• Extrapulmonary small cell carcinoma: a clinicopathological study with identification of potential diagnostic mimics.

      Quinn, A M; Blackhall, Fiona H; Wilson, G; Danson, S; Clamp, Andrew R; Ashcroft, Linda; Brierley, J; Hasleton, P; Department of Pathology, Manchester Royal Infirmary, Manchester, UK. (2012-09)
      To evaluate the clinicopathological features of small cell carcinoma arising outside the lung.
    • Phylogenetic ctDNA analysis depicts early stage lung cancer evolution.

      Abbosh, C; Birkbak, N; Wilson, G; Jamal-Hanjani, M; Constantin, T; Salari, R; Quesne, J; Moore, D; Veeriah, S; Rosenthal, R; et al. (2017-04-26)
      The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a tumour-specific phylogenetic approach to ctDNA profiling in the first 100 TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.
    • Precision oncology and genomically guided radiation therapy: a report from the American Society for Radiation Oncology/American Association of Physicists in Medicine/National Cancer Institute Precision Medicine Conference.

      Hall, W; Bergom, C; Thompson, R; Baschnagel, A; Vijayakumar, S; Willers, H; Li, X A; Schultz, C; Wilson, G; West, Catharine M L; et al. (2017-06-09)
      To summarize important talking points from a 2016 symposium focusing on real-world challenges to advancing precision medicine in radiation oncology, and to help radiation oncologists navigate the practical challenges of precision, radiation oncology.
    • A retrospective analysis of selective internal radiation therapy (SIRT) with yttrium-90 microspheres in patients with unresectable hepatic malignancies.

      Omed, A; Lawrance, Jeremy A L; Murphy, G; Laasch, Hans-Ulrich; Wilson, G; Illidge, Timothy M; Tipping, Jill; Zivanovic, M; Jeans, S; Manchester Medical School, University of Manchester, Stopford Building, Manchester, UK. aliomed0101@doctors.org.uk (2010-09)
      AIM: To evaluate the efficacy and safety of selective internal radiation therapy (SIRT). MATERIALS AND METHODS: A retrospective analysis was undertaken of all patients who underwent SIRT at a single institution. Diagnostic and therapeutic angiograms, computed tomography (CT) images, positron-emission tomography (PET) images, and planar isotope images were analysed. The response to SIRT was analysed using radiological data and tumour markers. Overall survival, complications, and side effects of SIRT were also analysed. RESULTS: The initial 12 patients were included on an intention-to-treat basis, between 21/09/2005 and 07/05/2008. All patients had advanced disease and multiple prior courses of chemotherapy. One patient did not receive yttrium-90 due to complex vascular anatomy; the remaining 11 patients underwent 13 SIRT treatment episodes following work-up angiography. A response was seen using PET in 80% of patients. Using CT, the response of the tumour to therapy in the treated hepatic segments demonstrated a 20% partial response, stable disease in 50%, and progressive disease in 30%. Estimated median survival was 229 days, with 64% of patients still alive at the time of writing. No major complications were observed, although 82% of patients experienced side-effects following SIRT, mainly nausea, vomiting, and abdominal pain. CONCLUSIONS: There have been no complications in the 12 SIRT patients. Tumour response was seen in four out of five patients who underwent PET. Objective CT response rates were mixed and are perhaps partially explained by advanced disease and limitations of using measurements to assess response. This complex and potentially hazardous service has been successfully and safely established.
    • Tracking the evolution of non-small-cell lung cancer.

      Jamal-Hanjani, M; Wilson, G; McGranahan, N; Birkbak, N; Watkins, T; Veeriah, S; Shafi, S; Johnson, D; Mitter, R; Rosenthal, R; et al. (2017-04-26)
      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 .).