B-cell infiltration is associated with survival outcomes following programmed cell death protein 1 inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. PATIENTS AND METHODS: NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. RESULTS: High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). CONCLUSIONS: Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression.

Galectin-3, Carotid Plaque Vulnerability, and Potential Effects of Statin Therapy.

OBJECTIVES: Galectin-3, a member of galectines, a family of b-galactoside-specific lectins, has been reported to propagate vascular inflammation. The role of galectin-3 in carotid atherosclerosis is controversial. The aim of this study was to investigate the relationship of galectin-3 with plaque vulnerability in patients with high grade carotid stenosis. METHODS: This was a cross sectional study of patients undergoing carotid endarterectomy (CEA). Carotid plaques obtained from 78 consecutive patients (40 symptomatic [SG], 38 asymptomatic [AG]) undergoing CEA were histologically analyzed for galectin-3, macrophages (CD68) and laminin. Pre-operatively the biochemical profile and plaque echogenicity (gray-scale median, GSM) score were determined. RESULTS: There were no significant differences in clinical and demographic parameters between SG and AG(p > .05). The SG had a lower GSM score (44.21 ± 18.24 vs. 68.79 ± 28.79, p < .001) and a smaller positive stained area for galectin-3 (4.89 ± 1.60% vs. 12.01 ± 5.91%, p < .001) and laminin (0.88 ± 0.71% vs. 3.46 ± 2.12%, p < .001) than the AG. On the other hand, intra-plaque macrophage content was increased in SG (p < .001). For the whole cohort, symptomatic status was independently associated with intra-plaque contents of both galectin-3 (OR=0.634, p < .001), and GSM score (OR=0.750, p < .001). Notably, patients on long term statin treatment had elevated galectin-3 and lowered macrophage intra-plaque concentrations compared with those on short term treatment (p < .05). CONCLUSIONS: A low galectin-3 intra-plaque concentration seems to correlate with clinically and ultrasonically defined unstable human carotid plaques. Long term statin treatment may induce increase of intra-plaque galectin-3 concentration mediating plaque stabilization.

Liquid based cytology and HPV DNA testing in a Greek population compared to colposcopy and histology.

Screening for cervical cancer in Greece is still unorganised and based on self- motivation. The purpose of this study was to evaluate the accuracy of cytological findings from a large observational population sample, originating from Western Athens, in association with reflex DNA test, colposcopic estimation, and final histologic diagnosis. The rate of invasive carcinoma, both squamous cell and adenocarcinoma, is indicative of a largely unscreened population. In this study, the estimated overall prevalence of human papilloma virus (HPV) was 41.1%, with HPV positivity at 37.4% of cytologically normal women. HPV testing did not seem to improve sensitivity of cytology for atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LGSIL) cases in identifying CIN 2+ lesions, but outperformed cytology in detecting CIN3+ for cytological high-grade squamous intraepithelial lesion (HGSIL) cases. For HGSIL cases sensitivity of colposcopy for detecting CIN3+ was comparable to cytology.

Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study.

INTRODUCTION: Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE). AIM AND METHODS: TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls. RESULTS: Seventy-nine individuals were included (mean age 69.77 ±â€¯0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035). CONCLUSIONS: Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.

Modafinil for the treatment of fatigue in lung cancer: a pilot study.

Cancer-related fatigue is the most prevalent and distressing symptom experienced by patients with advanced cancer. Central nervous system stimulants have been shown to relieve fatigue in nonmalignant disease. Modafinil is a stimulant with a selective site of action in the brain that is better tolerated than traditional stimulants, such as methylphenidate. The aim of this study was to determine the feasibility of conducting a randomised controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer. Twenty patients with non-small cell lung cancer were recruited to this open-label study. Modafinil was taken in a fixed dose-titration schedule of 100 mg daily for 7 days followed by 200 mg daily for 7 days. Fifteen patients completed the study. During the study period, there was a rapid and statistically significant reduction in the primary outcome, fatigue (P = 0.001) and the secondary outcomes of daytime sleepiness and depression/anxiety. This improvement in fatigue was also clinically significant. Ten patients chose to continue modafinil after the study and the drug was well-tolerated. It would be both feasible and worthwhile to conduct a definitive randomised controlled trial to determine the role of modafinil in the treatment of cancer-related fatigue.

Gallstones in a community free of obesity but prone to slow intestinal transit.

OBJECTIVES: To verify anecdotal reports that gallstones were frequent in a remote community where obesity is rare and to look for possible explanations of their occurrence, including slow intestinal transit. DESIGN: Population survey of gallbladder status and stool form. SETTING: Two villages in Ladakh, a mountainous region of northern India; for comparison, a stratified random sample from general practitioners' lists in East Bristol. SUBJECTS: Women aged 25-59 years, 437 in Ladakh and 974 in Bristol. MAIN OUTCOME MEASURES: Presence of gallstones on ultrasonography and response to questionnaires about parity, the intake of dried legume seeds (pulses) and bowel function including the form or appearance of the stools on a seven-point, transit-sensitive scale. Weight, height and waist circumference were also recorded. RESULTS: Gallstone disease was at least as frequent in Ladakh as in Bristol although Ladakhi women were uniformly slim and their weight, waist size and body mass index failed to rise with age. After adjustment for age, gallstone disease was associated with higher body mass index and waist size in Bristol but not in Ladakh. It was associated with increased parity in Bristol, but not significantly so after adjusting for age and not at all in Ladakh. Gallstone disease was not directly associated with bowel function but Ladakhis often reported their stools to be lumpy (42.4 vs. 26.5% of Bristol women) and seldom as soft or loose (6.4 vs. 42.5%), implying that their intestinal transit tends to be slow. CONCLUSION: Gallstones can be common in a population free of obesity but prone to intestinal stasis.

The biological impact of living with chronic breathlessness - a role for the hypothalamic-pituitary-adrenal axis?

Breathlessness is a common and distressing symptom in advanced cardiorespiratory disease, with recognised psychological, functional and social consequences. The biological impact of living with chronic breathlessness has not been explored. As breathlessness is often perceived as a threat to survival, we propose that episodic breathlessness engages the stress-response, as regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, we hypothesise that chronic breathlessness causes excessive stimulation of the HPA axis, resulting in dysfunctional regulation of the HPA axis and associated neuropsychological, metabolic and immunological sequelae. A number of observations provide indirect support for this hypothesis. Firstly, breathlessness and the HPA axis are both associated with anxiety. Secondly, similar cortico-limbic system structures govern both breathlessness perception and HPA axis regulation. Thirdly, breathlessness and HPA axis dysfunction are both independent predictors of survival. There is a need for direct observational evidence as well as experimental data to investigate this hypothesis which, if plausible, could lead to the identification of a new biomarker pathway to support breathlessness research.

Molecular epidemiology of HPV infection using a clinical array methodology in 2952 women in Greece.

The molecular epidemiology of human papillomavirus (HPV) infection in a sample of Greek women (n = 2952, mean age 42.2 ± 13.3 years) was examined. HPV prevalence was 50.7% (95% confidence interval, 48.8-52.6). The most frequent HPV types were HPV 53, 51 and 66 (10.2%, 9.4% and 9.3%, respectively). HPV positivity was associated with age, age of sexual debut, number of sexual partners and duration of sexual relationship, while marriage or multiparity protected against infection (all p <0.001). Follow-up of this cohort will assist in predicting the effect of vaccination with the new HPV vaccines on future screening with HPV-based tests for cervical cancer.