Flotte, Thomas James

Background Neoadjuvant treatment has become standard for patients with high-risk operable stage III melanoma, but the optimal regimen is unknown. Targeted therapy approaches yield high pathological response rates, while immunotherapy regimens show favorable recurrence-free survival (RFS). NeoACTIVATE was designed to address whether a neoadjuvant combination of both targeted therapy and immunotherapy might leverage the benefits of each. Methods We tested neoadjuvant treatment with 12 weeks of vemurafenib, cobimetinib, and atezolizumab for patients with BRAF-mutated (BRAFm) melanoma (cohort A) and cobimetinib and atezolizumab for patients with BRAF-wild-type (BRAFwt) melanoma (cohort B), regimens which we have shown generate a substantial major pathological response. After therapeutic lymph node dissection, patients received 24 weeks of adjuvant atezolizumab. Here, we report survival outcomes and their association with biomarkers assayed among the gut microbiome and peripheral blood immune subsets. Results With 49 months median follow-up, the median RFS was not reached for cohort A and was 40.8 months for cohort B. At 24 months after operation, 2 of 14 cohort A patients and 4 of 13 cohort B patients had experienced distant relapse. Key findings from correlative analyses included diversity, taxonomic and functional metagenomic gut microbiome signals associated with distant metastasis-free survival at 2 years. Notably, we observed a strong correlation between low microbial arginine biosynthesis (required for T-cell activation and effector function) and early distant recurrence (p=0.0005), which correlated with taxonomic differential abundance findings. Peripheral blood immune monitoring revealed increased double-positive (CD4+CD8+) T cells in patients with early recurrence. Conclusions Neoadjuvant treatment with cobimetinib and atezolizumab±vemurafenib was associated with a low rate of distant metastasis in patients with high-risk stage III melanoma. Freedom from early distant metastasis was highly associated with taxonomic differences in gut microbiome structure and with functional pathway alterations known to modulate T cell immunity. Identification of predictive biomarkers will permit optimization of neoadjuvant therapy regimens for individual patients. Trial registration number NCT03554083.

Abstract Objectives To learn what color vision–deficient pathologists and cytotechnologists consider their most significant problems and advantages as well as any accommodations. Methods An anonymous online survey developed for practicing pathologists and cytotechnologists regarding their experiences with stains was sent to the members of 4 national societies. Results We received 377 responses. Twenty-three people, all men, identified themselves as color vision deficient, with 22 reporting red-green color vision deficiency and 1 reporting uncertain type. Eight pathologists and cytotechnologists indicated that they thought that their color vision deficiency conferred advantages to them, including a greater appreciation of morphology, with less confusion resulting from variations in stain quality or intensity. Nineteen pathologists and cytotechnologists thought that their color vision deficiency conferred disadvantages; the most common disadvantages stated were the identification of eosinophils and acid-fast bacilli. Other difficulties included interpretation of RBCs and nucleoli and sometimes Alcian blue, Brown and Brenn, Congo red, crystal violet, Fite, Giemsa, mucicarmine, periodic acid–Schiff, and fluorescence in situ hybridization stains. Only 2 of the color vision–deficient pathologists and cytotechnologists found digital slides more difficult than glass slides. Conclusions Color vision–deficient pathologists and cytotechnologists report that they have developed approaches to viewing slides that do not compromise their interpretations. Digital pathology may provide several approaches for aiding color vision–deficient pathologists with the interpretation of certain stains.

BACKGROUNDThe amount of time available to pathologists with which to perform research is becoming limited due to an increasing manpower shortage in pathology, decreased reimbursement, and increased workload. This is occurring at the same time as demands escalate for pathologists to develop new companion tests, correlate the molecular findings with traditional methods, and assist in the development of individualized medicine. This study examined whether cytotechnologists may be integrated into a research team that uses their expertise in understanding pathology and clinical disease to provide interpretations of experiments that traditionally were performed by pathologists.METHODSCytotechnologists worked with pathologists to choose blocks for tissue microarrays (TMAs) and to interpret immunohistochemically stained TMA slides. The pathologist met with the cytotechnologist to review the study design. The cytotechnologists reviewed the slides and blocks and chose the most appropriate blocks for the TMA. Either 10% or all of the slides/blocks selected for TMA construction were reviewed by the supervising pathologist. The final selections were given to the TMA technologist to make the TMA. A minimum of 10% of the immunohistochemically stained TMA slides were reviewed by the supervising pathologist.RESULTSA total of 32 TMAs were created with 6 cytotechnologists collaborating with 6 pathologists. Immunohistochemical stains of 190 TMAs were interpreted by 4 cytotechnologists collaborating with 3 pathologists. All the TMAs and TMA interpretation data were used successfully for the research for which they were designed.CONCLUSIONSThe collaboration of cytotechnologists and pathologists in research can improve the quality of effort and increase satisfaction and productivity. Cancer Cytopathol 2018;126:232‐5. © 2018 American Cancer Society.