Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer.

Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.

Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.

BACKGROUND: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival. PATIENTS AND METHODS: A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis. RESULTS: F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69). CONCLUSION: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.

Ventricular remodelling in rabbits with sustained high-fat diet.

AIM: Excess weight gain and obesity are one of the most serious health problems in the western societies. These conditions enhance risk of cardiac disease and have been linked with increased prevalence for cardiac arrhythmias and sudden death. Our goal was to study the ventricular remodelling occurring in rabbits fed with high-fat diet (HFD) and its potential arrhythmogenic mechanisms. METHODS: We used 15 NZW rabbits that were randomly assigned to a control (n = 7) or HFD group (n = 8) for 18 weeks. In vivo studies included blood glucose, electrocardiographic, and echocardiographic measurements. Optical mapping was performed in Langendorff-perfused isolated hearts. RESULTS: Body weight (3.69 ± 0.31 vs. 2.94 ± 0.18 kg, P < 0.001) and blood glucose levels (230 ± 61 vs. 141 ± 14 mg dL(-1) , P < 0.05) were higher in the HFD group vs. controls. The rate-corrected QT interval and its dispersion were increased in HFD rabbits vs. controls (169 ± 10 vs. 146 ± 13 ms and 37 ± 11 vs. 9 ± 2 ms, respectively; P < 0.05). Echocardiographic analysis showed morphological and functional alterations in HFD rabbits indicative of left ventricle (LV) hypertrophy. Isolated heart studies revealed no changes in repolarization and propagation properties under conditions of normal extracellular K(+) , suggesting that extrinsic factors could underlie those electrocardiographic modifications. There were no differences in the dynamics of ventricular fibrillation (frequency, wave breaks) in the presence of isoproterenol. However, HFD rabbits showed a small reduction in action potential duration and an increased incidence of arrhythmias during hyperkalaemia. CONCLUSION: High-fat feeding during 18 weeks in rabbits induced a type II diabetes phenotype, LV hypertrophy, abnormalities in repolarization and susceptibility to arrhythmias during hyperkalaemia.

Fenofibrate decreases plasma fibrinogen, improves lipid profile, and reduces uricemia.

Plasma fibrinogen has been found to be a major cardiovascular disease risk factor. This 2-year trial was designed to assess the effect of fenofibrate on fibrinogen and, as secondary end points, on lipid profile and uric acid in patients with dyslipidemia. Eighty subjects (40 women and 40 men) were admitted to either a control or an active group. Sixty-seven (84%) had sole hypercholesterolemia, 13 (16%) subjects had mixed dyslipidemia. The effect attributable to fenofibrate was a decrease of 15% in fibrinogen, 26% in the ratio low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (-20% low-density lipoprotein cholesterol, +10% high-density lipoprotein cholesterol), 34% in triglycerides (median), and 13% in uric acid (P < .0001 for all). Fenofibrate simultaneously affected hemostasis (by lowering fibrinogenemia) and lipid profile. Because fenofibrate has few adverse effects, it could be a fair option for patients who need polytherapy and do not tolerate resins or niacin. Its clinical efficacy should be tested in long-term studies to assess its real capacity to prevent cardiovascular events.

Fibrinogen: a new major risk factor for cardiovascular disease. A review of the literature.

During the last decade, several epidemiological studies have reliably demonstrated that plasma fibrinogen is a strong and independent risk factor for cardiovascular disease that is at least as important as more traditional risk factors for the disease. The deleterious effects of this protein seem to be mediated through its role in hemorrheology, hemostasis, and the atherogenic process itself. According to prospective epidemiological studies, the risk of developing a cardiovascular event such as ischemic heart disease or stroke is 1.8 to 4.1 times higher in subjects with fibrinogen levels in the top third than in those with levels in the lower third. Epidemiological studies, clinical trials, pathophysiology, and therapeutical possibilities are reviewed in this paper.

Immunoglobulin production in man stimulated by an orally administered bacterial lysate.

The concentrations of secretory immunoglobulins in the saliva, and of immunoglobulin in the serum, have been measured by the radial immunodiffusion method in 12 healthy volunteers, before and after oral administration of Broncho-Vaxom which is a lysate of bacteria that usually cause infection in the upper respiratory tract. The mean concentration of secretory IgA in the saliva was increased by over 100% after the 10-day administration of the product. This increase was statistically significant between the 20th and 33rd day after the beginning of the treatment (p < 0.05). It fell to a normal level after a month in 4 subjects who received one treatment course only. In 8 subjects who received a second treatment course beginning 1 month after termination of the first course, the high concentration of IgAs in the saliva persisted for at least 3 months. A significant increase in the serum concentrations of IgG of about 50% and of IgM of at least 100% above the initial level was observed in the treated subjects in the time between day 35 and 5 months after the beginning of the experiment (p < 0.05).