Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.

BACKGROUND: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. METHODS: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131. FINDINGS: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02). INTERPRETATION: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. FUNDING: NIBIT Foundation, Fondazione AIRC, AstraZeneca.

Microbial Leakage at Morse Taper Conometric Prosthetic Connection: An In Vitro Investigation.

OBJECTIVE: To evaluate in vitro the sealing capability at the prosthetic connection interface of 2 conometric systems. MATERIALS AND METHODS: Two conometric systems with the same design and different material were used, for a total of 24 samples. Each sample was assembled by a tapered abutment and respective coping. In group A, the copings were made of gold, whereas in group B they were made of PEEK. Three µL of mix bacterial suspension (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Fusobacterium nucleatum species) was inoculated into the abutment screw hole, and the coping was inserted on the abutment. Samples were immersed into culture tubes and incubated for 24, 48, and 72 hours into anaerobic conditions. Visual evaluation of turbidity was performed at each time point. Qualitative-quantitative assessment using real-time polymerase chain reaction was performed at 72 hours. Any difference between the groups was checked by means of Fisher exact test. RESULTS: Microbial leakage occurred in both groups, and there was no statistically significant difference between groups. Microbial concentration resulted in a presence inferior to 1 × 10 copies/µL in all positive assemblies. CONCLUSIONS: Because of the low bacterial count, it can be concluded that a minimal bacterial infiltration may be allowed by conometric interfaces for prosthetic connection.

Efficacy of the ND:YAG laser therapy on EBV and HSV1 contamination in periodontal pockets.

AIM: The aim of this retrospective multicenter study was to verify the efficacy of Nd:YAG laser in the treatment of periodontal pockets infected by Epstein-Barr Virus (EBV) and Herpes Simplex Virus 1 (HSV1). METHODS: Subgingival plaque samples of 291 Italian periodontal patients were analyzed by Real Time PCR to evaluate the frequency of both viruses before and after Nd:YAG laser-assisted periodontal treatment. RESULTS: Before treatment, EBV and HSV1 were observed in 29.9% and in 3.8% of periodontal patients respectively, while co-infection with both viruses was detected in 1.7% of cases. Periodontal Nd:YAG laser treatment ("Periodontal Biological Laser-Assisted Therapy", PERIOBLAST) produced statistical significant benefits, especially in EBV periodontal infection: 78.2% of EBV positive patients became EBV-negative following treatment. CONCLUSIONS: Results of this preliminary study highlight that EBV is found in periodontal pockets more frequently than HSV1, supporting the theory of the potential role of EBV in the onset and progression of periodontal disease. Moreover, our data showed that Nd:YAG laser-assisted periodontal treatment (Perioblast) is also effective in case of viral infection, validating evidences that it represents a successful alternative approach to traditional periodontal protocols.

Vitamin D: relevance in dental practice.

OBJECTIVE: The potential role of VDR gene variations in modulating periodontal susceptibility have been a subject of scientific investigations. The aim of this paper is to perform a literature review of the potential correlation between Vitamin D Receptor (VDR) gene polymorphisms and periodontal disease. MATERIALS AND METHODS: A PubMed literature search was made using "vitamin d receptor polymorphisms periodontal disease" as keys words. Only clinical studies in "Humans" as species and "English" as language were considered. Titles and abstracts of all identified records were examined to determine if the candidate articles contained sufficient information on the association of the VDR polymorphisms and the risk of development periodontal disease. CONCLUSIONS: Vitamin D may affect the risk of developing periodontal disease via an effect on bone mineral density or via immunomodulatory effects. There are scientific evidences about the correlation between some VDR polymorphisms, periodontitis and bone metabolism. The use of new simple and economics diagnostic techniques of genetic screening, allows to the dental specialists to identify periodontal patients with possible decreased bone mineral density. The complete acquisition of awareness by dentists of the strong relationship between skeletal bone density with periodontal health and osteointegrated implant success, could open a new therapeutic approach for periodontists with an important role in the early detection of osteoporosis and a better patient compliance of the periodontal therapy.

Bacterial colonization patterns of periodontal pockets in different ages.

The aim of this study was to investigate subgingival bacterial composition of untreated Italian subjects with aggressive and chronic periodontitis. The total bacterial load, pathogenic bacteria belonging to "red" and "orange" complexes and Aggregatibacter actinomycetemcomitans were determined by Real-Time PCR in 1216 patients. Data were analysed by looking for relationships between bacteriological parameters, age and periodontal probing depth. The obtained results showed a significant higher number of red complex bacteria in older rather than in younger patients. The total number of bacteria and the presence of A. actinomycetemcomitans did not clearly associate with an age group.

IL-18 gene promoter polymorphisms are only moderately associated with periodontal disease in Italian population.

OBJECTIVE: The aim of this study was to determine the impact of the polymorphisms at position -607 (C/A) and -137 (G/C) in the promoter of the IL-18 gene and their haplotypes, on the individual susceptibility of developing Aggressive (AgP) and/or Chronic (CP) periodontitis. MATERIALS AND METHODS: A total of 213 unrelated Italian subjects with periodontitis (AgP=109 and CP=104) and 100 periodontal-health subjects were studied. IL-18 gene promoter polymorphisms were analyzed by TaqMan® SNP Genotyping Assays. Genotype and allele frequencies were analyzed using the chi-square test and multiple logistic regression analysis. RESULTS: χ(2) of comparisons between diseased patients and healthy controls indicated a significant differentiation between the control and AP and CP groups (χ(2)=26.359, P<0.02). Interestingly, genotypes AACG, AACC and AACG have a moderate association with AgP and CP. For alleles, multiple logistic regression analysis showed that the polymorphism CG at position -137 is moderately associated with AgP (ExpB=2.880), while the polymorphism AA at position -607 is moderately associated with CP (ExpB=2.076). Finally, a moderate association of CA at position -607 (ExpB=2.099) with the healthy status compared to aggressive periodontitis was found. CONCLUSIONS: Results obtained indicated the presence of some potential moderate protective and moderate susceptible alleles and genotypes to both aggressive and chronic periodontitis, demonstrating that IL-18 -607 C/A and -137 G/C gene promoter polymorphisms are not suitable diagnostic features for AgP and CP.