Upfront primary tumor resection versus upfront systemic therapy for metastatic colorectal cancer: a systematic review and meta-analysis.

PURPOSE: The standard initial treatment for metastatic colorectal cancer (mCRC) remains debated. This study investigated whether upfront primary tumor resection (PTR) or upfront systemic therapy (ST) provides better survival outcomes for patients with mCRC. METHODS: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for studies published at any time from January 1, 2004, to December 31, 2022. Randomized controlled trials (RCTs) and prospective or retrospective cohort studies (RCSs) utilizing propensity score matching (PSM) or inverse probability treatment weighting (IPTW) were included. We evaluated overall survival (OS) and short-term (60-day) mortality in these studies. RESULTS: After reviewing 3,626 articles, we identified 10 studies including a total of 48,696 patients. OS differed significantly between the upfront PTR and upfront ST arms (hazard ratio [HR] 0.62; 95% CI: 0.57-0.68; p < 0.001). However, a subgroup analysis identified no significant difference in OS in RCTs (HR 0.97; 95% CI: 0.7-1.34; p = 0.83), whereas significant difference in OS occurred between the treatment arms in RCSs with PSM or IPTW (HR 0.59; 95% CI: 0.54-0.64; p < 0.001). Short-term mortality was analyzed in three RCTs, and 60-day mortality differed significantly between the treatment arms (risk ratio [RR] 3.52; 95% CI: 1.23-10.10; p = 0.02). CONCLUSIONS: In RCTs, upfront PTR for mCRC did not improve OS and enhanced the risk of 60-day mortality. However, upfront PTR seemed to increase OS in RCSs with PSM or IPTW. Therefore, whether upfront PTR should be used for mCRC remains unclear. Further large RCTs are required.

Theoretical study of the remote control of hydrogen bond strengths in donor-bridge-acceptor systems: principles for designing effective bridges with substituent tuning.

Remote control of hydrogen bond strengths has been studied based on conjugated donor-bridge-acceptor (pyrrole-bridge-imine) systems. The neutral and protonated states of the imine can change the hydrogen bonding ability of the pyrrole because, in the protonated state, significant partial intramolecular charge transfer (ICT) is induced that causes partial delocalization of the positive charge onto the pyrrole moiety. An efficient bridge, regardless of its length, should help electrons to flow out of pyrrole. A previously developed design strategy for the bridge (low bridge HOMO/LUMO) leads to the study of cyano- and fluoro-substituted conjugated systems. Substitution positions are found to be of key importance for maximizing the protonation-induced response from the donor-bridge-acceptor systems. Our results not only help to identify useful bridge substitution patterns, but also highlight interesting issues regarding the bridge conformation and the fluorine lone-pair effect.

Control of hydrogen bond strengths through push-pull effects triggered by a remote reaction center: a theoretical study.

In an effort to manipulate the bond strengths of hydrogen bonds, we have studied a three-component chemical system consisting of a reaction center, a conjugated bridge, and a hydrogen-bonding site. Protonation of the reaction center triggers intramolecular charge transfer from the hydrogen-bonding site, altering its affinity to bind to an acceptor. Previously, we had found that this communication (signal transduction) between the reaction center and the hydrogen-bonding site does not necessarily die out with increasing length of the conjugated bridge. In certain cases, this signal transduction is maintained-and even amplified-over long distances (I. Chao, T.-S. Hwang, Angew. Chem. 2001, 113, 2775-2777; Angew. Chem. Int. Ed. 2001, 40, 2703-2705). In this study we report the results of an extensive theoretical investigation of this problem to provide insights into this intriguing phenomenon. In the systems we investigated it was found that the push-pull process between the hydrogen-bonding site and the protonatable reaction center was mediated with the greatest facility by conjugated bridges with low-lying pi and pi* orbitals.