The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation, progression, and drug resistance. Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling cascade. In addition, FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes, which are involved in chemotherapeutic drug sensitivity and resistance. Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients, and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Carcinogenesis ; genetics ; metabolism ; Drug Resistance, Neoplasm ; Forkhead Box Protein M1 ; Forkhead Box Protein O3 ; Forkhead Transcription Factors ; genetics ; metabolism ; Humans ; Neoplasms ; drug therapy ; metabolism ; pathology ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction

Purpose: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/ metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM−) LM at baseline. Materials and Methods: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM−: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM−: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan–Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM− subgroups was analyzed using the Cox regression model with reported interaction P-values. Results: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM− (OS HR, 0.71 [LM+] vs. 0.88 [LM−]; PFS HR, 0.47 [LM+] vs. 0.76 [LM−]).Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). Conclusions RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM.

Objective: While minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF) has shown superiority in key clinical metrics over the open approach, evidence regarding patient-reported outcomes remains limited. This study compared postoperative recovery trajectories and symptomatic improvement phases between MIS and open TLIF. Methods: This retrospective review included patients who underwent single-level MIS or open TLIF. Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS) for back and leg pain were collected preoperatively and postoperatively. Segmented regression analysis with mixed-effects modeling, allowing for identification of distinct recovery phases, compared symptomatic trends between approaches. Results: Of 324 patients (268 MIS, 56 open), baseline demographics were similar except for greater preoperative leg pain in the MIS group (NRS: 6.0 vs. 5.0, p = 0.027). A segmented regression model identified 4 ODI recovery phases: postoperative disability phase (PDP, day 0 to 13), early improvement phase (day 13 to 28), late improvement phase (day 28 to 110), and plateau phase (later than day 110). The MIS group exhibited significantly lower disability exacerbation during PDP (β = 0.93 vs. 1.42 points per day, p = 0.008). Additionally, the plateau of NRS back occurred significantly earlier in the MIS group than in the open group (MIS, 26.7 ± 2.6 days vs. open, 51.7 ± 6.6 days, p < 0.001). Conclusion MIS-TLIF resulted in lower postoperative disability during the first 2 weeks compared to the open approach. Furthermore, low back pain achieved an earlier plateau in back pain by about 4 weeks in the MIS approach.

Objective: While minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF) has shown superiority in key clinical metrics over the open approach, evidence regarding patient-reported outcomes remains limited. This study compared postoperative recovery trajectories and symptomatic improvement phases between MIS and open TLIF. Methods: This retrospective review included patients who underwent single-level MIS or open TLIF. Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS) for back and leg pain were collected preoperatively and postoperatively. Segmented regression analysis with mixed-effects modeling, allowing for identification of distinct recovery phases, compared symptomatic trends between approaches. Results: Of 324 patients (268 MIS, 56 open), baseline demographics were similar except for greater preoperative leg pain in the MIS group (NRS: 6.0 vs. 5.0, p = 0.027). A segmented regression model identified 4 ODI recovery phases: postoperative disability phase (PDP, day 0 to 13), early improvement phase (day 13 to 28), late improvement phase (day 28 to 110), and plateau phase (later than day 110). The MIS group exhibited significantly lower disability exacerbation during PDP (β = 0.93 vs. 1.42 points per day, p = 0.008). Additionally, the plateau of NRS back occurred significantly earlier in the MIS group than in the open group (MIS, 26.7 ± 2.6 days vs. open, 51.7 ± 6.6 days, p < 0.001). Conclusion MIS-TLIF resulted in lower postoperative disability during the first 2 weeks compared to the open approach. Furthermore, low back pain achieved an earlier plateau in back pain by about 4 weeks in the MIS approach.

Objective: While minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF) has shown superiority in key clinical metrics over the open approach, evidence regarding patient-reported outcomes remains limited. This study compared postoperative recovery trajectories and symptomatic improvement phases between MIS and open TLIF. Methods: This retrospective review included patients who underwent single-level MIS or open TLIF. Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS) for back and leg pain were collected preoperatively and postoperatively. Segmented regression analysis with mixed-effects modeling, allowing for identification of distinct recovery phases, compared symptomatic trends between approaches. Results: Of 324 patients (268 MIS, 56 open), baseline demographics were similar except for greater preoperative leg pain in the MIS group (NRS: 6.0 vs. 5.0, p = 0.027). A segmented regression model identified 4 ODI recovery phases: postoperative disability phase (PDP, day 0 to 13), early improvement phase (day 13 to 28), late improvement phase (day 28 to 110), and plateau phase (later than day 110). The MIS group exhibited significantly lower disability exacerbation during PDP (β = 0.93 vs. 1.42 points per day, p = 0.008). Additionally, the plateau of NRS back occurred significantly earlier in the MIS group than in the open group (MIS, 26.7 ± 2.6 days vs. open, 51.7 ± 6.6 days, p < 0.001). Conclusion MIS-TLIF resulted in lower postoperative disability during the first 2 weeks compared to the open approach. Furthermore, low back pain achieved an earlier plateau in back pain by about 4 weeks in the MIS approach.

Objective: While minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF) has shown superiority in key clinical metrics over the open approach, evidence regarding patient-reported outcomes remains limited. This study compared postoperative recovery trajectories and symptomatic improvement phases between MIS and open TLIF. Methods: This retrospective review included patients who underwent single-level MIS or open TLIF. Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS) for back and leg pain were collected preoperatively and postoperatively. Segmented regression analysis with mixed-effects modeling, allowing for identification of distinct recovery phases, compared symptomatic trends between approaches. Results: Of 324 patients (268 MIS, 56 open), baseline demographics were similar except for greater preoperative leg pain in the MIS group (NRS: 6.0 vs. 5.0, p = 0.027). A segmented regression model identified 4 ODI recovery phases: postoperative disability phase (PDP, day 0 to 13), early improvement phase (day 13 to 28), late improvement phase (day 28 to 110), and plateau phase (later than day 110). The MIS group exhibited significantly lower disability exacerbation during PDP (β = 0.93 vs. 1.42 points per day, p = 0.008). Additionally, the plateau of NRS back occurred significantly earlier in the MIS group than in the open group (MIS, 26.7 ± 2.6 days vs. open, 51.7 ± 6.6 days, p < 0.001). Conclusion MIS-TLIF resulted in lower postoperative disability during the first 2 weeks compared to the open approach. Furthermore, low back pain achieved an earlier plateau in back pain by about 4 weeks in the MIS approach.

Objective: While minimally invasive-transforaminal lumbar interbody fusion (MIS-TLIF) has shown superiority in key clinical metrics over the open approach, evidence regarding patient-reported outcomes remains limited. This study compared postoperative recovery trajectories and symptomatic improvement phases between MIS and open TLIF. Methods: This retrospective review included patients who underwent single-level MIS or open TLIF. Oswestry Disability Index (ODI) and Numerical Rating Scale (NRS) for back and leg pain were collected preoperatively and postoperatively. Segmented regression analysis with mixed-effects modeling, allowing for identification of distinct recovery phases, compared symptomatic trends between approaches. Results: Of 324 patients (268 MIS, 56 open), baseline demographics were similar except for greater preoperative leg pain in the MIS group (NRS: 6.0 vs. 5.0, p = 0.027). A segmented regression model identified 4 ODI recovery phases: postoperative disability phase (PDP, day 0 to 13), early improvement phase (day 13 to 28), late improvement phase (day 28 to 110), and plateau phase (later than day 110). The MIS group exhibited significantly lower disability exacerbation during PDP (β = 0.93 vs. 1.42 points per day, p = 0.008). Additionally, the plateau of NRS back occurred significantly earlier in the MIS group than in the open group (MIS, 26.7 ± 2.6 days vs. open, 51.7 ± 6.6 days, p < 0.001). Conclusion MIS-TLIF resulted in lower postoperative disability during the first 2 weeks compared to the open approach. Furthermore, low back pain achieved an earlier plateau in back pain by about 4 weeks in the MIS approach.