In oropharyngeal squamous cell carcinoma (OPC), high CD8
tumor-infiltrating lymphocyte (CD8
TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with ...durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8
TIL density, safety, and efficacy in patients with OPC.
Patients with newly diagnosed stage II-IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8
TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes.
Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8
TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (
= 0.97; 95% CI: -1.07-2.28). In each group, 6 patients (43%, 95% CI: 17.66-71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8
TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8
TIL change in patients with a MPR was seen (
= 0.059; 95% CI: -0.33-3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence.
Durvalumab + tremelimumab did not increase CD8
TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.
Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that ...circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently ...a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease.
A retrospective study of subjects who had undergone bronchoscopic cryobiopsy for evaluation of DPLD at an academic tertiary care center from January 1, 2012 through January 15, 2013 was performed. The procedure was performed using a flexible bronchoscope to acquire biopsies of lung parenchyma. H&E stained biopsies were reviewed by an expert lung pathologist.
Twenty-five eligible subjects were identified. With a mean area of 64.2 mm(2), cryobiopsies were larger than that typically encountered with traditional transbronchial forceps biopsy. In 19 of the 25 subjects, a specific diagnosis was obtained. In one additional subject, biopsies demonstrating normal parenchyma were felt sufficient to exclude diffuse lung disease as a cause of dyspnea. The overall diagnostic yield of bronchoscopic cryobiopsy was 80% (20/25). The most frequent diagnosis was usual interstitial pneumonia (UIP) (n = 7). Three of the 25 subjects ultimately required surgical lung biopsy. There were no significant complications.
In patients with suspected diffuse parenchymal lung disease, bronchoscopic cryobiopsy is a promising and minimally invasive approach to obtain lung tissue with high diagnostic yield.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The collection of microbes that live in and on the human body – the human microbiome – can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The ...mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell–cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology – a systems biology approach.
Microbiomes impact on human health in many ways and likely impact on cancer progression and response to therapy.The effects of microbiomes on cancer may be direct or indirect.The interactions between microbiomes and cancers – two complex systems on their own – require a systems biology approach.Treatments that alter microbiome composition of cancer patients are already under investigation in trials.
We present a method for determining the phase and contrast of a single shot of an atom interferometer. The application of a phase shear across the atom ensemble yields a spatially varying fringe ...pattern at each output port, which can be imaged directly. This method is broadly relevant to atom-interferometric precision measurement, as we demonstrate in a 10 m 87Rb atomic fountain by implementing an atom-interferometric gyrocompass with 10 mdeg precision.
Patient-centered quality outcomes such as disposition after surgery are increasingly being scrutinized. Preoperative factors predictive of nonhome discharge (DC) may identify at-risk patients for ...targeted interventions. This study examines the association among preoperative risk factors, frailty, and nonhome DC after elective vascular surgery procedures in patients living at home.
The 2011-2012 National Surgical Quality Improvement Project database was queried to identify all home-dwelling patients who underwent elective vascular procedures (endovascular and open aortic aneurysm repair, suprainguinal and infrainguinal bypasses, peripheral endovascular interventions, carotid endarterectomy, and stent). Preoperative frailty was measured using the modified frailty index (mFI; derived from Canadian Study of Health and Aging). Univariate and multivariate logistic regression analysis was performed to examine the association of frailty and nonhome DC.
Of 15,843 home-dwelling patients, 1,177 patients (7.4%) did not return home postoperatively. Frailty (mFI > 0.25) conferred a significantly increased 2-fold risk of nonhome DC disposition for each procedure type. Frailty, female gender, open procedures, increasing age, end-stage renal disease, and occurrence of any postoperative complication were associated with increased risk of nonhome DC. On multivariate logistic regression analysis, frailty increased the odds of nonhome DC by 60% (odds ratio 1.6, 95% confidence interval 1.4-1.8) after adjusting for other covariates. In the presence of complications, the risk of nonhome DC was 27.5% in frail versus 16.5% in nonfrail patients (P < 0.001). In the absence of complications, although absolute risk was lower, frail patients were nearly twice as likely to not return home (frail 5.5% vs. nonfrail 2.75%, P < 0.001).
Frail home-dwelling patients undergoing elective vascular procedures are at high risk of not returning home after surgery. Preoperative frailty assessment appears to hold potential for counseling regarding postsurgery disposition and DC planning.
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