RESUMO
Background: Lymphocytic infiltration at diagnosis is prognostic in EOC, however, the impact of NACT on tumour infiltrating lymphocytes (TILs) or PD-L1 expression remains poorly described. Patients and methods: Patients with EOC and sequential samples (pre-NACT, post-NACT or relapse) were retrospectively identified. TILs were evaluated on whole sections; stromal TILs (sTILs) scored as percentage of stromal area with high sTILs defined as ≥50%; intra-epithelial TILs (ieTILs) scored semi-quantitatively (0-3) with high ieTILs ≥2. A smaller number were available for PD-L1 evaluation, cut-off for positivity was ≥5% staining. Results: sTILs were detected in all tumours at diagnosis (range 2-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired pre/post-NACT samples (N = 83), an overall increase in median sTILs from 20% to 30% was seen following NACT (P = 0.0005); individually the impact of NACT varied with sTILs increasing in 51% (42/83), decreasing in 25%, and stable in 24%. Post-NACT sTILs were predictive of platinum-free interval (PFI), patients with PFI ≥6 months had significantly higher post-NACT sTILs (sTILs 28% versus 18% for PFI <6 months, P = 0.026); pre-NACT sTILS were not predictive. At diagnosis, 23% showed high ieTILs, and following NACT 33% showed increasing ieTILs. Proportion of tumours with PD-L1-positive immune cells was 30% (15/50) pre-NACT and 53% (27/51) post-NACT (P = 0.026). Among paired tumours, 63% of PD-L1-negative tumours became positive after NACT, furthermore cisplatin induced PD-L1 expression in PD-L1-negative EOC cell lines. On multivariate analysis, high sTILs both pre- and post-NACT were independent prognostic factors for progression-free survival (PFS) (HR 0.49, P = 0.02 and HR 0.60, P = 0.05, respectively). No prognostic impact of ieTILs or PD-L1 expression was detected. Conclusions: In EOC, sTILs levels are prognostic at diagnosis and remain prognostic after NACT. TILs and PD-L1 expression increase following NACT. Evaluation of immune parameters in the post-NACT tumour may help select patients for immunotherapy trials.
Assuntos
Antígeno B7-H1/genética , Quimioterapia Adjuvante , Recidiva Local de Neoplasia/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , PrognósticoRESUMO
The investigation was undertaken to determine the response to Nobetec, a modified zinc oxide-eugenol cement, widely used as a negative control material in pulpal studies, under conditions of high- and low-speed cavity preparation, with and without a cavity liner Dycal. The pulpal responses were evaluated at intervals of 2 days, 2 weeks and 8 weeks in the permanent maxillary and mandibular incisors in 26 vervet monkeys using labial Class V cavities prepared in 208 teeth. Nobetec was found to be more irritant to the dental pulp than Dycal although this difference was not statistically significant and the degree of irritation was low. The pulpal irritation caused by high- and low-speed cavity preparation was similar and choice of speed should be a matter of personal preference.