El should be utilized and given responsibility for tissue acquisition and transport, physician training, and other aspects of sample acquisition and handling. Moreover, surgeons, interventional radiologists, and others obtaining samples should be properly trained and tightly integrated into the research team. Inclusion of patients as well as I-CBP112 supplier clinical personnel in the scientific discussion, when feasible, will increase patient willingness to donate tissue specimens and ultimately result in better sample quality. Further, proper annotation of research samples is critical to document the anatomic site (preferably including sub-localization within a given lesion), as well as parameters related to tissue collection and handling, such as time from biopsy/excision to fixation (warm and cold ischemia time), and freezing or other storage/processing steps. Where feasible, samples should be annotated with data related to the location of the lesion on radiographic imaging to allow for appropriate PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28607003 data interpretation in the respective context and the longitudinal resampling of the same anatomic site.Multi-institutional studiesSpecial considerations are necessary when performing tumor immune monitoring in the context of multi-institutional studies. Quality control measures and analytical approaches should be put in place to both minimize and quantify site-dependent variability. This can include centralized specimen shipping kit preparation, overnight specimen shipment in temperature controlled containers, and processing upon arrival. For example, standardized approaches to sample processing, fixation and embedding (or alternate tissue preparation approaches appropriate for a given protocol), as well as sample storage and shipping should be used. It is desirable to centralize as many analytical steps as possible, including tissue sectioning and preparation (e.g., nucleic acid extraction) and analytical assay work. Samples received from multiple institutions should be analyzed in batches, and batched (or real-time) analysis should be used to support the early detection of preanalytical or analytical quality control issues to ensure that these sources of variation are minimized. Any potentially problematic samples should be annotated accordingly to flag them.Other sources for variabilityPre-analytical variability is influenced not only by technical factors, but also by biological heterogeneity. Where such heterogeneity cannot be fully controlled, it must be well characterized in order to guide the proper design of hypothesis-driven translational research studies [80].Stroncek et al. Journal for ImmunoTherapy of Cancer (2017) 5:Page 7 ofIntra-tumoral heterogeneity of tumor cell clonotypes has been clearly documented through the observation of distinct somatic mutation profiles at different regions within a single lesion [81, 82]. Clonotypic heterogeneity between primary and metastatic lesions and from one metastasis to the next has also been well documented and can directly translate to the heterogeneity of clinical response between lesions within a single patient, which impacts overall disease outcome and treatment opportunities [6, 7]. Likewise, the immune TME may exhibit inter- and intra-lesional heterogeneity. For example, PDL1 expression has been observed to be discordant between tumor sites in some cases [83]. Preliminary data also show significant intra-patient, inter-lesional diversity in TCR clonality and immune gene expression. Experimentally,.