No abstract

Regulatory T cells (T reg ) inhibit the generation of host-versus-tumor immunity via suppression of tumor-specific effector T-cell responses and development of immune tolerance to neoplastic cells. The transcription factor forkhead box P3 (FOXP3) is an intracellular key molecule for T reg development and function and is considered to represent the most specific T reg cell marker. Tumor-infiltrating lymphocytes (TILs) are considered to be the primary host immune response against solid tumors. Recent results have shown a correlation between survival and density of TILs in colorectal cancer (CRC) patients. 1 Furthermore, there is accumulating evidence that the type of immune cells, rather than their sheer quantity, controls the efficiency of the host-versus-tumor immune response.2 However, the role of TILs in predicting CRC prognosis remains a matter of ongoing debate. Controversy may arise from the uncertainty concerning the in vivo activity of TILs as well as from the lack of discriminating patients according to the underlying type of genomic instability (microsatellite stable vs. unstable). Approximately 10-15% of sporadic CRC and all cases with hereditary nonpolyposis colorectal cancer (HNPCC) are associated with high frequency of microsatellite instability as a result of inactivation or loss of expression of the mismatch repair (MMR) genes MLH1, MSH2 and MSH6 (so-called MMR-deficient tumors). Compared to the majority of sporadic CRC that are MMR-proficient tumors, MMR-deficient tumors are characterized a priori by a higher frequency of TILs and are associated with significantly improved prognosis. 3 Increasing evidence suggests that regulatory T cells (T reg ) have the ability to inhibit the generation of host-versustumor immunity in the microenvironment of tumors via suppression of tumor-specific effector T-cell responses.4,5 The transcription factor forkhead box P3 (FOXP3) is an intracellular key molecule for T reg development and function and is considered to represent the most specific T reg cell marker so far. [6][7][8] In the majority of solid tumors studied so far, high frequency of tumor-infiltrating FOXP3 þ T reg predicted an impaired patient survival. [7][8][9][10][11][12][13][14][15][16] Paradoxically, increased frequency of T reg was recently found to be associated with improved prognosis in lymphoma patients 17 and also in CRC

Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1+ TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1+ TIL were present in 104 (15.8 %) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1+ TIL was associated with a significantly worse overall survival (HR = 2.736, p < 0.001). In subset analyses, the presence of PD-1+ TIL was associated with significantly worse overall survival in the luminal B HER2− subtype (HR = 2.678, p < 0.001), the luminal B HER2+ subtype (HR = 3.689, p < 0.001), and the basal-like subtype (HR = 3.140, p < 0.001). This is the first study to demonstrate that the presence of PD-1+ TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.

The morbidity after SLN biopsy alone is not negligible but significantly lower compared with level I and II ALND. SLN biopsy can be performed with similar short- and intermediate-term morbidity in academic and nonacademic centers.

When cefuroxime is used as a prophylactic antibiotic, administration 59 to 30 minutes before incision is more effective than administration during the last half hour.