Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.Experimental Design: We obtained pre-and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4 þ T cells showed enhanced IFNg production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8 þ T-cell and CD45RO þ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3 þ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in postversus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025-36. Ó2016 AACR.
Objective To assess prospectively the ability of two multiparameter diagnostic models and their individual components to predict the outcome of early pregnancies which could not be identi®ed on transvaginal ultrasound scan.Design Prospective observational study. Setting Dedicated early pregnancy unit in an inner city teaching hospital.Population Women with a positive urine pregnancy test and clinical suspicion of early pregnancy complications.Methods A full medical history, clinical examination and transvaginal ultrasound scan were carried out at the initial visit. When the location of the pregnancy could not be ascertained by ultrasound, serum beta-human chorionic gonadotrophin (b -hCG) and progesterone levels were measured. All women were managed expectantly until either a normal pregnancy was visualised on scan; the pregnancy resolved spontaneously or intervention was required due to a worsening of clinical symptoms or non-declining b -hCG levels. Main outcome measures Spontaneous resolution of pregnancy (i.e. cessation of symptoms and decline in serum b -hCG level to , 20 iu/L) without need for any active intervention. Results Of the 104 women recruited, 72 (69%) pregnancies resolved spontaneously. Both multiparameter diagnostic models identi®ed resolving pregnancies with positive predictive values $ 95%. Their performances were not signi®cantly better compared with individual progesterone levels which achieved a positive predictive value of 97% using a cutoff level of 20 nmol/L.
ConclusionSerum progesterone measurement alone is as accurate as more complex diagnostic models for the prediction of successful expectant management in pregnancies of unknown location.
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