The path to a better biomarker: Application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying 651% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin\u2013stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. \ua9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Above- and below-ground biomass accumulation, production, and distribution of sweetgum and loblolly pine grown with irrigation and fertilization.

Abstract: Increased forest productivity has been obtained by improving resource availability through water and nutrient amendments. However, more stress-tolerant species that have robust site requirements do not respond consistently to irrigation. An important factor contributing to robust site requirements may be the distribution of biomass belowground, yet available information is limited. We examined the accumulation and distribution of above- and below-ground biomass in sweetgum (Liqrridambar sfyrac$lua L.) and loblolly pine (Pinus taeda L.) stands receiving irrigation and fertilization. Mean annual aboveground production after 4 years ranged from 2.4 to 5.1 ~g.ha-'.year' for sweetgum and from 5.0 to 6.9 ~g.ha-l.year-l for pine. Sweetgum responded positively to irrigation and fertilization with an additive response to irrigation + fertilization. Pine only responded to fertilization. Sweetgum root mass fraction (RME)in creased with fertilization at 2 years and decreased with fertilization at 4 years. There were no detectable treatment differences in loblolly pine RMF. Development explained from 67% to 98% of variation in shoot versus root allometry for ephemeral and perennial tissues, fertilization explained no more than 5% of the variation in for either species, and irrigation did not explain any. We conclude that shifts in allocation from roots to shoots do not explain nutrient-induced growth stimulations

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

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

Horizontal drilling in shallow reservoirs

The objectives of this joint horizontal drilling effort by the US DOE and Belden Blake in the complex, low permeability Clinton Sandstone will focus on the following objectives: (1) apply horizontal drilling technology in hard, abrasive, and tight Clinton Sandstone; (2) evaluate effects of multiple hydraulic fracturing in a low permeability horizontal wellbore; (3) assess economic viability of horizontal drilling in the Clinton and similar tight gas sands