Oncotarget最新文献

Approximately two-thirds of patients with colorectal cancer (CRC) undergo resection with curative intent; however, 30% to 50% of these patients experience recurrence. The concentration of cell-free DNA (cfDNA) before and after surgery may be related to the prognosis of patients with CRC, but there is limited information regarding cfDNA levels at the time of surgery. Here, we analyzed surgical cfDNA release using plasma samples from 30 colorectal cancer patients at three key points during surgery: preoperative (immediately before surgery), intraoperative (during surgery), and postoperative (at the end of surgery). Automated electrophoresis was used to analyze cfDNA concentrations and fragment sizes, which were then correlated with clinical variables. Our findings indicate a significant increase in cfDNA release during and after surgery (2.8- and 2.2-fold higher respectively, p < 0.01). Characteristic fragments of cfDNA (<400 bp) predominated at all surgical stages; however, the release of genomic material (>400 bp) was also observed. We found that cfDNA concentration increases during and after surgery in patients over 60 years old (2.9-fold higher intraoperatively than preoperatively and 2.3 folds higher postoperatively than preoperatively, p < 0.01); in patients with comorbidities (3.0-fold higher intraoperatively and 2.3-fold higher postoperatively, p < 0.01); and in patients with CEA levels >5 ng/mL (3.1-fold higher intraoperatively and 1.3-fold higher postoperatively, p < 0.01). Interestingly, cfDNA release during surgery is significantly higher in patients with adverse clinical characteristics. Patients bearing locally advanced tumors or metastasis had a 3.1-fold increase in cfDNA release intraoperatively and 2.4-fold increase postoperatively, p < 0.01. cfDNA concentration also increases intraoperatively in patients with a high score of tumor buds (2.6 folds higher, p < 0.02), patients with perineural invasion (3.4-fold higher, p < 0.02) and in patients with lymphovascular invasion (3.1-fold higher, p < 0.05). Furthermore, we observed that cfDNA concentration may rise in correlation with the duration of the surgery, highlighting its potential as a marker of surgical quality. Taken together, our results suggest that in addition to physiological age, comorbidities and unfavorable clinical traits, intense surgical manipulation from the tumor's extent, may result in greater tissue damage and elevated cfDNA release.

Recently, combination checkpoint therapy of cancer has been recognized as producing additive as opposed to synergistic benefit due in part to positively correlated effects. The potential for uncorrelated or negatively correlated therapies to produce true synergistic benefits has been noted. Whereas the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT have been collectively characterized as exhaustion receptors, another inhibitory receptor KLRG1 was historically characterized as a senescent receptor and received relatively little attention as a potential checkpoint inhibitor target. The anti-tumor effects of KLRG1 blockade has relatively recently been demonstrated in preclinical in vivo studies. Here, expression of the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and KLRG1 was studied in publicly available gene expression datasets. Bulk RNA microarray and RNAseq, and single cell RNAseq data from healthy blood and tumor tissue samples were analyzed for Pearson correlation. CD8 T cell differentiation of memory T cells from the TEM to TEMRA states is characterized by PD-1/KLRG1 anti-correlation, with decreased PD-1 expression but increased KLRG1 expression. Single cell RNAseq analysis of tumor infiltrating CD8 T cells shows positive correlation of CTLA-4, TIM-3, LAG-3, TIGIT, GITR, 4-1BB, and OX40 with PD-1 but negative correlation of KLRG1 with PD-1. The anti-correlation of PD-1 and KLRG1 expression in human tumor infiltrating CD8 T cells suggests the potential for combination therapy supra-additive benefits of anti-PD-1 and anti-KLRG1 therapies.

The FDA approval on September 29, 2023, for "class III de novo" blood tests to assess hereditary cancer risk make widely available tests that may be obtained through a Direct to Consumer (DTC) path. There is concern that germ-line predisposition tests may not be reimbursed by insurance adding financial burdens to individuals and families. It is generally agreed in the fields of oncology and genetics that germ-line testing for disease susceptibility including cancer is best performed under care of a healthcare provider with genetic counseling. Our recommended cautions and call for change may seem paternalistic to some and may appear to infringe upon constitutional rights as they may relate to DTC, but there is a real concern with harm from germ-line testing of both adults and minors that can occur through DTC tests. The DTC option of germ-line testing for cancer susceptibility should be discouraged given the risks of anxiety, lack of adequate interpretation for variants not strongly associated with cancer, potential for minors to be tested outside the healthcare system and potential for loss of follow-up if test results are not shared with health care professionals or never make it into the medical record. The FDA should consider clear unambiguous guidance when it comes to germ-line DTC testing for cancer susceptibility for adults and especially for minors.