Efficacy and safety of atezolizumab and bevacizumab in appendiceal adenocarcinoma.

PURPOSE: Appendiceal Adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors (ICIs) have not been previously explored. PATIENTS AND METHODS: We conducted a prospective, single arm phase 2 study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 PR, 15 SD) with progression free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, p = .041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-FU based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted.

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-omics Approach Using Patient-Derived Xenografts.

Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including MKI67 and EXO1. Peritoneal tumors were also enriched for proliferative gene sets, including E2F and Myc Targets. Proteomic studies found a 2.5-fold increased ratio of active-to-inactive phosphoforms of the YAP oncoprotein in peritoneal tumors, indicating downregulation of Hippo signaling. IMPLICATIONS: The peritoneal microenvironment promotes growth of appendiceal tumors and expression of proliferative pathways in PDXs.

Influence of access cavity design on calcium hydroxide removal using different cleaning protocols: a confocal laser scanning microscopy study.

Objectives: The purpose of this study was to evaluate the influence of endodontic access cavities design on the removal of calcium hydroxide medication of the apical third of mandibular incisor root canal walls and dentinal tubules with different cleaning protocols: EDDY sonic activation, Er,Cr:YSGG laser-activated irrigation, or conventional irrigation with IrriFlex. Materials and Methods: Seventy-eight extracted human mandibular incisors were assigned to 6 experimental groups (n = 13) according to the endodontic access cavity and cleaning protocol for calcium hydroxide removal: traditional access cavity (TradAC)/EDDY; ultraconservative access cavity performed in the incisal edge (UltraAC.Inc)/EDDY; TradAC/Er,Cr:YSGG; UltraAC.Inc/Er,Cr:YSGG; TradAC/IrriFlex; or UltraAC.Inc/IrriFlex. Confocal laser scanning microscopy images were used to measure the non-penetration percentage, maximum residual calcium hydroxide penetration depth, and penetration area at 2 and 4 mm from the apex. Data were statistically analyzed using Shapiro-Wilk and WRS2 package for 2-way comparison of non-normally distributed parameters (depth of penetration, area of penetration, and percentage of non-penetration) according to cavity and cleaning protocol with the significance level set at 5%. Results: The effect of cavity and cleaning protocol interactions on penetration depth, penetration area and non-penetration percentage was not found statistically significant at 2 and 4 mm levels (p > 0.05). Conclusions: The present study demonstrated that TradAC or UltraAC.Inc preparations with different cleaning protocols in extracted mandibular incisors did not influence the remaining calcium hydroxide at 2 and 4 mm from the apex.

Comparison of root canal shaping ability of different heat-treated NiTi single files: a micro-CT study.

OBJECTIVE: The purpose of this study was to evaluate the root canal shaping abilities of different heat-treated NiTi engine--driven single files. METHOD AND MATERIALS: A total of 45 mandibular first molar teeth with a root canal curvature of between 25 and 35 degrees were selected for this in vitro study. The mesial roots were separated and scanned with micro-CT. The specimens were randomly divided into three groups. Root canal preparations were performed using HyFlex EDM OneFile in Group 1; OneCurve (25/06) in Group 2, and WaveOne Gold Primary in Group 3. Root canals were scanned again with micro-- CT after root canal preparation. Apical transportation value and centering ability ratio of files were evaluated using the preinstrumentation and postinstrumentation micro-CT images at 1, 2, 3, 4, and 7 mm. The data were statistically analyzed using the Kruskal-Wallis test. The Bonferroni-Dunn test was used for multiple comparisons. The level of statistical significance was set at P < .05. RESULTS: There was no significant difference between the apical transportation values of experimental groups in mesiodistal direction (P > .05) and buccolingual direction (P > .05). The OneCurve file group showed better centering ability in the buccolingual direction than the WaveOne Gold file group at 4 mm (P = .048). The difference between the centering ability values of experimental groups was not significant at other levels (P > .05). CONCLUSION: According to the results of this study, all tested single files caused apical transportation and showed similar centering ratio at most of the root sections.

The effect of atmospheric cold plasma on the dentinal tubule penetration of calcium silicate-based sealer used with different obturation techniques: A confocal laser scanning microscopy study.

The aim of this study was to evaluate the effect of atmospheric cold plasma (ACP) on dentinal tubule penetration of EndoSequence BC. Sixty premolars were divided into four groups according to the obturation technique and plasma treatment. Root canals were filled with single cone in Group 1 (SC), single cone after ACP application in Group 2 (SC-P), warm vertical compaction in Group 3 (WVC), warm vertical compaction after ACP application in Group 4 (WVC-P). Horizontal sections were imaged using confocal laser scanning microscopy. The maximum penetration and percentage of penetration values were measured. These data were statistically analysed (P < 0.01). In the coronal region, the percentage of penetration values were higher in SC-P and WVC-P than in SC and WVC. In the middle region, SC-P and SC showed a higher penetration percentage than WVC and WVC-P. In the apical region, WVC showed a higher percentage of penetration value than SC-P, WVC-P and SC did. Maximum penetration of WVC was higher than of SC and SC-P. Within the limitations of this study, ACP improved the percentage of penetration values of EndoSequence BC when used with single-cone technique.

CSF levels of HoxB3 and YKL-40 may predict conversion from clinically isolated syndrome to relapsing remitting multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) often initiates with an acute episode of neurological disturbance, known as clinically isolated syndrome (CIS). There is an unmet need for biomarkers that differentiate patients who will convert to MS and who will remain as CIS after the first attack. METHODS: First attack serum and cerebrospinal fluid (CSF) samples of 33 CIS patients were collected and these patients were divided as those who converted to MS (CIS-MS, n=17) and those who continued as CIS (CIS-CIS, n=16) in a 3-year follow-up period. Levels of homeobox protein Hox-B3 (HoxB3) and YKL-40 were measured by ELISA in samples of CIS-CIS, CIS-MS, relapsing remitting MS (RRMS) patients (n=15) and healthy controls (n=20). RESULTS: CIS-CIS patients showed significantly reduced CSF levels of YKL-40 and increased serum/CSF levels of HoxB3 compared with CIS-MS and RRMS patients. CIS-MS and RRMS patients had comparable YKL-40 and HoxB3 level profiles. Receiver operating characteristic (ROC) curve analysis showed the highest sensitivity for CSF HoxB3 measurements in prediction of CIS-MS conversion. Kaplan-Meier analysis demonstrated that CIS patients with lower CSF HoxB3 (<3.678 ng/ml) and higher CSF YKL-40 (>654.9 ng/ml) displayed a significantly shorter time to clinically definite MS. CONCLUSION: CSF levels of HoxB3 and YKL-40 appear to predict CIS to MS conversion, especially when applied in combination. HoxB3, which is a transcription factor involved in immune cell activity, stands out as a potential candidate molecule with biomarker capacity for MS.

Dentinal tubule penetration of endodontic sealers after nonthermal plasma treatment: A confocal laser scanning microscopy study.

One of the factors affecting the success of endodontic treatment is to fill the root canal system hermetically. The aim of this in vitro study was to evaluate the effect of nonthermal plasma (NP) on dentinal tubule penetration of root canal sealers using confocal laser scanning microscopy. Forty mandibular premolar teeth were selected and the root canals were prepared with large-Waveone-Gold rotary-files. Specimens were divided into four experimental groups according to sealer and NP treatment (n = 10). G1: AH-Plus (AH) G2: nonthermal plasma application + AH-Plus(AH-P) G3: Endosequence-BC(BC) G4: nonthermal plasma application + Endosequence-BC(BC-P). Cold lateral-condensation technique was used for the obturation of root canals. The roots were sectioned horizontally and the sections were examined under confocal laser scanning microscopy. The maximum tubule penetration and percentage of penetration values were obtained from the microscopy images and were statistically analyzed with repeated measurements-ANOVA and the Tukey (HSD) test (p < 0.05). The percentages of dentinal tubule penetration of the groups were not statistically different. The maximum tubule penetration of the AH-P was statistically lower than that of the BC-P (p < 0.05). Plasma application had no affect on the percentage of dentinal tubule penetration. Under the conditions of this in vitro Endosequence-BC sealer showed higher maximum tubule penetration values than AH-Plus after NP treatment. Percentage of dentinal tubule penetration values of experimental groups was similar.

Effects of Different Glide Path Files on Apical Debris Extrusion in Curved Root Canals.

INTRODUCTION: Creating a glide path before root canal preparation with nickel-titanium rotary files is essential to prevent the file fracture and to maintain the original root canal configuration. Both rotary glide path files and manual K-files are used to create a glide path. The aim of this study was to compare the amount of apically extruded debris after using different glide path files before preparing curved root canals with the WaveOne Gold single-file reciprocating system (Dentsply Maillefer, Ballaigues, Switzerland). METHODS: Sixty extracted mandibular first molar teeth with curved mesial roots were selected for this study. The mesial roots of the teeth were removed from the cementoenamel junction. Cone-beam computed tomographic imaging was used to evaluate the curvature of the mesial root canals. Specimens were randomly divided into 6 experimental groups according to the root canal preparation (n = 10): group G-File, a glide path with G-Files (Micro-Mega, Besancon, France) + WaveOne Gold preparation; group One G, a glide path with One G (Micro-Mega, Besancon, France) + WaveOne Gold preparation; group ProGlider, a glide path with ProGlider (Dentsply Maillefer) + WaveOne Gold preparation; group PathFile, a glide path with PathFiles (Dentsply Maillefer) + WaveOne Gold; group K-files, a glide path with a K-file + WaveOne Gold preparation; and group without a glide path, WaveOne Gold preparation without a glide path file. Roots were attached to preweighed Eppendorf tubes. All instruments were used according to the manufacturers' instructions. During root canal preparation, a total of 8 mL distilled water was used for each specimen. Apically extruded debris was collected in Eppendorf tubes. After the completion of root canal preparation, Eppendorf tubes were removed from the specimens and stored in an incubator at 68°C for 5 days. Eppendorf tubes were weighed after evaporation to calculate the amount of extruded debris. The data were statistically analyzed with 1-way analysis of variance and post hoc Tukey honest significant difference tests (P = .05). RESULTS: A statistically significant difference was observed between the One G and K-File groups. The One G group was associated with significantly less debris extrusion than the K-file group. There was no statistically significant difference between K-files and ProGlider, G-Files, PathFiles, and WaveOne Gold without a glide path, and also there was no statistically significant difference between One G and ProGlider, G-Files, PathFiles, and WaveOne Gold without a glide path. All experimental groups caused apical debris extrusion. CONCLUSIONS: Under the conditions of this in vitro study, all rotary path file systems were associated with similar apical debris extrusion before preparing root canals with the WaveOne Gold single-file reciprocating system. K-files caused more apically extruded debris than the One G files.

Effects of ultrasonic root-end cavity preparation with different surgical-tips and at different power-settings on glucose-leakage of root-end filling material.

AIM: The aim of this in vitro study was to evaluate the effects of different ultrasonic surgical-tips and power-settings on micro-leakage of root-end filling material. MATERIALS AND METHODS: The root canals were instrumented using rotary-files and were filled with tapered gutta-percha and root canal sealer using a single-cone technique. The apical 3 mm of each root was resected and the roots were divided into six experimental groups; negative and positive control groups. Root-end cavities were prepared with diamond-coated, zirconum-nitride-coated and stainless-steel ultrasonic retro-tips at half-power and high-power settings. The time required to prepare the root-end cavities for each group was recorded. Root-end cavities were filled with Super-EBA. Leakage values of all samples evaluated with glucose penetration method on 7, 14, 21 and 28(th) days. The results were statistically analyzed with Kruskal-Wallis and Hollander-Wolfe tests. RESULTS: The mean time required to prepare retro cavities using diamond-coated surgical tip at high-power setting was significantly less than other groups (P < 0.01). There were no statistically significant differences in the glucose penetration between the groups at first and second weeks (P > 0.01). Diamond-coated surgical tip showed the least leakage at high-power setting at 3(rd) and 4(th) weeks (P < 0.01). CONCLUSIONS: Under the conditions of this study, cavity preparation time was the shortest and the leakage of the root-end filling was the least when diamond-coated retro-tip used at high-power setting.

Mineral trioxide aggregate apical plug method for the treatment of nonvital immature permanent maxillary incisors: Three case reports.

Treatment of nonvital immature permanent teeth with calcium-hydroxide is associated with some difficulties such as weakened tooth fracture, root canal reinfection and long treatment time. Mineral trioxide aggregate (MTA) apical plug method is an alternative treatment option for open apices, and has gained popularity in the recent times. In this case report, we have attempted to present successful treatment of three maxillary incisors with open apices and periapical lesions with MTA. After preparing the access cavity, the working length was determined. The root canals were irrigated with 2.5% Sodium hypochlorite (NaOCl) and disinfected with calcium-hydroxide for two weeks. MTA was then placed in the apical 3 millimeters of the root canal. The remaining part of the root canal was filled with gutta-percha and the coronal restoration was finished with composite resin. After six months the radiographic examination showed a decrease of periapical lesions. At a 1-year and 18-months follow up, radiological and clinical successful healing of the incisor teeth was seen. MTA seems as an effective material for the apical plug method for the treatment of nonvital immature permanent teeth with open apices.

Sealing ability of Hybrid Root SEAL (MetaSEAL) in conjunction with different obturation techniques.

OBJECTIVE: The objective of this study was to evaluate the apical sealing ability of Hybrid Root SEAL (MetaSEAL) in conjunction with different obturation techniques. METHODOLOGY: Sixty-eight extracted human mandibular straight single-rooted teeth with mature apices were prepared using a step-back technique and divided into 4 experimental groups (n = 15). An additional 8 teeth were prepared for controls (3 for positive, 3 for negative control, and 2 more for calculating 100% leakage). The experimental groups were obturated with Hybrid Root SEAL (MetaSEAL) using cold lateral condensation, vertical condensation, Thermafil, and Ultrafil techniques. Fluid movement along the filled canals was measured using a fluid filtration method. Measurements were made at 2-minute intervals for 8 minutes. The data were calculated as microL/min and statistically analyzed using 1-way ANOVA and Duncan Test. RESULTS: Cold lateral and vertical condensation had significantly less fluid movement than the Thermafil and Ultrafil groups. Thermafil group had the highest fluid movement values when compared with the other groups (P < .01). CONCLUSION: Hybrid Root SEAL (MetaSEAL) had less fluid movement with cold lateral and vertical condensation techniques when compared with Thermafil and Ultrafil techniques.