irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

SignificanceThis study defines clinical indications for using telomere length (TL) measurement as a diagnostic tool in a hospital setting. It shows that, in contrast to other methods, TL measurement by flow cytometry and FISH (flowFISH) can be standardized, and has reproducible and definable upper and lower normal boundaries. In telomerase mutation carriers and carriers of other mutant telomere maintenance genes, TL had prognostic value, correlating with the age of onset of short telomeres syndrome phenotypes, as well as the predominant complication. In a prospective study, TL results were actionable in one-fourth of cases with idiopathic bone marrow failure affecting the stem cell donor choice and/or treatment regimen. The data show that, for targeted clinical indications, and in a hospital setting, TL measurement by flowFISH informs patient care decisions.

Background: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.Materials and methods: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre-and on-treatment specimens from n ¼ 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 ¼ no irPR features to 3 ¼ major pathologic response on biopsy (MPR bx , 10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre-and on-treatment biopsies (n ¼ 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).Results: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P ¼ 0.009) and MPR bx associated with increased overall survival (n ¼ 51; HR 0.13; 95%CI, 0.054-0.31, P ¼ 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPR bx , indicating a disconnect between pathologic and radiographic features at the 4-week ontherapy timepoint for some patients.Conclusions: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.