Background: Within the tumor microenvironment, regulatory T cells (Tregs) are potent facilitators of immune tolerance, and in most solid tumors a higher proportion of Tregs compared to cytotoxic T cells predicts a worse outcome. However, the role of Tregs in colorectal cancer (CRC) is more controversial, possibly due in part to the effect of the gut microbiome on colorectal tumors. We explore the association between colorectal cancer (CRC) Treg density, cancer biology, and clinical outcome. The aim of the study is to investigate the clinical relevance of the fraction of Tregs within the colorectal cancer TME using xCell score with mRNA expression data across several CRC cohorts. Methods: We used xCell to estimate intra-tumoral Tregs in 898 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts. into two groups based on high versus low proportions of Tregs. We studied the correlation between intra-tumoral Treg density and cancer biology including host immune response, ICM expression, and the tumor microbiome by comparing gene ex-pression between the two groups. We further examined two CRC cohorts which contained data on response to neoadjuvant chemotherapy using mFOLFOX6 and bevacizumab, in order to explore the association between Treg infiltration and response to treatment. Results: High-Treg CRCs enriched immune response-related gene sets; inflammatory response, IFN-γ and IFN-α response, IL2/IL6 signaling, and allograft rejection, and had significantly high infiltration of CD8, CD4, M1/M2 macrophage, and dendritic cells in both cohorts. While high-Treg CRCs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-β, TNF-α, and angiogenesis, Treg infiltration was surprisingly associated with earlier CRC stage in TCGA. Metastatic CRCs with more Tregs showed a significantly better response to mFOLFOX6 versus low-Treg CRC metastases (88.9% response vs. 16.7%, p < 0.001). Finally, high-Treg CRCs were associated with increased expression of immune check-point molecules PD-L1/PD-L2, CTLA4, TIGIT and BTLA, implying susceptibility to immunotherapy. Conclusion: We show that unlike in other cancers, Tregs in CRC are not necessarily a marker of poor prognosis. High-Treg CRC enriched not only cancer aggravating gene sets, such as EMT, KRAS, TGF-β and angiogenesis, but also immune response-related gene sets, which is consistent with high infiltration of anti-cancerous immune cells. High Treg density was a predictor of response to chemotherapy in metastatic CRC. Citation Format: Masanori Oshi, Joy Sarkar, Rongrong Wu, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Clinical relevance of intra-tumoral density of regulatory T cells as a predictive factor for chemotherapy response in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6112.
Vasopressors are gaining renewed interest as treatment adjuncts in hemorrhagic shock. The ideal vasoconstrictor will increase systemic blood pressure without increasing pulmonary vascular resistance (PVR), which hinders pulmonary perfusion and exacerbates hypoxemia. However, the selectivity of pressors for pulmonary versus systemic vasoconstriction during hemorrhage has not been characterized. The purpose of this study was to test the hypothesis that vasopressin (VP) has distinct effects on pulmonary versus systemic hemodynamics, unlike the catecholamine vasopressors norepinephrine (NE) and phenylephrine (PE). Anesthetized and ventilated pigs were assigned to resuscitation with saline only (n = 7) or saline with VP (n = 6), NE (n = 6), or PE (n = 6). Animals were hemorrhaged to a target volume of 30 mL/kg and a mean arterial pressure of 35 mmHg. One hour after the start of hemorrhage, animals were resuscitated with saline up to one shed blood volume, followed by either additional saline or a vasopressor. Hemodynamics and oxygenation were measured hourly for 4 h after the start of hemorrhage. Vasopressin increased systemic vascular resistance (SVR) while sparing the pulmonary vasculature, leading to a 45% decrease in the PVR/SVR ratio compared with treatment with PE. Conversely, NE induced pulmonary hypertension and led to an increased PVR/SVR ratio associated with decreased oxygen saturation. Phenylephrine and crystalloid had no significant effect on the PVR/SVR ratio. Sparing of pulmonary vasoconstriction occurs only with VP, not with administration of crystalloid or catecholamine pressors. The ability of VP to maintain blood oxygenation indicates that VP may prevent hypoxemia in the management of hemorrhagic shock.
Aim Liver transplantation (LT) is the most effective treatment for long-term survival from hepatocellular carcinoma (HCC); however, insufficient donors limit therapy. We sought to identify characteristics that predicted long-term survival after non-transplant therapies in patients with small HCC. Methods In a database of 1,050 HCC patients, we identified those with single HCC ≤ 3.0 cm, who underwent hepatic resection (HR, n = 16), radiofrequency ablation (RFA, n = 55), or LT (n = 23) with 5-years follow-up. Survival and odds-ratios for survival (OS) after HR/RFA were calculated for MELD score, platelet count, creatinine, albumin, AST/Platelet Ratio Index (APRI), INR, and bilirubin. Results LT patients had 3 and 5-year OS of 82.6% and 73.9% compared to HR/RFA patients with 3 and 5-year OS of 40.8% and 33.8%. The strongest predictors of survival after HR/RFA were MELD < 10 (OR 4.43, 95% CI 1.85–10.58) and APRI ≤ 0.5 (OR 4.25, 95% CI 1.63–11.08). HR/RFA patients with both MELD < 10 and APRI ≤ 0.5 had 3- and 5-year OS of 77.3% and 72.7%. Conclusion Patients with MELD < 10 and APRI ≤ 0.5 who undergo HR/RFA have survival approaching LT. Perhaps patients who meet these criteria can safely undergo non-transplant therapy and donor livers can be allocated to patients with a greater need.
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