Mediastinal lymph node removal modulates natural killer cell exhaustion in patients with non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death globally. In this study, the effect of complete removal of mediastinal lymph nodes by video-assisted mediastinoscopic lymphadenectomy (VAMLA) on natural killer (NK) cell phenotype and functions in patients with NSCLC was evaluated. The study included 21 NSCLC patients (cIA-IVA) undergoing VAMLA staging and 33 healthy controls. Mononuclear cells were isolated from peripheral blood of all participants and mediastinal lymph nodes of the patients. NK cells were analyzed by flow cytometry to define NK subsets, expressions of PD-1, CTLA-4, activating/inhibitory receptors, granzyme A, and CD107a. The plasma levels of soluble PD-1, PDL-1, and CTLA-4 were measured by ELISA. Mediastinal lymph nodes of NSCLC patients had increased ratios of exhausted NK cells, increased expression of PD-1 and IL-10, and impaired cytotoxicity. Mediastinal lymph nodes removal increased CD56dimCD16bright cytotoxic effector phenotype and reduced exhausted NK cells. PD-1+ NK cells were significantly more abundant in patients' blood, and VAMLA significantly reduced their ratio as well. The ratio of IL-10 secreting regulatory NK cells was also reduced after VAMLA. Blood NK cells had increased cytotoxic functions and spontaneous IFN-γ secretion, and these NK cell functions were also recovered by VAMLA. Mediastinal lymph node removal reversed NK cell exhaustion, reduced regulatory NK cells, and improved antitumoral functions of NK cells. Tumor-draining lymph nodes may contribute to tumor evasion from antitumoral immune responses. The role of their removal needs to be further studied both to better understand this mechanism and as a potential immunotherapeutic approach.

Mediastinal lymph node removal ameliorates cytotoxic T-lymphocyte functions in patients with non-small cell lung cancer.

INTRODUCTION: Mediastinal lymph node (MLN) removal by video-assisted mediastinoscopic lymphadenectomy (VAMLA) for preoperative cancer staging was reported to be associated with increased survival. The aim of this study was to evaluate the immunologic effects of complete MLN removal by VAMLA on cytotoxic T lymphocyte (CTL) phenotype and function. METHODS: Seventeen patients with non-small cell lung cancer (NSCLC) (stage cT1-4N0-3M0-1A) and 20 healthy participants were included in this study. Blood samples were collected before and 4 weeks after the procedure. Lymphocytes were isolated from the removed MLNs. CTL phenotypes and functions were evaluated by flow cytometry. Plasma levels of soluble programmed cell death protein 1 (sPD-1), soluble programmed cell death protein 1 ligand, and soluble CTL antigen 4 (sCTLA-4) were measured with enzyme-linked immunosorbent assay. RESULTS: The ratio of the immunosenescent CTLs (CD3+CD8+CD28-) was increased in peripheral blood and MLNs of the patients with NSCLC compared to controls (p = 0.037), and MLN removal did not change this ratio. PD-1 and CTL antigen 4 expressions were significantly reduced in peripheral blood CTLs after MLN removal by VAMLA (p = 0.01 and p = 0.01, respectively). Granzyme A expression was significantly reduced in the peripheral blood CTLs of the patients compared to controls (p = 0.006) and MLN removal by VAMLA significantly improved Granzyme A expression in CTLs (p = 0.003). Plasma concentrations of sPD-1 and sCTLA-4 remained unchanged after VAMLA. CONCLUSION: CTLs in the MLNs and peripheral blood of the patients with NSCLC had an immunosenescent phenotype, increased immune checkpoint receptor expression, and impaired cytotoxicity. MLN removal by VAMLA improved these phenotypic and functional characteristics of CTLs. These changes may explain the potential contribution of VAMLA to improved survival.

Efficacy and Safety of Trastuzumab Emtansine in Her2 Positive Metastatic Breast Cancer: Real-World Experience.

AIM: The aim of this study is to evaluate the efficacy and toxicity of trastuzumab emtansine (T-DM1) in cases with metastatic breast cancer (mBC) in different lines of treatment. METHOD: Retrospective analysis of T-DM1 results of human epidermal growth factor receptor 2 (Her2) positive 414 cases with mBC from 31 centers in Turkey. FINDINGS: Except 2, all of the cases were female with a median age of 47. T-DM1 had been used as second-line therapy in 37.7% of the cases and the median number of T-DM1 cycles was 9. Progression-free survival (PFS) and overall survival (OS) times were different according to the line of treatment. The median OS was found as 43, 41, 46, 23 and 17 months for 1st, 2nd, 3rd, 4th and 5th line, respectively (p = 0.032) while the median PFS was found as 37, 12, 8, 8 and 8 months, respectively (p = 0.0001). Treatment was well tolerated by the patients. The most common grade 3-4 adverse effects were thrombocytopenia (2.7%) and increased serum gamma-glutamyl transferase (2%). DISCUSSION: The best of our knowledge this is the largest real-life experience about the safety and efficacy of T-DM1 use in cases with mBC after progression of Her2 targeted treatment. This study suggests and supports that T-DM1 is more effective in earlier lines of treatment and is a reliable option for mBC.

Classical versus non-classical EGFR mutations: Erlotinib response and impact of renal insufficiency.

INTRODUCTION: Erlotinib is an effective treatment option for EGFR-mutant non-small cell lung cancer. It is important to predict patients who will respond better to erlotinib. We designed this study to investigate the effect of renal insufficiency (RI) on erlotinib treatment outcomes. METHODS: All patients receiving erlotinib were stratified into 3 groups. Group 1 consisted of non-RI subjects with classical epidermal growth factor receptor (EGFR) mutations, Group 2 consisted of those with RI (Estimated glomerular filtration rate <60 mL/min) and classical EGFR mutations, and Group 3 consisted of those with non-classical EGFR mutations. RESULTS: 82 patients were included in the study. Median progression-free survival (PFS) in patients with classical mutation was approximately 6 months shorter in those with RI, although not statistically significant. Median overall survival (OS) in Group 1, 2 and 3 was 34.1 months, 35.2 months, and 15 months, respectively and although not statistically significant, median OS was 20 months shorter in Group 3. Univariate and multivariate cox-regression analysis revealed shorter PFS and OS in males and those with ECOG ≥2 while PFS and OS were longer in those with recurrent lung tumors and generating rash during erlotinib treatment. There was no difference between RI and non-RI patients in terms of adverse events except for fatigue and appetite loss. CONCLUSIONS: This research showed OS in patients with and without RI was comparable. Although not statistically significant, PFS in patients with classical mutation was approximately 6 months shorter in those with RI patients.

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer.

INTRODUCTION: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. METHODS: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. RESULTS: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti-programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti-programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. CONCLUSION: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

The effect of inherited thrombophilia on second trimester combined aneuploidy screening test markers.

PURPOSE: To determine whether inherited thrombophilia affects components of second trimester combined aneuploidy screening test. METHODS: A case-control study was performed between 1 December 2010 and 1 February 2012, at a tertiary referral hospital. Singleton pregnancies with inherited thrombophilia that underwent second trimester (16-19(+6) week) combined aneuploidy screening test were included in the study. Maternal serum alfa fetoprotein, unconjugated estriol, human chorionic gonadotropin levels and multiple of median (MoM) levels were compared between the study group and controls. RESULTS: Within the study period, 18,943 women with singleton pregnancies had a combined second trimester aneuploidy screening test at our institution. Among these, 26 women met the criteria of thrombophilia. A control group that comprised 275 women with similar gestational age was generated, using a 1:1 ratio. Unconjugated estriol MoM levels were significantly lower in women with inherited thrombophilia (p = 0.02). But there was no statistically significant difference for unconjugated estriol levels, human chorionic gonadotropin, alfa fetoprotein and their MoM levels. CONCLUSIONS: Our study suggest that in patients with hereditary thrombophilia a new correction factor should be used, when calculating unconjugated estriol MoM value, which is one of the markers of second trimester aneuploidy screening test.