br Of the significant proteins
Of the significant proteins found in the study, BDNF is the least stud-ied serum protein in ovarian cancer, compared to PDGF.AA, and PDGF. ABBB, but arguably the best predictor of PFS in our study. There is not a large amount of literature published about role of BDNF in ovarian cancer; however, BDNF has been shown to play a role in the immune system with a previous study showing activated T cells and Spectinomycin se-crete BDNF . Supporting this conclusion, in a study by Cao et al.,  mice with higher serum levels of BDNF were shown to have supe-riorly functioning immune systems and increased survival in both colon
Fig. 2. A. Comparison of Kaplan Meyer PFS prediction by stage, optimal cytoreduction, and the combination of PDGF.AA and BDNF. When considering the stage Kaplan Meyer curve patients with stage 1 and 2 disease were grouped together and patients with stage 3 and 4 disease were grouped together. B. Progression free survival prediction of BDNF, PDGF.AA and PDGF.ABBB when considering only patients with stage 3 disease or later and an optimal debulking (n = 51).
and melanoma cancer models in mice. This coincides with our results that with increasing BDNF level there is an increase in PFS even when considering only advanced stage optimally debulked patients (30th per-centile HR: 1.85, p-value: 0.06; 50th percentile HR: 2.16, p-value: 0.02; 80th percentile HR: 2.93, p-value 0.03). Given this information, it is es-sential to validate the findings on BDNF in a larger scale study. If vali-dated, BDNF could provide a key piece of insight for early intervention in ovarian cancer patients, while in remission.
The PDGF molecules may also serve as valuable serum markers for potential immune deficiency resulting in the inability to resolve micro-scopic cancer. PDGF has been shown to be secreted by platelets to stim-ulate dendritic cell differentiation, T-cell migration, and early T-cell activation . Consistent with the findings in this study, previously our group showed that PDGF molecules are higher in controls compared to patients with ovarian cancer . In line with this reasoning, it has also been shown that some tumors overexpressing PDGF.BB have im-paired growth . However, PDGF has a variety of other functions, which have been shown to potentiate malignancy such as stimulating angiogenesis . However, our results indicate that elevated levels of serum PDGF are protective. This may indicate a possible improved im-mune response against residual microscopic cancer. Additional studies are required for further validation of the PDGF molecules as predictors of prognosis in ovarian cancer, as well as, differentiating in which situa-tions their functions act to inhibit or promote cancer.
The combination of BDNF and PDGF.AA (HR 4.61, CI 1.94–10.94, p-value: 4.46 × 10−5) showed encouraging results when combined to predict prognosis among all patients. However, BDNF levels appear to be the main determinant of patient prognosis in this combination. Inter-estingly, when considering advanced stage ovarian cancer patients with
an optimal debulking; it was BDNF and PDGF.ABBB that were most pre-dictive of prognosis (HR 4.21 p-value: 0.001). The fact that BDNF and the PDGF molecules predict prognosis and have a positive correlation in ex-pression supports that they could have a potential functional and inter-active role in promoting a prolonged remission. Thus, these molecules should be investigated further in the future which may also eventually aide in choosing when and when not to intervene in a patient who ap-pears to be in remission. However, based on the known contribution of stage and optimal cytoreduction to patient prognosis, we then made a separate model, Serous High-Grade Ovarian Cancer Score (SHOCS), which could be applied to all patients in remission based on a combina-tion of clinical factors and serum protein concentration.
The SHOC score, consisted of two clinical components: stage and op-timal debulking, as well as, serum levels of 8 different proteins: BDNF, sIL6R, sgp130, sTNFRI, IGFBP6, MIP1B, IL6, and IFNG. This combination had the best ability to predict PFS (HR 6.55, p-value 1.12 × 10−6) when considering all patients in the entire cohort (n = 71). This score correctly identified 40 of the 45 patients who had a recurrence. Al-though stage and optimal debulking were key parts of the score, protein components were far from negligible. BDNF carried almost twice the relative impact of optimal cytoreduction. Furthermore, proteins with small relative contribution when considered collectively have a large impact. Interestingly of the 23 patients in the low score group, 10 had stage 3 disease. The SHOC score also did correctly identify the lone stage 2 patient who had a recurrence. Because of this, it seems that a fa-vorable or unfavorable proteomic profile can indeed greatly impact a patient's overall prognosis despite their clinical determinants. It is also worth noting, of the four patients who had a recurrence but were pre-dicted to not recur by the SHOC score, one had stage 1 disease and