Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma.

The phase 3 SELENE study evaluated ibrutinib + chemoimmunotherapy (CIT; bendamustine and rituximab [BR]; or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) for patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Adult patients who had received ≥1 prior line of CIT were randomized 1:1 to oral ibrutinib (560 mg) or placebo daily, plus 6 cycles of BR/R-CHOP. The primary end point was investigator-assessed progression-free survival (PFS). Overall, 403 patients were randomized to ibrutinib + CIT (n = 202) or placebo + CIT (n = 201). Most patients received BR (90.3%) and had FL (86.1%). With a median follow-up of 84 months, median PFS was 40.5 months in the ibrutinib + CIT arm and 23.8 months in the placebo + CIT arm (hazard ratio [HR], 0.806; 95% confidence interval [CI], 0.626-1.037; P = .0922). Median overall survival was not reached in either arm (HR, 0.980; 95% CI, 0.686-1.400). Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 85.6% and 75.4% of patients in the ibrutinib + CIT and placebo + CIT arms, respectively. In each arm, 13 patients had TEAEs leading to death. The addition of ibrutinib to CIT did not significantly improve PFS compared with placebo + CIT. The safety profile was consistent with known profiles of ibrutinib and CIT. This trial was registered at www.clinicaltrials.gov as #NCT01974440.

Ibrutinib plus RICE or RVICI for relapsed/refractory mature B-cell non-Hodgkin lymphoma in children and young adults: SPARKLE trial.

Part 1 results of the open-label, randomized, global phase 3 SPARKLE trial supported continued assessment of ibrutinib with either modified rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) in pediatric patients with relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). We report final results of Part 2 evaluating the efficacy of ibrutinib plus RICE or RVICI vs RICE/RVICI alone. Patients aged 1 to 30 years (initial diagnosis <18 years) were randomized 2:1 to receive ibrutinib with or without RICE/RVICI. Primary endpoint was event-free survival (EFS) based on independent committee-confirmed events. Fifty-one patients were enrolled. Median age was 15 years; Burkitt lymphoma, Burkitt leukemia, and Burkitt-like lymphoma (total: 45%) and diffuse large B-cell lymphoma/primary mediastinal B-cell lymphoma (51%) were the most common subtypes. At the preplanned interim analysis, median EFS was 6.1 vs 7.0 months with ibrutinib plus RICE/RVICI vs RICE/RVICI, respectively (hazard ratio, 0.9; 90% confidence interval, 0.5-1.6; P = .387); further enrollment was ceased. With ibrutinib plus RICE/RVICI vs RICE/RVICI, median overall survival was 14.1 vs 11.1 months, overall response rate was 69% vs 81%, and 46% vs 44% proceeded to stem cell transplantation. In both treatment arms, 100% of patients experienced grade ≥3 treatment-emergent adverse events. No EFS benefit was seen with ibrutinib. Salvage was generally poor in patients who received prior rituximab, regardless of treatment arm. No new safety signals were observed. Ibrutinib exposure in pediatric patients fell within the target range of exposure in adults. Trial is registered on www.clinicaltrials.gov (NCT02703272).

Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p (n = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286]; p < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822]; p = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.

COMPARISON OF CANADIAN AND UNITED STATES PREDOCTORAL DENTAL IMPLANT EDUCATION.

OBJECTIVE: The objective of this study was to assess the current status of Canadian predoctoral implant programs in terms of director demographics, curriculum characteristics and preferences in the techniques that are used to teach and carry out implant therapy. We compared the findings to analogous data recently acquired from dental schools in the United States. METHODS: A survey instrument was sent electronically to directors of predoctoral implant programs at all 10 accredited dental schools in Canada. RESULTS: All 10 dental schools responded to the survey. Program directors were affiliated with prosthodontics (90%) or oral surgery (10%) departments. Most Canadian institutions (90%) formally integrate their implant program into the third year of the curriculum. Clinical implant curricula include simulated exercises and direct patient care under supervision in 90% of predoctoral programs. Frequently taught restorative modalities include the posterior single-tooth implant crown (100%), mandibular implant-retained overdenture (90%), anterior implant-supported single crown (60%) and posterior 3-unit implant-supported bridge (50%). All programs reported the routine use of guided surgery planning software and surgical guides to aid in implant treatment planning. Preferred clinical protocols include implant-level impressioning (90%), use of open-tray impression copings (70%), custom abutment fabrication (60%), coronal fixation by screw-retention (60%) and use of titanium (100%) or zirconia (60%) abutments. Half of the program directors reported feeling that graduating students were adequately prepared to provide implant therapy on graduation. The demographics of Canadian directors of predoctoral implant programs were very similar to those of their counterparts in the United States. The largest divergences existed in clinical curriculum preferences and subjective perception of student preparedness in oral implantology on graduation. CONCLUSION: Greater homogeneity exists among Canadian dental schools with regard to predoctoral implant program curricula, compared with those in the United States. Further investigation is warranted to examine the reasons for Canadian program directors' current perceptions of lack of preparedness of graduating predoctoral students.

Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis.

OBJECTIVES/HYPOTHESIS: Tracheal cartilage ring structural abnormalities have been reported in cystic fibrosis (CF) mice and pigs. Whether similar findings are present in humans with CF is unknown. We hypothesized that tracheal cartilage ring shape and size would be different in people with CF. STUDY DESIGN: Tracheal cartilage ring size and shape were measured in adults with (n = 21) and without CF (n = 18). METHODS: Ultrasonography was used in human subjects to noninvasively assess tracheal cartilage ring structure in both the sagittal and the transverse planes. Tracheal cartilage ring thickness was also determined from histological sections obtained from newborn non-CF and CF pigs. These values were compared with human data. RESULTS: Human CF tracheas had a greater width and were less circular in shape compared to non-CF subjects. CF tracheal cartilage rings had a greater midline cross-sectional area and were thicker compared to non-CF rings. Maximal tracheal cartilage ring thickness was also greater in both newborn CF pigs and human adults with CF, compared to non-CF controls. CONCLUSIONS: Our findings demonstrate that structural differences exist in tracheal cartilage rings in adults with CF. Comparison with newborn CF pig data suggests that some of these changes may be congenital in nature. LEVEL OF EVIDENCE: 3b

An overview of U.S. predoctoral dental implant programs and their directors.

The aim of this study was to provide an overview of current predoctoral implant programs in the United States, including curricular characteristics and clinical practices regarding implant therapy education and program directors' characteristics. An electronic survey was sent to predoctoral implant program directors of all 64 accredited U.S. dental schools; 52 of the 60 eligible programs responded, for a response rate of 87%. The responding program directors were primarily affiliated with either prosthodontics departments (44%) or restorative dentistry departments (40%). Structurally, 80.8% of the responding schools integrate their implant programs into the third year of the curriculum. Clinical implant therapy exercises reported were simulation exercises without direct patient care (90.4% of responding schools) and direct patient care under supervision (94.2%). The most frequently taught restorative modalities are posterior single-tooth implant crown (96.2%), mandibular implant-retained overdenture (88.5%), and anterior implant-supported single crown (61.5%). A majority (74.5%) of responding programs utilize analog surgical guide planning, while 25.5% reported use of digital guided surgery planning software. All schools in the Northwest and 66.7% in the South Central regions utilize custom abutments as the primary abutment design, while a majority of schools in the North Central (62.5%), Northeast (53.8%), Southwest (66.7%), and Southeast (80%) regions use stock abutments (p=0.02). Regional differences were significant with regard to fixation modality, with all the Northwest programs using screw retention and 90% of Southeast and 87.5% of North Central programs using cement retention (p=0.002). This study demonstrated that while institutions share program director and curricular similarities, clinical practices and modalities vary significantly by region.