Vineet Prakash

Tracking the Evolution of Non–Small-Cell Lung Cancer

BACKGROUND Among patients with non‐small‐cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early‐stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole‐exome sequencing on 100 early‐stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence‐free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy‐number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy‐number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy‐number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10‐4), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601.)

The role of texture analysis in imaging as an outcome predictor and potential tool in radiotherapy treatment planning

Predicting a tumours response to radiotherapy prior to the start of treatment could enhance clinical care management by enabling the personalization of treatment plans based on predicted outcome. In recent years, there has been accumulating evidence relating tumour texture to patient survival and response to treatment. Tumour texture could be measured from medical images that provide a non-invasive method of capturing intratumoural heterogeneity and hence could potentially enable a prior assessment of a patients predicted response to treatment. In this article, work presented in the literature regarding texture analysis in radiotherapy in relation to survival and outcome is discussed. Challenges facing integrating texture analysis in radiotherapy planning are highlighted and recommendations for future directions in research are suggested.

Towards Detecting High-Uptake Lesions from Lung CT Scans Using Deep Learning.

Automatic detection of lung lesions from computed tomography (CT) and positron emission tomography (PET) is an important task in lung cancer diagnosis. While CT scans make it possible to retrieve structural information, PET images reveal the functional aspects of the tissue, hence combined PET/CT imagery allows for detecting metabolically active lesions. In this paper, we explore how to exploit deep convolutional neural networks to identify the active tumour tissue exclusively from CT scans, which, to the best of our knowledge, has not been attempted yet. Our experimental results are very encouraging and they clearly indicate the possibility of detecting lesions with high glucose uptake, which could increase the utility of CT in lung cancer diagnosis.

A case of aortitis during cisplatin-based chemotherapy for cervical cancer

A case of aortitis in a patient undergoing adjuvant cisplatin and topotecan chemotherapy for cervical cancer following presentation with pyrexia of unknown origin and raised inflammatory markers is presented. Although many chemotherapy agents are known to cause small vessel vasculitis and there are several reported cases of large vessel vasculitis following gemcitabine chemotherapy, there is only one previously described case of aortitis following cisplatin administration. This case is presented with corresponding CT and 18F-FDG PET-CT imaging with discussion of the literature regarding vasculitis and chemotherapy.

Factors influencing the robustness of P-value measurements in CT texture prognosis studies

Several studies have recently reported on the value of CT texture analysis in predicting survival, although the topic remains controversial, with further validation needed in order to consolidate the evidence base. The aim of this study was to investigate the effect of varying the input parameters in the Kaplan-Meier analysis, to determine whether the resulting P-value can be considered to be a robust indicator of the parameters prognostic potential. A retrospective analysis of the CT-based normalised entropy of 51 patients with lung cancer was performed and overall survival data for these patients were collected. A normalised entropy cut-off was chosen to split the patient cohort into two groups and log-rank testing was performed to assess the survival difference of the two groups. This was repeated for varying normalised entropy cut-offs and varying follow-up periods. Our findings were also compared with previously published results to assess robustness of this parameter in a multi-centre patient cohort. The P-value was found to be highly sensitive to the choice of cut-off value, with small changes in cut-off producing substantial changes in P. The P-value was also sensitive to follow-up period, with particularly noisy results at short follow-up periods. Using matched conditions to previously published results, a P-value of 0.162 was obtained. Survival analysis results can be highly sensitive to the choice in texture cut-off value in dichotomising patients, which should be taken into account when performing such studies to avoid reporting false positive results. Short follow-up periods also produce unstable results and should therefore be avoided to ensure the results produced are reproducible. Previously published findings that indicated the prognostic value of normalised entropy were not replicated here, but further studies with larger patient numbers would be required to determine the cause of the different outcomes.