We investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT). 84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated. At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis. polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC.

Background: A long-term prospective assessment of QoL in cervical cancer patients is still lacking. Here, we provide the first 2-years prospective, longitudinal study evaluating emotional distress and QoL in early stage (ECC) and locally advanced (LACC) cervical cancer patients who remained disease-free 2-years from diagnosis. Methods: The questionnaires: Hospital Anxiety and Depression Scale (HADS), Global Health Status items of EORTC QLQ-C30 (GHS), and EORTC QLQ-CX24 (CX24) have been administered by a dedicated team of psycho-oncologists, administered at baseline, and after 3, 6, 12 and 24 months from surgery The Generalized Linear Model for repeated measure was used to analyze modifications of QoL measures over time. Results: In both groups, an early reduction of the percentage of patients with anxiety levels ≥11 was observed at the 3-month evaluation (ECC: 25.7% at baseline Vs 14.7% after 3 months, p value=0.001; LACC: 22.2% at baseline Vs 15.4% after 3 months, p value=0.001). Despite this favorable trend, after 2 years from diagnosis, 11.9% of ECC and 15.6% of LACC patients still showed an anxiety score ≥11. No significant changes over time were observed in term of Depression levels. Focusing on QoL issues, mean GHS and Sexual Activity scores showed an improvement over time in both groups compared to baseline (GHS: 5.7% difference for ECC, p value=0.001, and 11.0% in LACC, p value=0.001; SXA: 13.9% difference for ECC, p value=0.001; and 6.1% in LACC, p value=0.008). On the other hand, Body Image mean scores were significantly impaired by chemoradiation administration in LACC patients, without long-term recovery (7.5% difference, p value=0.001). Finally, in both groups, lymphedema (LY) and menopausal symptoms (MS) showed an early worsening which persisted 2-year after surgery (LY: 19.5% difference for ECC, p value=0.014, and 27.3% in LACC, p value=0.001; MS: 14.4% difference for ECC, p value=0.004, and 16.0% in LACC, p value=0.002). Conclusions: Despite a significant improvement over time, elevated anxiety levels are still detectable at 24 months after surgery in approximately 10% of cervical cancer patients. Much more attention should be focused on surgical/medical approaches able to minimize the negative impact of lymphedema and menopausal symptoms on QoL.