Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Long-term evaluation of peri-implant keratinized mucosa stability after free epithelialized graft and keratinized mucosa shifting procedures: A retrospective study up to 13 years.

OBJECTIVES: This study aimed to assess the risk of less than 2 mm keratinized mucosa (KM) width occurrence after free epithelialized graft (FEG) and keratinized mucosa shifting (KMS) procedures using survival analysis. In addition, KM dimensional changes were evaluated. MATERIALS AND METHODS: This study included 76 implants in 36 patients with insufficient KM (<2 mm). The implants underwent either FEG or KMS procedures. The mid-buccal KM width was measured from surgery to the end of a one 13-year follow-up period. RESULTS: Mean follow-up durations were 9.2 ± 3.9 years for FEG and 6.3 ± 4.2 years for KMS. Two implants in FEG and nine implants in KMS exhibited a KM width of less than 2 mm during follow-up. The hazard ratios for KMS compared to FEG were 6.48 (crude) and 6.54 (adjusted), both statistically significant (p < .05). The incidence rate of KMS (4.06%) was higher than that of FEG (0.63%), with an average incidence time of 3.38 years for KMS and 8.82 years for FEG post-surgery. FEG showed a significant shrinkage within 6 months (33% ± 22%), whereas KMS demonstrated a gradual decrease over 13 years (34% ± 25%). FEG exhibited significantly greater width change than KMS during a 5-year follow-up (p < .05). CONCLUSIONS: FEG and KMS enhanced PIKM but exhibited different long-term reduction patterns. FEG demonstrated rapid shrinkage, while KMS displayed gradual and continuous reduction. Moreover, KMS presented a higher risk and incidence of KM width less than 2 mm compared to FEG.

Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.

AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).

JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. CONCLUSION: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV.

PROPEL: a randomized trial of mericitabine plus peginterferon alpha-2a/ribavirin therapy in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment-naïve HCV genotype 1 or 4 patients were randomized to double-blind treatment with oral mericitabine at a dosage of 500 mg twice-daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha-2a (Peg-IFNα-2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A-C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A-E) continued Peg-IFNα-2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow-up; SVR-24). VR rates were higher in arms A-D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non-CC IL28B genotypes. However, the overall SVR-24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response-guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine-resistance mutations (S282T) were observed during mericitabine therapy. CONCLUSION: Treatment with mericitabine plus Peg-IFNα-2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN-free and IFN-containing trials of mericitabine of longer treatment duration are ongoing.

Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies.

AIMS: The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C). METHODS: We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin. RESULTS: Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1). CONCLUSIONS: Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine.

Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CLCR ] >80 mL/min, n = 10) or stable renal impairment (mild: CLCR 50-80 mL/min, n = 10; moderate: CLCR 30-49 mL/min, n = 10) received oral mericitabine 1000 mg twice daily (BID) (500 mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0-12 h) (AUC0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0-12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0-12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

Efficacy of customized crown-level position jig in measuring peri-implant crestal bone level on periapical radiographs: An in vitro study.

Background/purpose: Accuracy of using implant length on periapical radiographs as calibration reference for measurements has not been verified. This study aimed to verify the measurements of peri-implant crestal bone level (piCBL) on periapical radiographs taken by the paralleling technique and using the implant length for calibration; and to propose a customized crownlevel position (CLP) jig to improve the measurement accuracy of piCBL. Materials and methods: A typodont installed an implant and a screw-retained crown at maxillary central incisor was used. To simulate piCBL, a metal post was placed near the implant at the same height of implant platform. The CLP jig was designed and 3-dimensionally printed out to allow implant projected orthogonally on periapical film. Thirty periapical radiographs were taken using paralleling technique with and without the jig by three examiners. The implant axis and implant length on radiographs were acquired by image segmentation. The discrepancy of piCBL determination (ΔD) from these measurements were compared and further analyzed when using the implant length for calibration. Results: The piCBL measurement errors were smaller when the jig was used for all examiners (P < 0.001). The inter-rater differences were insignificant. After calibration, ΔD with and without jig were 0.09 (0.07-0.11) and 0.43 (0.38-0.49) mm, respectively. Conclusion: Conventional long-cone paralleling technique using true implant length for calibration demonstrated imprecise piCBL measurement on periapical radiographs. Transferring the implant axis to the CLP jig allowed orthogonal projection of radiography which provided reliable measurements of piCBL with an accuracy of less than 0.1 mm.

Pharmacokinetics and pharmacodynamics of tocilizumab after subcutaneous administration in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the pharmacokinetics, pharmacodynamics, safety and efficacy of subcutaneous tocilizumab 162 mg weekly (QW) or every other week (Q2W) in rheumatoid arthritis patients on methotrexate. METHODS: This was a multicenter, open-label, randomized, parallel group study. Patients were randomly assigned to receive tocilizumab 162 mg subcutaneously QW or Q2W for 12 weeks. Pharmacokinetic and pharmacodynamic measurements were taken from baseline through to treatment end. Efficacy was assessed at baseline and Q4W thereafter. Safety and tolerability were monitored. RESULTS: 29 patients received tocilizumab treatment for 12 weeks. After final QW and Q2W dosing, mean ± SD for Cmax, Cmin and AUC0-168h/0-336h was 39.4 ± 18.1 and 10.7 ± 6.6 µg/ml, 27.9 ± 14.7 and 2.3 ± 3.2 µg/ml and 5,505 ± 2,632 and 2,332 ± 1,696 µg×h/ml. Median tmax was 2 - 3 days. Mean soluble interleukin-6 receptor (sIL-6R) complex concentration increased within 1 week and plateaued (670 ± 211 (QW); 387 ± 194 ng/ml (Q2W)) by final dosing; median C-reactive protein (CRP) levels decreased to below upper limit of normal after first and third doses; mean ± SD (range) reduction in Disease Activity Score using 28 joints at Week 12 was similar between groups (-2.5 ± 1.2 (-4 to -1); -3.1 ± 1.1 (-5 to -2)). Patients experiencing ≥ 1 adverse event were comparable between groups (71% vs. 80%). CONCLUSIONS: Greater tocilizumab exposure and sIL-6R elevation and more rapid CRP level normalization occurred with QW than with Q2W dosing. Both regimens demonstrated clinical benefit and were well tolerated.

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

Electrochromic properties of tungsten-titanium oxide films.

The last decade has seen great in electrochromic (EC) technology for smart windows and displays. In this study, WTiOx films formed from TiO2 and WO3 were deposited onto ITO glass with a sheet resistance of 10 Omega cm and on silicon substrates, by pulsed magnetron sputtering using a W and Ti alloy target. The films were deposited at plasma powers 100, 200, 300, 400 and 500 W using a gaseous Ar (150 sccm)/O2 (50 sccm) mixture; the working pressure was fixed at 5E-2 torr. The film thickness increased with the plasma power. However, increasing the plasma power yielded a more crystalline structure with poorer electrochromic properties. The influence of Ti doping and plasma power on the structural, optical and electrochromic properties of the WTiOx thin films was studied. WTiOx films grown at various plasma powers of under 400 W were amorphous. Deposition of films at 400 W yielded the optimal electrochromic properties, with high optical modulation, high coloration efficiency and the lowest color memory effect at wavelengths 400, 550 and 800 nm. An XPS study indicated that Ti can stabilize the valence state of W6+. The improvements caused by the doping with Ti were tested: an optical density (OD) of close to 0.85 and a maximum delta T (%) at 400 nm of 25.8%, at 550 nm of 52.5% and at 800 nm (in the near-IR region) of 62.4%.

Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer.

INTRODUCTION: The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy. AREAS COVERED: Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant. EXPERT OPINION: Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.

Differences in parent-perceived and patient-reported quality of life among young adult burn patients: A prospective longitudinal study.

PURPOSE: This study examines the differences in parent-perceived and patient-reported quality of life (QoL) among young adult burn patients three years after injury and the factors affecting these differences. METHOD: The sample comprised 35 burn patients from the Formosa Fun Coast Water Park dust explosion and their parents. The study was conducted from June 2016 to August 2018. We used self-report questionnaires to collect socio-demographic data, the adapted Chinese version of the Burn Specific Health Scale-Brief, and the Impact of Events Scale for Burn. RESULTS: The analysis indicated that simple abilities recovered the fastest, while body image recovered the slowest. The variation trends of these factors were similar but parents' scores were lower than patients' scores. Parents' post-traumatic stress disorder (PTSD) scores were higher than that of patients, but were not statistically significant. Parents' gender and PTSD levels and patients' burn area affected differences in parent-perceived QoL among patients. PTSD levels were significantly higher among mothers. CONCLUSIONS: For parents, PTSD is a common response to their children experiencing burn injuries. Parents' observations of warning signs enable early medical intervention. Establishing a family-centered care plan, providing psychological support for both parents and patients, and forming a continuous care system with efficient communication can support patients' return to society.

Influence of maxillary antrolith on the clinical outcome of implants placed simultaneously with osteotome sinus floor elevation: A retrospective radiographic study.

BACKGROUND: Large antroliths and those located adjacent to the sinus floor can affect clinical interventions and increase the difficulty of implant placement performed simultaneously with osteotome sinus floor elevation surgery. PURPOSE: This retrospective study investigated the clinical outcomes of implants placed simultaneously with osteotome sinus floor elevation subjacent to maxillary antroliths. MATERIAL AND METHODS: Twenty implants inserted subjacent to or intruding into the antrolith after sinus floor elevation were evaluated in 18 patients. Cone-beam computed tomography (CBCT) was used to measure antrolith size and membrane thickness at sites of osteotome sinus floor elevation. Periapical radiographs were used to assess the height of grafted bone. Generalized estimating equation (GEE) analysis was performed to correlate the occurrence of antroliths with patient background characteristics and dental outcomes, based on a sample population of 239, among whom 33 presented antroliths. RESULTS: The 20 implants remained clinically stable over a mean follow-up period of 42.4 months. The mean thickness of the sinus membrane at osteotome sites was 5.4 ± 3.3 mm. None of the cases presented sinus membrane perforation or sinus symptoms following osteotome intervention. The mean gain in the height of grafted sinus bone was 4.0 ± 1.4 mm at the last follow-up. The occurrence of antroliths was higher among females and the elderly (>49 years old). The multivariable GEE analysis showed that the adjusted odds ratio for the occurrence of antroliths with root canal fillings was significantly lower than those without root canal fillings (odds ratio = 0.33; 95% confidence interval = 0.11-0.96). CONCLUSION: Our findings indicate that osteotome sinus floor elevation is a surgical procedure with a risk <17%. Thorough planning based on CBCT and careful management during surgery can eliminate the negative effects of antroliths on implant performance.

Tumor Time-Course Predicts Overall Survival in Non-Small Cell Lung Cancer Patients Treated with Atezolizumab: Dependency on Follow-Up Time.

The large heterogeneity in response to immune checkpoint inhibitors is driving the exploration of predictive biomarkers to identify patients who will respond to such treatment. We extended our previously suggested modeling framework of atezolizumab pharmacokinetics, IL18, and tumor size (TS) dynamics, to also include overall survival (OS). Baseline and model-derived variables were explored as predictors of OS in 88 patients with non-small cell lung cancer treated with atezolizumab. To investigate the impact of follow-up length on the inclusion of predictors of OS, four different censoring strategies were applied. The time-course of TS change was the most significant predictor in all scenarios, whereas IL18 was not significant. Identified predictors of OS were similar regardless of censoring strategy, although OS was underpredicted when patients were censored 5 months after last dose. The study demonstrated that the tumor-time course-OS relationship could be identified based on early phase I data.

Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women.

The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.

Management of postvitrectomy diabetic vitreous hemorrhage with volume homeostatic fluid-fluid exchanger.

BACKGROUND: To evaluate the clinical outcome of patients with postvitrectomy diabetic vitreous hemorrhage (PDVH) who underwent vitreous cavity lavage (VL) by volume homeostatic fluid-fluid exchange. METHODS: We performed a retrospective chart review for 88 eyes of 80 consecutive patients who underwent VL for PDVH. Final best-corrected visual acuity after VL was compared to those before VL. Anatomic outcome, including rate of fundus clear-up, recurrent vitreous hemorrhage, increased intraocular pressure, iris neovacularization and anterior hyaloid fibrovascular proliferation were considered. RESULTS: Between July 1999 and January 2006, 88 eyes of 80 patients underwent this procedure. Significant visual improvement was observed after VL (2.86 +/- 0.40 logMAR at baseline vs 1.71 +/- 0.97 logMAR at last visit, p < 0.0001). The fundus clear-up rate after VL was achieved in 84 out of 109 times (77.1%). Recurrent vitreous hemorrhage was found in 17 of 88 eyes (19.3%) with the mean interval of 92.6 +/- 126.7 days after VL. CONCLUSIONS: For patients suffering from postvitrectomy diabetic vitreous hemorrhage, volume homeostatic vitreous cavity lavage can be an alternative method for removing the bloody content in the vitreous cavity efficiently and permitting rapid visual recovery.