Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

The influence of sagittal profile alteration and final lordosis on the clinical outcome of cervical spondylotic myelopathy. A Delta-Omega-analysis

<div><p>Purpose</p><p>Decompression and maintaining or restoring a cervical lordosis are major goals in the surgical treatment of cervical spondylotic myelopathy (CSM). Numerous studies support the assumption that cervical lordosis is a key factor for neurological recovery and pain reduction. However, even kyphotic patients can be asymptomatic. The balance of the spine is subject of an increasing number of publications. The main purpose of the study was to evaluate the validity of lordotic alignment on the course of CSM and to set this parameter in context with well-validated tools, namely the modified Japanese Orthopaedic Association scoring system (mJOAS) and the visual analogue scale (VAS), to predict and measure the clinical outcome after surgery.</p><p>Methods</p><p>This is a retrospective study with prospectively collected data of a heterogeneous cohort. The authors analyzed the records of 102 patients suffering from CSM that underwent decompressive surgery and instrumentation. Clinical outcome was assessed by using the mJOAS, VAS and Odom’s criteria. The radiological analysis involved comparison of pre- and postoperative radiographs. The patients were divided into subgroups to be able to compare the influence of various amounts of correction (3 Delta-groups: <0°, 1–7° and ≥8°) and final lordosis (4 Omega-groups: 0–7°, 8–14°, 15–21°, ≥22°).</p><p>Results</p><p>219 levels were fused in 102 patients. Surgery improved the clinical outcome of all groups significantly. A lordotic profile was achieved in all analyzed groups. Patients that showed small lordosis after surgery (<8°) did not have an inferior clinical outcome compared to patients with larger cervical lordosis (>14°). The comparison of Odom’s criteria showed that preoperatively kyphotic patients benefitted more from surgery than lordotic patients (p = 0.029), but no differences could be seen comparing neck pain and neurological improvement. The improvement of pain and neurological impairment measured by VAS and mJOAS supports the statistical impact and validity of the data despite comparatively small numbers of patients. The lack of postoperative kyphosis is a major limitation of the study to encompass the impact of sagittal alignment on clinical outcome.</p><p>Conclusions</p><p>Decompression and stabilization appear to be key elements of surgical treatment of CSM. While the achievement of cervical lordosis remains a major goal of surgery, clinical improvement is not hindered in patients who show small lordosis. However, kyphosis should be eliminated in symptomatic patients. The terms “balance” and “physiologic lordosis” remain complex entities without clear definition. To check the results of our study controlled randomized trials to validate and determine the exact role of cervical balance on the course of CSM would be helpful.</p></div

Polymethylmethacrylate-assisted ventral discectomy: Rate of pseudarthrosis and clinical outcome with a minimum follow-up of 5 years

Abstract Background Polymethylmethacrylate (PMMA) assisted ventral discectomy has been criticized for high rates of graft migration and pseudarthrosis when compared with various other fusion procedures for the treatment of cervical degenerative disc disease (DDD), therefore rendering it not the preferred choice of treatment today. Recently however spine surgery has been developing towards preservation rather than restriction of motion, indicating that fusion might not be necessary for clinical success. This study presents a long term comparison of clinical and radiological data from patients with pseudarthrosis and solid arthrodesis after PMMA assisted ventral discectomy was performed. Methods From 1986 to 2004 416 patients underwent ventral discectomy and PMMA interposition for DDD. The clinical and radiological outcome was assessed for 50 of 127 eligible patients after a mean of 8.1 years. Based on postoperative radiographs the patients were dichotomized in those with a pseudarthrosis (group A) and those with solid arthrodesis (group B). Results Pseudarthrosis with movement of more than 2 of the operated segment was noted in 17 cases (group A). In 33 cases no movement of the vertebral segment could be detected (group B). The analysis of the clinical data assessed through the neck disability index (NDI), the visual analogue scale (VAS) of neck and arm pain and Odom's criteria did not show any significant differences between the groups. Patients from group B showed a trend to higher adjacent segment degeneration (ASD) than group A (p = 0.06). This correlated with the age of the patients. Conclusions PMMA assisted discectomy shows a high rate of pseudarthrosis. But the clinical long-term success does not seem to be negatively affected by this.</p

Surgical technique stratified by preoperative alignment.

<p>Surgical technique stratified by preoperative alignment.</p

Radiological data of changed cervical sagittal alignment (Delta groups).

<p>Radiological data of changed cervical sagittal alignment (Delta groups).</p

Clinical data in context with final sagittal alignment (Omega).

<p>Clinical data in context with final sagittal alignment (Omega).</p

Clinical data compared to sagittal change (Delta).

<p>Clinical data compared to sagittal change (Delta).</p