The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.

INTRODUCTION: The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. METHODS: We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. RESULTS: The analysis included 66 stage I-III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I-III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16-0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17-0.81, p: 0.013) for multivariate analysis. CONCLUSIONS: Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I-III SCLCs and warrants further investigation.

[Behaviour of serum CPK curves in acute myocardial infarction treated with digitalis, verapamil and combined verapamil-digitalis (author's transl)]. / Comportamento della curva della creatinfosfochinasi sierica nell'infarto acuto del miocardio trattato con digitale, verapamil e l'associazione verapamil-digitale.

In order to compare the effectiveness of different therapeutic regimens in reducing infarct size serial determinations of CPK activity (at 4 hourly intervals in the first 48 hours from the admission to CCU, at the 72th and at 120th hours) were performed in 100 patients with transmural AMI (53 anterior and 47 inferior) with no obvious evidence of LV failure and basal CPK levels lower than 50 U/L. 20 patients (control group) have been treated with glucose-insulin-potassium (GIK). 20 patients have been treated with GIK plus Verapamil (GIK + V). Verapamil was administered at the dose of 50 mg in continuous drip. 20 patients received GIK plus digoxin at the dose of 0.25 mg b.i.d. (GIK + D). 40 patients received GIK, Verapamil and digoxin at the above doses (GIK + V + D). Different values of CKr and infarct size (IS.) show a statistically significant difference between the various regimens, which is more evident if we consider the whole series. Infarct size was greater in patients treated with digoxin with respect to controls, while it was smaller in patients treated with Verapamil. Combined Verapamil-digoxin therapy is associated to an enzymatic behaviour not different from controls. Authors emphasize that in uncomplicated AMI digoxin causes an increase in infarct size while Verapamil reduces significantly it. Association of Verapamil allows the use of digoxin, if clinically justified, without increase in infarct size.