Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.

BACKGROUND: In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab-paclitaxel in aTNBC. PATIENTS AND METHODS: Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. RESULTS: Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab-paclitaxel versus 5.7 months with placebo-paclitaxel]. In the PD-L1-positive population, atezolizumab-paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo-paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab-paclitaxel versus 28.3 months with placebo-paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. CONCLUSION: Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. CLINICALTRIALS.GOV: NCT03125902.

Poly-glutamic dendrimer-based conjugates for cancer vaccination - a computational design for targeted delivery of antigens.

Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly(glutamic acid) (PG)-dendrimers as nanocarriers of the tumour associated antigens (TAA) MART-1, gp100:44 and gp100:209. Molecular dynamics simulations and docking studies were performed. Nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however, the Frontier Molecular Orbital Theory study evidenced that only 32 of those were available to form covalent bonds. When the number of mannosamines conjugated to dendrimer was increased from 16 to 32, the dendrimer interacted with the receptor with higher affinity. However, 16 mannosamines-NBD-PG-G4-dendrimer was chosen to conjugate TAA for added functionality as no carboxylic end groups were available for further conjugation in the 32 mannosamines-dendrimer. Docking results showed that the majority of TAA-conjugated NBD-PG-G4-dendrimer demonstrated a favourable interaction with mannosamine binding site on mannose receptor, thus constituting a promising tool for TAA targeted delivery. Our in silico approach effectively narrows down the selection of the best candidates for the synthesis of functionalised PG-dendrimers with desired functionalities. These results will significantly reduce the time and efforts required to experimentally synthesise modified dendrimers for optimal antigen delivery.

Seven-year clinical performance of resin composite versus resin-modified glass ionomer restorations in noncarious cervical lesions.

PURPOSE: The purpose of this study was to comparatively assess the seven-year clinical performance of a one-bottle etch-and-rinse adhesive with resin composite (RC) and resin-modified glass ionomer (RMGI) restorations in noncarious cervical lesions. METHODS AND MATERIALS: One operator placed 70 restorations (35 restorations in each group) in 30 patients under rubber dam isolation without mechanical preparation. The restorations were directly assessed by two independent examiners, using modified US Public Health Service criteria at baseline and 6, 12, 24, 60, and 84 months. The obtained data were tabulated and statistically analyzed using the Fisher and McNemar tests. A difference was significant if p<0.05. RESULTS: Twenty patients were available for recall after seven years (66.6%), and 25 RC and 26 RMGI restorations out of 70 restorations were evaluated. Excellent agreement was registered for all criteria between examiners (κ≥0.85). Alfa and bravo scores were classified as clinically acceptable. The McNemar test detected significant differences within RC restorations between baseline and seven-year evaluations for anatomic form, marginal integrity, and retention (p<0.05). For RMGI restorations, a significant difference was identified for marginal integrity (p<0.05). As to material comparison, the Fisher exact showed a better retention performance for RMGI restorations than for RC restorations (p<0.05). Twelve composite restorations were dislodged (52.0% retention) and three ionomer restorations were lost (88.5% retention). The cumulative success rate for RC and RMGI was 30% and 58.1%, respectively. CONCLUSIONS: After seven years of service, the clinical performance of RMGI restorations was superior to that of the adhesive system/resin composite restorations in this study.

In vivo acid etching effect on bacteria within caries-affected dentin.

Acid etching procedures may disrupt residual bacteria and contribute to the success of incomplete caries removal followed by adhesive restoration. This study evaluated the in vivo effect of acid etching on cariogenic bacterial activity within affected dentin after minimally invasive treatment of caries lesions. Twenty-eight carious permanent teeth received standardized selective caries removal and random acid etch treatment (E) or not (NE) prior to adhesive restoration. Baseline and 3-month dentin biopsies were collected. The number of bacteria and activity of total bacterial cells and Streptococcus mutans were determined by quantitative PCR and RT-PCR. No statistically significant differences were observed in total bacterial number and activity between E and NE treatments (p > 0.3008). For NE, however, the residual S. mutans bacterial cells were reduced (p = 0.0027), while the activity per cell was significantly increased (p = 0.0010) after reentry at 3 months after restoration. This effect was not observed in group E. Although no significant differences were found between groups, this study suggests that acid etching of affected dentin prior to adhesive restoration may directly or indirectly have an inhibitive effect on the activity of residual cariogenic bacteria. Further research is required to investigate this potential effect.

In vivo dentin remineralization by calcium-phosphate cement.

Minimally invasive caries-removal procedures remove only caries-infected dentin and preserve caries-affected dentin that becomes remineralized. Dental cements containing calcium phosphate promote remineralization. This study evaluated the in vivo remineralization capacity of resin-based calcium-phosphate cement (Ca-P) used for indirect pulp-capping. Carious and sound teeth indicated for extraction were randomly restored with the Ca-P base or without base (control), followed by adhesive restoration. Study teeth were extracted after three months, followed by elemental analysis of the cavity floor. Mineral content of affected or sound dentin at the cavity floor was quantified by electron probe micro-analysis to 100-mum depth. After three months, caries-affected dentin underneath the Ca-P base showed significantly increased calcium and phosphorus content to a depth of 30 mum. Mineral content of treated caries-affected dentin was in the range of healthy dentin, revealing the capacity of Ca-P base to promote remineralization of caries-affected dentin.

Clinical evaluation of two packable posterior composites: 2-year follow-up.

The clinical performance of two packable posterior composites, Alert (A)-Jeneric/Pentron and SureFil (S)-Dentsply, was evaluated in 33 patients. Each patient received one A and one S restoration, resulting in a total of 66 restorations. The restorations were placed by one operator according to the manufacturer's specifications and were finished and polished after 1 week. Photographs were taken at baseline and after 2 years. Two independent evaluators conducted the clinical evaluation by using modified United States Public Health Service criteria. After 2 years, 60 restorations (30 A and 30 S), 27 class I (16 A and 11 S) and 33 class II (14 A and 19 S) were evaluated in 30 patients. Criterion A for recurrent caries, vitality, and retention was applicable to all 60 restorations. Criterion B was distributed among 40 restorations as follows: surface texture (15 A; 2 S), color (5 A; 6 S), postoperative sensitivity (1 S), marginal discoloration (8 A), marginal adaptation (3 A), and wear resistance (2 A). Data were analyzed using the Exact Fisher and McNemar tests. After 2 years, S showed a significantly better performance than A with respect to surface texture and marginal discoloration. The clinical performance of both materials was considered acceptable over the 2-year period. Further evaluations are necessary for a more in-depth analysis.