radiomics, to predict response to checkpoint inhibitors and overall survival for patients with NSCLC treated with Nivolumab (a PD1 inhibitor) on a retrospective data set of 111 patients (D1) including 56 responders and 45 non-responders. Patients who did not receive Nivolumab after 2 cycles due to a lack of response or progression as per Response Evaluation Criteria in Solid Tumors (RECIST) were classified as non-responders, patients who had radiological response or stable disease as per RECIST were classified as responders. On D1, in conjunction with a linear discriminant analysis (LDA) classifier the QVT features were able to predict response to immunotherapy with an AUC of 0.73_0.04. Kaplan Meier analysis showed significant difference of overall survival between patients with low risk and high risk defined by the radiomics classifier (p-value = 0.004, HR= 2.29, 95% CI= 1.35 - 3.87).
Immune checkpoint inhibitors targeting the programmed cell death (PD)1/ L1 axis have been approved for treatment of chemotherapy refractory advanced non-small cell lung cancer (NSCLC) for a few years. While higher PD-L1 expression is associated with better outcomes after monotherapy with immune checkpoint inhibitors, it is not a perfect predictive biomarker for clinical benefit from immunotherapy, because some patients with low PD-L1 expression have sustained responses. In clinical practice, using radiological tools like Response Evaluation Criteria in Solid Tumors (RECIST), tends to underestimate the benefit of therapy. For instance, some patients treated with immunotherapy suffer from pseudoprogression while actually having a favorable response, RECIST in this setting is inadequate to capture the response. In this study we sought to explore whether radiomic texture features extracted from both inside and outside of the tumor from baseline CT scans were associated with overall patient survival (OS) in 139 NSCLC patients being treated with IO from two separate sites. Patients were divided into a discovery (D1 = 50; nivolumab from Cleveland Clinic) and two validation sets (D2 = 62 from Cleveland Clinic, D3 = 27 from University of Pennsylvania Health System. Patients in the validation sets had been treated with different types of checkpoint inhibitor drugs including nivolumab, pembrolizumab, and atezolizumab. 454 radiomic texture features from within (intra-tumoral) and outside the tumor (peri-tumoral) were extracted from baseline contrast CT images. Following feature selection on the discovery set, a radiomic risk-score signature was generated by using least absolute shrinkage and selection operator. Using a Cox regression model, the association of the radiomic signature with overall survival (OS) was evaluated in the discovery and two validation sets. In addition, 95% confidence intervals (CI) and relative hazard ratios (HR) were calculated. Our results revealed that the radiomics signature was significantly associated with OS, both in the discovery set (HR = 5.06, 95%CI = 3, 8.55; p-value < 0.0001) and the two validation data sets (D2: HR = 5.88, 95% CI = 2.19, 21.63, p-value = 0.0009; D3: HR = 5.37, 95% CI = 1.74, 16.57, p-value = 0.0034). Our initial results appear to suggest that our radiomic signature could serve as a non-invasive way of predicting and monitoring response to checkpoint inhibitors for patients with non-small cell lung cancer.
Differentiation between benign and malignant nodules is a problem encountered by radiologists when visualizing computed tomography (CT) scans. Adenocarcinomas and granulomas have a characteristic spiculated appearance and may be fluorodeoxyglucose avid, making them difficult to distinguish for human readers. In this retrospective study, we aimed to evaluate whether a combination of radiomic texture and shape features from noncontrast CT scans can enable discrimination between granulomas and adenocarcinomas. Our study is composed of CT scans of 195 patients from two institutions, one cohort for training (N = 139) and the other (N = 56) for independent validation. A set of 645 three-dimensional texture and 24 shape features were extracted from CT scans in the training cohort. Feature selection was employed to identify the most informative features using this set. The top ranked features were also assessed in terms of their stability and reproducibility across the training and testing cohorts and between scans of different slice thickness. Three different classifiers were constructed using the top ranked features identified from the training set. These classifiers were then validated on the test set and the best classifier (support vector machine) yielded an area under the receiver operating characteristic curve of 77.8%.
Automatic detection of lymphocytes could contribute to develop objective measures of the infiltration grade of tumors, which can be used by pathologists for improving the decision making and treatment planning processes. In this article, a simple framework to automatically detect lymphocytes on lung cancer images is presented. This approach starts by automatically segmenting nuclei using a watershed-based approach. Nuclei shape, texture, and color features are then used to classify each candidate nucleus as either lymphocyte or non-lymphocyte by a trained SVM classifier. Validation was carried out using a dataset containing 3420 annotated structures (lymphocytes and non-lymphocytes) from 13 1000 × 1000 fields of view extracted from lung cancer whole slide images. A Deep Learning model was trained as a baseline. Results show an F-score 30% higher with the presented framework than with the Deep Learning approach. The presented strategy is, in addition, more flexible, requires less computational power, and requires much lower training times.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide. The treatment of choice for early stage NSCLC is surgical resection followed by adjuvant chemotherapy for high risk patients. Currently, the decision to offer chemotherapy is primarily dependent on several clinical and visual radiographic factors as there is a lack of a biomarker which can accurately stratify and predict disease risk in these patients. Computer extracted image features from CT scans (radiomic) and (pathomic) from H&E tissue slides have already shown promising results in predicting recurrence free survival (RFS) in lung cancer patients. This paper presents new radiology-pathology fusion approach (RaPtomics) to combine radiomic and pathomic features for predicting recurrence in early stage NSCLC. Radiomic textural features (Gabor, Haralick, Law, Laplace and CoLlAGe) from within and outside lung nodules on CT scans and intranuclear pathology features (Shape, Cell Cluster Graph and Global Graph Features) were extracted from digitized whole slide H&E tissue images on an initial discovery set of 50 patients. The top most predictive radiomic and pathomic features were then combined and in conjunction with machine learning algorithms were used to predict classifier. The performance of the RaPtomic classifier was evaluated on a training set from the Cleveland Clinic (n=50) and independently validated on images from the publicly available cancer genome atlas (TCGA) dataset (n=43). The RaPtomic prognostic model using Linear Discriminant Analysis (LDA) classifier, in conjunction with two radiomic and two pathomic shape features, significantly predicted 5-year recurrence free survival (RFS) (AUC 0.78; p<0.005) as compared to radiomic (AUC 0.74; p<0.01) and pathomic (AUC 0.67; p<0.05) features alone.
Tumor-infiltrating lymphocytes (TILs) have proved to play an important role in predicting prognosis, survival, and response to treatment in patients with a variety of solid tumors. Unfortunately, currently, there are not a standardized methodology to quantify the infiltration grade. The aim of this work is to evaluate variability among the reports of TILs given by a group of pathologists who examined a set of digitized Non-Small Cell Lung Cancer samples (n=60). 28 pathologists answered a different number of histopathological images. The agreement among pathologists was evaluated by computing the Kappa index coefficient and the standard deviation of their estimations. Furthermore, TILs reports were correlated with patient’s prognosis and survival using the Pearson’s correlation coefficient. General results show that the agreement among experts grading TILs in the dataset is low since Kappa values remain below 0.4 and the standard deviation values demonstrate that in none of the images there was a full consensus. Finally, the correlation coefficient for each pathologist also reveals a low association between the pathologists’ predictions and the prognosis/survival data. Results suggest the need of defining standardized, objective, and effective strategies to evaluate TILs, so they could be used as a biomarker in the daily routine.
Tumor-infiltrating lymphocytes occurs when various classes of white blood cells migrate from the blood stream towards the tumor, infiltrating it. The presence of TIL is predictive of the response of the patient to therapy. In this paper, we show how the automatic detection of lymphocytes in digital H and E histopathological images and the quantitative evaluation of the global lymphocyte configuration, evaluated through global features extracted from non-parametric graphs, constructed from the lymphocytes’ detected positions, can be correlated to the patient’s outcome in early-stage non-small cell lung cancer (NSCLC). The method was assessed on a tissue microarray cohort composed of 63 NSCLC cases. From the evaluated graphs, minimum spanning trees and K-nn showed the highest predictive ability, yielding F1 Scores of 0.75 and 0.72 and accuracies of 0.67 and 0.69, respectively. The predictive power of the proposed methodology indicates that graphs may be used to develop objective measures of the infiltration grade of tumors, which can, in turn, be used by pathologists to improve the decision making and treatment planning processes.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.