In a randomized trial involving previously untreated patients with metastatic intermediate- or poor-risk renal-cell cancer, nivolumab plus ipilimumab was associated with higher response rates, longer ...overall survival, and greater improvement in quality of life than sunitinib.
The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell ...carcinoma (aRCC). We report updated efficacy data from the second interim analysis.
Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1–positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.
Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 95% confidence interval (CI) 0.490–0.777}; one-sided P < 0.0001; median 13.8 (95% CI 10.1–20.7) versus 7.0 months (95% CI 5.7–9.6); overall population: HR 0.69 (95% CI 0.574–0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1–15.3) versus 8.0 months (95% CI 6.7–9.8). OS data were immature PD-L1+ population: HR 0.828 (95% CI 0.596–1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616–1.027); one-sided P = 0.0392.
Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.
NCT02684006.
•Avelumab plus axitinib significantly prolonged progression-free survival versus sunitinib in advanced renal cell carcinoma.•Although overall survival data were immature, results favored the combination over sunitinib across prespecified subgroups.•Adjusting for subsequent use of PD-1/PD-L1 inhibitors in the sunitinib arm predicted a survival benefit for the combination.•Among all randomized patients, avelumab plus axitinib had a longer mean duration of response than sunitinib.•Avelumab plus axitinib prolonged progression-free survival on next-line therapy versus sunitinib.
Sensing small biomolecules in biofluids remains challenging for many optical chemosensors based on supramolecular host-guest interactions due to adverse interplays with salts, proteins, and other ...biofluid components. Instead of following the established strategy of developing alternative synthetic binders with improved affinities and selectivity, we report a molecular engineering approach that addresses this biofluid challenge. Here we introduce a cucurbit8uril-based rotaxane chemosensor feasible for sensing the health-relevant biomarker tryptophan at physiologically relevant concentrations, even in protein- and lipid-containing human blood serum and urine. Moreover, this chemosensor enables emission-based high-throughput screening in a microwell plate format and can be used for label-free enzymatic reaction monitoring and chirality sensing. Printed sensor chips with surface-immobilized rotaxane-microarrays are used for fluorescence microscopy imaging of tryptophan. Our system overcomes the limitations of current supramolecular host-guest chemosensors and will foster future applications of supramolecular sensors for molecular diagnostics.
Background
Several clinicopathological parameters have been implicated in prognosis, recurrence and survival, following oral squamous cell carcinoma (OSCC). The purpose of this retrospective study ...was to review the outcome of patients with oral cavity squamous cell carcinoma treated at a single institution by primary surgical resection with or without adjuvant radiotherapy or radiochemotherapy, or brachytherapy and to identify the factors affecting survival and locoregional control.
Materials and methods
We retrospectively reviewed the records of 429 consecutive patients after primary radical R0 tumor resection and 55 patients after brachytherapy in our department between 1997 and 2010. OSCC pathological parameters were analyzed including age, gender, site distribution, tumor size, lymph node involvement, grading, microvascular invasion, lymphatic vessel involvement, and distant metastasis. Descriptive statistics were calculated for each variable and survival was calculated using the univariate Kaplan–Meier method. Prognostic factors were analyzed using the multivariate Cox proportional hazard model.
Results
Average tumor size was 10.9 mm (95 % CI for the mean 9.6–12.3). Disease-free survival at 5 years was 65 % and overall 5-year survival was 62 %. On univariate analysis, patients with increased tumor size, lymph node involvement, microvascular invasion, and lymphatic vessel involvement had a significant poor prognosis. Multivariate analysis showed that independent prognostic factors were increased tumor size and microvascular invasion.
Conclusion
This hospital-based retrospective cohort study points out different clinicopathological prognostic factors of survival in a large patient cohort treated for OSCC. It highlights increased tumor size and microvascular invasion as the most independent prognostic factors in predicting survival in patients with OSCC.
To evaluate the Prostate Imaging Reporting and Data System, version 2.1 (PIRADS V2.1) criteria for seminal vesicle invasion (SVI) and examine whether the timing of last ejaculation influences the ...detection of SVI.
The study population consisted of 68 patients (34 with SVI, 34 without SVI, matching groups by age and prostate volume) who underwent PIRADS V2.1-compliant multiparametric magnetic resonance imaging (MRI; 34 at 1.5 T, 34 at 3 T). Before the examination, the time of last ejaculation (38/68 ≤ 5 days, 30/68 > 5 days) was collected via a questionnaire. The five PIRADS V2.1 criteria for SVI with subsequent overall assessment were evaluated retrospectively by two independent examiners (examiner 1 with >10 years of experience, examiner 2 with 6 months of experience) in a single-blinded fashion for all patients using a questionnaire and a six-point scale (0 = no, 1 = very likely not, 2 = probably not, 3 = possible, 4 = probable, 5 = certain).
E1 achieved high specificity (100%) and positive predictive value (PPV; 100%) in the overall assessment, independent of the time of last ejaculation (sensitivity = 76.5%, negative predictive value NPV = 81%). The area under the curve (AUC) value was 0.882; for E2, it was 0.765. At ≤5 days, the AUC values of E1 and E2 differed significantly (0.867 versus 0.681, p=0.016), as did the diffusion restriction criterion (0.833 versus 0.681, p=0.028). E1 showed high AUC values independent of time. E2 had better values for all criteria at >5 days than at ≤5 days. There were no significant differences between the examiners in all observations at >5 days.
The PIRADS V2.1 criteria are well suited for an experienced examiner to detect SVI independent of time point. An inexperienced examiner will benefit from patients being abstinent >5 days prior to MRI.
Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute ...disease in adults following primary infection, little is known about the virological and immunological events during EBV's lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral genomes increasing in the blood and oral cavity, possibly due to a systemic type I interferon response. This study provides the first description of events during the incubation period of natural EBV infection in humans and definitive data upon which to formulate theories of viral control and disease pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The intraluminal conditions of the fed stomach are critical for drug release from solid oral dosage forms and thus, often associated with the occurrence of food effects on oral bioavailability. In ...this study, intragastric pH and pressure profiles present after the ingestion of the high-caloric, high-fat (964kcal) FDA standard breakfast were investigated in 19 healthy human subjects by using the telemetric SmartPill® capsule system (26×13mm). Since the gastric emptying of such large non-digestible objects is typically accomplished by the migrating motor complex phase III activity, the time required for recurrence of fasted state motility determined the gastric emptying time (GET). Following the diet recommendations of the FDA guidance on food effect studies, the mean GET of the telemetric motility capsule was 15.3±4.7h. Thus, the high caloric value of the standard breakfast impeded gastric emptying before lunch in 18 out of 19 subjects. During its gastric transit, the capsule was exposed to highly dynamic conditions in terms of pH and pressure, which were mainly dependent on further meal and liquid intake, as well as the intragastric capsule deposition behavior. Maximum pH values in the stomach were measured immediately after capsule intake. The median pH value of the 5min period after capsule ingestion ranged between pH3.3 and 5.3. Subsequently, the pH decreased relatively constantly and reached minimum values of pH0–1 after approximately 4h. The maximum pressure within the stomach amounted to 293±109mbar and was clearly higher than the maximum pressure measured at the ileocaecal junction (60±35mbar). The physiological data on the intraluminal conditions within the fed stomach generated in this study will hopefully contribute to a better understanding of food effects on oral drug product performance.
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To compare objective and subjective image quality parameters of three image reconstruction algorithms of different generations at routine multidetector computed tomographic (CT) examinations of the ...abdomen.
This institutional review board-approved study included 22 consecutive patients (mean age, 56.1 years ± 15.8 standard deviation; mean weight, 79.1 kg ± 14.8) who underwent routine CT examinations of the abdomen. A low-contrast phantom was used for objective quality control. Raw data sets were reconstructed by using filtered back projection (FPB), adaptive statistical iterative reconstruction (ASIR), and a model-based iterative reconstruction (MBIR). Radiologists used a semiquantitative scale (-3 to +3) to rate subjective image quality and artifacts, comparing both FBP and MBIR images with ASIR images. The Wilcoxon test and the intraclass correlation coefficient were used to evaluate the data. Measurements of objective noise and CT numbers of soft tissue structures were compared with analysis of variance.
The phantom study revealed an improved detectability of low-contrast targets for MBIR compared with ASIR or FBP. Subjective ratings showed higher image quality for MBIR, with better resolution (median value, 2; range, 1 to 3), lower noise (2; range, 1 to 3), and finer contours (2; range, 1 to 2) compared with ASIR (all P < .001). FBP performed inferiorly (0, range, -2 to 0; -1 range, -3 to 0; 0 range, -1 to 0, respectively; all, P < .001). Mean interobserver correlation was 0.9 for image perception and 0.7 for artifacts. Objective noise for FBP was 14%-68% higher and for MBIR was 18%-47% lower than that for ASIR (P < .001).
The MBIR algorithm considerably improved objective and subjective image quality parameters of routine abdominal multidetector CT images compared with those of ASIR and FBP.
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