Context.— The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility. Objective.— To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology. Design.— The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review. Results.— The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, −0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities. Conclusions.— WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

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PurposeGiven the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.Experimental designUsing prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody.ResultsTILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets.ConclusionIntratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS.

Background Neoadjuvant radiotherapy (RT) is increasingly advocated in the management of soft tissue sarcoma (STS). Therefore, we sought to characterize the impact of neoadjuvant RT on rates of R0 resection and overall survival (OS) in extremity STS patients undergoing surgery. Methods From January 2003 to December 2012, we identified patients with a diagnosis of extremity STS from the National Cancer Database. After excluding patients with age < 18 years, not undergoing surgery, metastases at diagnosis, intraoperative RT, and missing/unknown data, we identified 27,969 patients. Using logistic regression and Cox-proportional hazard analysis, we compared rates of R0 resection among preoperative, postoperative and no RT cohorts and determined predictors of R0 resection and OS. Results The mean age was 59.5 (±17.1) years, and 45.9% were female. Median tumor size was 10.5cm. 51% of patients did not receive RT, 11.8% received pre-operative RT and 37.2% received post-operative RT. Rates of R0 resection for preoperative RT, postoperative RT, and no RT cohorts were 90.1%, 74.9%, and 79.9%, respectively (P<0.001). Independent predictors of achieving R0 resection included academic facility type (OR 1.36, 95% CI 1.20-1.55), histologic subtype, tumor size (OR 0.99, 95% CI 0.99-0.99), Charlson score (OR 0.92, 95% CI 0.84 – 0.99), and preoperative RT (OR 1.83, 95% CI 1.61-2.07). R0 resection as well as RT (pre-operative or post-operative) was associated with increased OS. Conclusions Pre-operative RT independently predicts higher rates of R0 resection in patients with extremity STS undergoing surgical resection. Negative surgical margins and pre-operative or post-operative RT are associated with improved OS.

Re-excision rates for breast cancer lumpectomy procedures are currently nearly 25% due to surgeons relying on inaccurate or incomplete methods of evaluating specimen margins. The objective of this study was to determine if cancer could be automatically detected in breast specimens from mastectomy and lumpectomy procedures by a classification algorithm that incorporated parameters derived from fluorescence lifetime imaging (FLIm). This study generated a database of co-registered histologic sections and FLIm data from breast cancer specimens (N  =  20) and a support vector machine (SVM) classification algorithm able to automatically detect cancerous, fibrous, and adipose breast tissue. Classification accuracies were greater than 97% for automated detection of cancerous, fibrous, and adipose tissue from breast cancer specimens. The classification worked equally well for specimens scanned by hand or with a mechanical stage, demonstrating that the system could be used during surgery or on excised specimens. The ability of this technique to simply discriminate between cancerous and normal breast tissue, in particular to distinguish fibrous breast tissue from tumor, which is notoriously challenging for optical techniques, leads to the conclusion that FLIm has great potential to assess breast cancer margins. Identification of positive margins before waiting for complete histologic analysis could significantly reduce breast cancer re-excision rates.