Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer.

The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM-3, LAG-3 and PD-1 in patients with stage I-III colorectal cancer. Immunohistochemistry was employed to detect TIM-3, LAG-3, PD-1 and PD-L1 in 773 patients with stage I-III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG-3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00-2.09, p = 0.049) and PD-1 (HR 1.34 95% CI 1.00-1.78, p = 0.047) associated with poor survival, whereas high TIM-3 (HR 0.60 95% CI 0.42-0.84, p = 0.003), LAG-3 (HR 0.58 95% CI 0.40-0.87, p = 0.006) and PD-1 (HR 0.65 95% CI 0.49-0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD-L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG-3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42-0.78, p = 0.001). The results suggest that individual and combined high expression of TIM-3, LAG-3, and PD-1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

Combined PET and biopsy evidence of marrow involvement improves prognostic prediction in diffuse large B-cell lymphoma.

UNLABELLED: Bone marrow is an important extranodal site in diffuse large B-cell lymphoma (DLBCL), and marrow histology has been incorporated into the new National Comprehensive Cancer Network international prognostic index. Marrow involvement demonstrated histologically confers poor prognosis but is identified by staging PET in more cases. How information from staging PET and biopsy should be combined to optimize outcome prediction remains unclear. METHODS: The International Atomic Energy Agency sponsored a prospective international cohort study to better define the use of PET in DLBCL. As a planned subsidiary analysis, we examined the interplay of marrow involvement identified by PET and biopsy on clinical outcomes. RESULTS: Eight countries contributed 327 cases with a median follow-up of 35 mo. The 2-y outcomes of cases with no evidence of marrow involvement (n = 231) were 81% (95% confidence interval [CI], 76%-86%) for event-free survival (EFS) and 88% (83%-91%) for overall survival (OS); cases identified only on PET (n = 61), 81% (69%-89%) for EFS and 88% (77%-94%) for OS; cases indentified only on biopsy (n = 10), 80% (41%-95%) for EFS and 100% for OS; or cases identified by both PET and biopsy (n = 25), 45% (25%-64%) for EFS and 55% (32%-73%) for OS. The hazard ratios for PET-negative/biopsy-negative cases versus PET-positive/biopsy-positive cases were 2.67 (95% CI, 1.48-4.79) for EFS and 3.94 (1.93-8.06) for OS. CONCLUSION: This large study demonstrates that positive iliac crest biopsy histology only confers poor prognosis for patients who also have abnormal marrow (18)F-FDG uptake identified on the staging PET scan. Abnormal (18)F-FDG uptake in marrow, when iliac crest biopsy histology is normal, has no adverse effect on outcomes.