Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

The presence of an unerupted supernumerary tooth, or tooth bud between the 2 central incisors or as unilateral or bilateral teeth in the midline of the maxilla was noted as mesiodens on radiographs. Eighty-five cases of mesiodens in 69 patients were found. Complete documentation, including radiographs, for these 69 patients were studied and analyzed. In addition to gender and age, the following information about the mesiodens was recorded: 1) number; 2) shape; 3) position; 4) complications caused by the mesiodens; 5) treatment. Of the 69 patients, the ratio of boys (47 cases) to girls (22 cases) was 2.1:1. Fifty-three (76.8%) of the children had 1 mesiodens, and 16 (23.1%) had 2 mesiodentes bilaterally to the midline. Of the 85 mesiodentes, 67 (78.8%) were fully impacted, 6 (7%) were partially erupted, and 12 (14.1%) were fully erupted. Most of the mesiodentes (55.2%) were found in the vertical position, followed by inverted position (37.6%), and horizontal position (7%). The main complications were delayed eruption of the permanent incisors (38.8%), maxillary midline diastema (17.6%), axial rotation or inclination of erupted permanent incisors (16.4%), and resorption of the adjacent teeth (4.7%) The prevelance of mesiodens has been estimated to be 0.15% to 2

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Objective: The purpose of this study was to assess the prevalence of dens invaginatus and to classify the types of dens invaginatus in a sample of the Turkish population.. Study Design: A retrospective study was performed using periapical and panoramic radiographs of 5355 patients who presented to the Department of Oral Diagnosis and Radiology at the Ondokuz Mayıs University Dentistry Faculty between January 2009 and December 2010. Maxillary and mandibular anterior teeth were evaluated for the presence and characteristics of dens invaginatus. Statistical evaluation of the presence of dens invaginatus related to gender was performed by the Pearson chi-squared test. Results: Dens invaginatus was observed in 116 of 4556 subjects, with a frequency of 2.5%. There was only one periapical lesion in teeth with type I dens invaginatus, but 8.1% of patients with type II and 87.5% of patients with type III dens invaginatus had apical periodontitis at the time of referral. There were 116 (72%) females and 32 (27%) males with dens invaginatus. Conclusion: This data represents the only study carried out in a large population in Turkey, and no dens invaginatus was found in mandibular teeth. The most commonly observed type of dens invaginatus was type I (69.8%). Key words:Dens invaginatus, dens in dente, dental anomaly, Turkish.

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4513 Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P < 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.

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Over the last decade, the treatment paradigm of metastatic renal cell carcinoma has rapidly evolved, with notable changes in the front-line setting. Combination therapies involving the use of either doublet therapy with immune checkpoint inhibitors or combination VEGFR-directed therapies with immune checkpoint inhibitors have significantly improved clinical outcomes, including prolonged overall survival and durable response to treatment. We aim to highlight the Food and Drug Administration-approved front-line therapy options, the navigation of treatment selection, and the future directions of metastatic renal cell carcinoma therapies.