Subgingival Microbiota and Longitudinal Glucose Change: The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS).

Microbial communities along mucosal surfaces throughout the digestive tract are hypothesized as risk factors for impaired glucose regulation and the development of clinical cardiometabolic disease. We investigated whether baseline measures of subgingival microbiota predicted fasting plasma glucose (FPG) longitudinally. The Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) enrolled 230 diabetes-free adults (77% female) aged 20 to 55 y (mean ± SD, 34 ± 10 y) from whom baseline subgingival plaque and longitudinal FPG were measured. DNA was extracted from subgingival plaque, and V3 to V4 regions of the 16S rRNA gene were sequenced. FPG was measured at baseline and again at 2 y; glucose change was defined as follow-up minus baseline. Multivariable linear models regressed 2-y glucose change onto baseline measures of community diversity and abundances of 369 individual taxa. A microbial dysbiosis index (MDI) summarizing top individual taxa associated with glucose change was calculated and used in regression models. Models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and baseline glucose levels. Statistical significance was based on the false discovery rate (FDR; <0.05) or a Bonferroni-corrected P value of 1 × 10-4, derived from the initial 369 hypothesis tests for specific taxa. Mean 2-y FPG change was 1.5 ± 8 mg/dL. Baseline levels of 9 taxa predicted FPG change (all FDR <0.05), among which Stomatobaculum sp oral taxon 097 and Atopobium spp predicted greater FPG change, while Leptotrichia sp oral taxon 498 predicted lesser FPG change (all 3 P values, Bonferroni significant). The MDI explained 6% of variation in longitudinal glucose change (P < 0.001), and baseline glucose levels explained 10% of variation (P < 0.0001). FPG change values ± SE in the third versus first tertile of the MDI were 4.5 ± 0.9 versus 1.6 ± 0.9 (P < 1 × 10-4). Subgingival microbiota predict 2-y glucose change among diabetes-free men and women.

[Vaccines for the treatment of non-small cell lung cancer]. / Les thérapies vaccinales dans le cancer bronchique.

Antigen-specific immunotherapy also known as cancer vaccination offers a novel approach for the treatment of non-small cell lung cancer patients. It relies on specific priming of the immune system in order to provoke or increase adaptive antitumor immune response against the vaccine component. Several molecules have been developed in lung cancer, based on whole-tumor cells, dendritic cells, peptides, recombinant proteins, or viral vectors. The aim of this review is to describe the mechanism of action of these vaccines and the results of the main clinical studies.

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.

BACKGROUND: EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database. PATIENTS AND METHODS: Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients. RESULTS: EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients. CONCLUSION: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. / Réponse prolongée sous paclitaxel après immunothérapie par pembrolizumab dans le cancer bronchique.

INTRODUCTION: Pembrolizumab, a humanized monoclonal antibody IgG4 anti-PD-1, having offered promising results in patients suffering from non-small cell lung cancer metastatic and heavily pretreated. OBSERVATION: We report here the case of an unexpected good response after pembrolizumab failure obtained with paclitaxel in a 68-year-old patient with stage IV lung adenocarcinoma. Moreover, the response duration with paclitaxel was more than fourteen months. CONCLUSION: Our case suggests a mutual potentiation of chemotherapy and immunotherapy, and raises the issue of the treatment sequence to favor.

[Safety culture assessment in a university pulmonary medicine department]. / Mesure de la culture de sécurité des soins dans un service universitaire de pneumologie.

INTRODUCTION: Improvement in treatment safety is a major issue in Western healthcare systems, with the aim of reducing the number of treatment associated undesirable events. The safety culture, defined as an integrated and coherent collection of individual and organizational behavior that seeks continuously to reduce harm to patients, possibly related to treatment, could fulfill this aim. METHODS: We have used an adaption of the American "Hospital Survey on Patient Safety" questionnaire (HSOPSC), which examines professionals' perception of treatment safety, to assess the safety culture in our respiratory medicine service in the Strasbourg University Hospital. RESULTS: Of the 110 questionnaires distributed to the service personnel, 93 were returned (85 %). The level of treatment safety was judged "acceptable" for 56 % of the personnel, "very good" for 32 %, against "weak" or "failing" for 10 %. Of the 10 dimensions explored, 8 were considered to need improvement and 2 had a level of positive responses greater than 50 %. CONCLUSIONS: Treatment safety culture seems to be an area to develop in our service. A strong safety culture should allow health care professionals to adhere better to treatment safety mechanisms.

[Stereotactic body radiation radiotherapy for oligometastatic non-small cell lung cancer (NSCLC): A case report]. / Radiothérapie exclusive curative chez un patient atteint d'un carcinome bronchique non à petites cellules de stade IV oligométastatique : cas clinique et revue de la littérature.

Metastatic non-small cell lung cancer is associated with a poor prognosis, and palliative chemotherapy is the mainstay of treatment. However, long-time survival has been observed in oligometastatic patients treated with locally ablative therapies to all sites of metastatic disease. An 80-year-old man was diagnosed with an adenocarcinoma of the lung. The right upper lobe lesion was classified cT2aN0M0 and was treated with stereotactic body radiation therapy at the dose of 60Gy in eight fractions. A few months after, he successively presented with two brain metastases and one left adrenal metastasis, with a complete response on the primary tumor. The three secondary lesions were treated with stereotactic body radiation therapy alone. Thirty months after the diagnosis and 12months after metastases' apparition, primary and brain lesion kept controlled (complete response). Oligometastatic non-small cell lung cancer management is not clear. Locally ablative therapies such as stereotactic body radiation therapy, surgery and radiofrequency are efficient and should be considered. A phase III study should evaluate radical treatment strategies in such patients.

[Targeted therapies in non-small cell lung cancer in 2014]. / Les thérapies ciblées dans les cancers bronchiques non à petites cellules en 2014.

For several years, the identification of molecular sequencing alterations has considerably changed the perception and treatment of non-small cell lung cancer (NSCLC). These alterations have been defined as "driver mutations", such as mutations in EGFR and EML4-ALK fusion gene, and are highly sensitive to specific therapies. Other targets have also been identified recently. Personalized medicine is now a reality for patients with advanced NSCLC on the basis of routine screening for EGFR, HER2, KRAS, BRAF, PI3KCA mutations and EML4-ALK rearrangement. This article describes identified biomarkers, available targeted therapies, and the main clinical research approaches in NSCLC.

p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation.

p14ARF is a tumour suppressor which plays a critical role in p53-dependent or -independent cell growth control. Several studies have recently provided evidence that p14ARF can also interfere either directly or indirectly with some components of the RB signalling pathway to mediate its antiproliferative activity. The aim of this study was to explore the existence of direct relationships between p14ARF and RB proteins. We show that p14ARF promotes the accumulation of a hypoacetylated RB protein, when it is upregulated in a model of stable-inducible clones or physiologically induced following cell exposure to cytotoxic agents. Looking for the mechanisms involved in this process, we demonstrate that the histone acetyl transferase Tip60 directly interacts with RB and stimulates its degradation by the proteasome through acetylation of its C-terminus. Furthermore, and consistent with p14ARF-induced RB accumulation, we provide evidence that p14ARF prevents Tip60-mediated RB acetylation, therefore precluding its proteasomal degradation. Overall, our results identify a novel mechanism by which p14ARF controls the RB pathway to trigger its antiproliferative function.

Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1.

Treatment of metastatic prostate cancer with androgen-ablation often elicits dramatic tumor regressions, but the response is rarely complete, making clinical recurrence inevitable with time. To gain insight into therapy-related progression, changes in gene expression that occurred following androgen-deprivation of an androgen-dependent prostate tumor xenograft, CWR22, and the emergence of an androgen-independent tumor, CWR22-R, were monitored using microarray analysis. Androgen-deprivation resulted in growth arrest of CWR22 cells, as evidenced by decreased expression of genes encoding cell cycle components and basal cell metabolism, respiration and transcription, and the induced expression of putative negative regulatory genes that may act to sustain cells in a nonproliferative state. Evolution of androgen-independent growth and proliferation, represented by CWR22-R, was associated with a reentry into active cell cycle and the up-regulation of several genes that were expressed at low levels or absent in the androgen-dependent tumor. Androgen repletion to mice bearing androgen-independent CWR22-R tumors induced, augmented, or repressed the expression of a number of genes. Expression of two of these genes, the calcium-binding protein S100P and the FK-506-binding protein FKBP51, was decreased following androgen-deprivation, subsequently reexpressed in CWR22-R at levels comparable with CWR22, and elevated further upon treatment with androgens. The dysregulated behavior of these genes is analogous to other androgen-dependent genes, e.g., prostate-specific antigen and human kallikrein 2, which are commonly reexpressed in androgen-independent disease in the absence of androgens. Other androgen-responsive genes whose expression decreased during androgen-deprivation and whose expression remained decreased in CWR22 were also identified in CWR22-R. These results imply that evolution to androgen-independence is due, in part, to reactivation of the androgen-response pathway in the absence of androgens, but that this reactivation is probably incomplete.

Role of endovaginal sonography in the diagnosis and management of ectopic pregnancy.

Although diagnostic laparoscopy is still considered the standard reference in the diagnosis of ectopic pregnancy (EP), use of high-resolution endovaginal sonography, in conjunction with qualitative serum assays of the beta subunit of human chorionic gonadotropin (beta-hCG), allows detection of earlier and smaller EPs. The most common endovaginal sonographic finding of EP (89%-100% of cases) is an extraovarian, round or elongated, solid tubal mass. A tubal ring (an extrauterine saclike structure) is the second most common finding (40%-68% of cases). Pelvic fluid may be present, but it is a nonspecific finding. An EP may have a pseudosac, which can be distinguished sonographically from the true gestational sac of an intrauterine pregnancy. Color Doppler techniques can complement endovaginal sonographic findings, but they should be performed only after a thorough real-time evaluation of the adnexal region. Current therapeutic options for EP include expectant management (ie, close follow-up), medical treatment (usually injections of methotrexate), and surgery. Accurate diagnosis with endovaginal sonography is the prerequisite to nonsurgical management, since surgery is the logical treatment if laparoscopy is used for diagnosis.

Non-specific adherence of oxide particles as a means of quantifying protein adsorption on surfaces.

This paper reports quantification of a method for measuring amounts of protein adsorbed to a surface; the method is especially useful for revealing macroscopic spatial patterns of adsorption. The experiments tested the effectiveness of iron oxide suspensions adsorbed onto the adsorbed protein to indicate, in separate trials, the amount of either human plasma fibrinogen or human serum albumin (HSA) present on glass slides. Corresponding trials, using radioactively labeled proteins, were performed to calibrate the amount of either albumin or fibrinogen adsorbed onto similar slides out of solutions of varying bulk concentrations. The oxide deposits were quantified using a scanner and an image analysis program. The isotherms produced from the collected data indicate a continuous, monotonic correlation between light absorbed by adherent oxide and surface concentration of protein. The same correlation applies to albumin and fibrinogen when surface concentrations are expressed in weight units. These results confirm that patterns of oxide deposition correspond to patterns of protein deposition and show clearly how qualitative observations, such as those previously reported, can be made quantitative with scanning and digital image analysis.

Assessment of laryngeal cancer: CT scan versus endoscopy.

In order to assess the value of the systematic use of CT scan in the workup for laryngeal cancer, a retrospective study was conducted on 66 consecutive previously untreated cases of laryngeal cancer. Endoscopic and CT scan findings were systematically compared. The areas of particular difficulty in CT scan assessment are described. CT scan alone understaged laryngeal cancers in 10.6% of cases, all of them being superficial spreading tumors within the larynx or in the juxtalaryngeal areas. CT scan worsened the staging in 22.7% of cases, all of them being deep invasions overlooked by endoscopy. CT was most useful in lesions initially classified as T2 and T3, which included all those reclassified by CT. None of the T1 lesions was upgraded after CT, and systematic use of CT for this stage is not warranted. CT scan workup changed the therapeutic attitude in 10 of the 66 patients (15.1%), causing a switch to conservative surgery in seven patients and total laryngectomy with radiotherapy for the three others. CT was also valuable in choosing the most suitable technique for conservation surgery.

The reliability of routine pathologic diagnosis of colorectal adenocarcinoma.

The diagnosis of colorectal adenocarcinoma is generally considered as being reliable. However, the reproducibility of the classification of specific histologic patterns and the interrater agreement on the gradings have not been firmly established. A panel of three independent expert pathologists reviewed histologic sections from 128 patients selected among 1848 with colorectal cancer, diagnosed in 11 hospitals of the same region. The panel agreed with 92.6% of the original diagnoses of colorectal adenocarcinoma. As for agreement between panel members, the kappa value was 0.78 for the diagnosis of adenocarcinoma and 0.62 for confirmation of colorectal origin. The intraclass correlation coefficient for tumor differentiation features was 0.75. The proportion of villous and adenomatous components also generated good agreement. However, the grading of mucin secretion showed poor agreement (intraclass correlation coefficient = 0.44). Results confirm the reliability of routine pathological diagnosis and also demonstrate the reproducibility of basic diagnostic categories and pathognomonic features. Thus, to obtain reliable information from medical records for epidemiologic and clinical studies, data should be limited to well-defined diagnostic and histopathologic categories.

Sex differences in the changing anatomic distribution of colorectal carcinoma.

The anatomic site distribution of large bowel cancer was studied in 2079 patients between 1967 and 1980. To measure the trend in the localization of the carcinomas, the slope of the regression line of the proportions at each site over the years was computed. The large bowel was divided into five segments: cecum, ascending colon and hepatic flexure, transverse and descending colon, sigmoid and rectosigmoid junction, and rectum. A significant decrease in the proportions of cancer in the sigmoid for both sexes (slope parallel b = -0.89; P less than 0.001) and an increase of cecal cancer (b = 0.54; P less than 0.004) was observed. Sex-specific results indicated the diminishing proportion of sigmoid cancer in men (b = -1.04; P less than 0.004) with an increase in transverse and descending colon cancer proportions (b = 0.52; P = 0.012). In women, a negative slope of -0.74 was not significant for sigmoid cancer, but cancer of the cecum showed an increase in proportions (b = 0.80; P = 0.01). The age distribution indicated a significant decrease in proportion of men older than 80 years and of women in the age group of 40 to 49 years and an increase in women older than 80 years. However, age adjustment did not change any of the previous conclusions. The observed sex differences in the changing distribution within the large bowel over a 14-year period cannot be explained by the improvement of diagnostic tools in the last years. In view of these findings, it is important to evaluate the possible sex-related bias in the application of screening and preventive measures as well as the changes in the ecologic features of the large intestine.