Phase Ia/b Study of Giredestrant ± Palbociclib and ± Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer.

PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.

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.

American Academy of Ophthalmology Recommendations on Screening for Endogenous Candida Endophthalmitis.

The American Academy of Ophthalmology evaluated the practice of routine screening for intraocular infection from Candida septicemia. In the United States, ophthalmologists are consulted in the hospital to screen for intraocular infection routinely for patients with Candida bloodstream infections. This practice was established in the era before the use of systemic antifungal medication and the establishment of definitions of ocular disease with candidemia. A recent systematic review found a rate of less than 1% of routinely screened patients with endophthalmitis from Candida septicemia. Other studies found higher rates of endophthalmitis but had limitations in terms of inaccuracies in ocular disease classification, lack of vitreous biopsies, selection biases, and lack of longer-term visual outcomes. Some studies attributed ocular findings to Candida infections, rather than other comorbidities. Studies also have not demonstrated differences in medical management that are modified for eye disease treatment; therefore, therapy should be dictated by the underlying Candida infection, rather than be tailored on the basis of ocular findings. In summary, the Academy does not recommend a routine ophthalmologic consultation after laboratory findings of systemic Candida septicemia, which appears to be a low-value practice. An ophthalmologic consultation is a reasonable practice for a patient with signs or symptoms suggestive of ocular infection regardless of Candida septicemia.

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.

PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade ≥ 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m2 docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m2 paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Utility of Ophthalmologic Screening for Patients With Candida Bloodstream Infections: A Systematic Review.

Importance: The Infectious Diseases Society of America recommends ophthalmologic examinations for everyone with positive Candida blood culture results (candidemia) to screen for endophthalmitis, a practice that remains controversial because of multiple concerns for its limited usefulness and potential for harm. Objective: To determine guideline efficacy by reconciling discrepancies in the incidence of endophthalmitis and evaluating outcomes of studies assessing ophthalmologic screening for candidemia. Evidence Review: PubMed literature searches, including the search terms candidemia, fungemia, chorioretinitis, and endophthalmitis, identified longitudinal studies prior to 2018 of patients who underwent ophthalmologic evaluations in the setting of positive fungal blood culture results regardless of symptoms or clinical status. Additional studies not captured by these queries were found by manually scanning references within the articles captured by the queries. Ambiguous studies of patients with concomitant bacterial or viral infections were excluded. Findings: Thirty-eight applicable studies of 7472 patients who underwent ophthalmologic screening for candidemia or fungemia were identified. Criteria were compared with the conventional definition of endophthalmitis based on present (concordant) or absent (discordant) frank vitreous involvement. Concordant (59 of 6693 [0.9%]) and discordant (114 of 779 [14.6%]) endophthalmitis incidence rates differed by 13.8% (95% CI, 11.4%-16.4%; P < .001). Visual acuity for each case was recorded verbatim as subjective report provided by each study, when available. None of the concordant endophthalmitis cases reported direct, intraocular, microscopic evidence of Candida or other fungal organisms. Outcomes were available for 19 patients with concordant endophthalmitis; 6 died within 4 weeks of screening. The rate of substantial vision loss was associated (φ = 0.58; 95% CI, 0.01-0.86; P = .046) with additional invasive intervention (3 of 6 [50.0%]) compared with medical management alone (0 of 6). Conclusions and Relevance: In this systematic review without meta-analysis, inconsistent definitions of endophthalmitis accounted for discrepancies of its incidence and overreporting among patients with candidemia, contributing to bias and resulting in the construction of guidelines. As few as 3 of 7472 patients had potential improvement, while routine examination overall could lead to additional interventions and harm in this population. These findings suggest that indiscriminate screening based on candidemia alone does not appear to be supported by the literature and should be reevaluated for inclusion as a recommendation from the Infectious Diseases Society of America.

The Effect of Varying the Composition of Fingerprint Sweat Deposits on the Corrosion of Brass and Fingerprint Visibility.

Corrosion of α-phase brass by sebaceous sweat fingerprint deposits produced identifiable impressions in a majority of samples (n = 40) 4 days after deposition. Combining sebaceous with eccrine sweat yielded a greater percentage of identifiable fingerprint deposits, although this increase was not statistically significant. Production of identifiable fingerprints from eccrine sweat deposits was dependent on the sampling time of year with deposits taken during summer months giving similar percentages of identifiable fingerprints to sebaceous deposits. A statistically significant positive correlation was found between elapsed days after deposition and identifiable eccrine (ρ = 0.787, p < 0.05), sebaceous (ρ = 0.724, p < 0.05), and eccrine/sebaceous mixture (ρ = 0.908, p < 0.01) fingerprints deposited during summer months. The summer increase in the percentage of identifiable eccrine sweat deposits was statistically significant compared to winter eccrine deposits (p < 0.0001). Observations were consistent with results obtained from artificial sebaceous and eccrine sweat.

Visualizing Indented Writing on Thermal Paper by the Controlled Application of Heat.

Indented writing on thermal paper made with either one, two, or three sheets of paper above the thermal paper has been visualized by the controlled application of heat to the thermal paper at temperatures below the paper's normal color change temperature. Indentations created by applying a variable pressure to a steel letter stamp showed that, with one sheet above the thermal paper, indentations were more visible at lower pressures than with either two or three sheets above. Handwriting from 20 volunteers produced indented writing graded with most of the text clear and easy to read for all samples with one sheet above, half the samples with two sheets above and eight samples with three sheets above. Comparison with ESDA showed that, with three sheets above, there was a statistically significant difference (p < 0.01), with heating producing more samples than ESDA with most of the text clear and easy to read.

A Modified Electrostatic Adsorption Apparatus for Latent Fingerprint Development on Unfired Cartridge Cases.

Visualization of latent fingerprints on metallic surfaces by the method of applying electrostatic charging and adsorption is considered as a promising chemical-free method, which has the merit of nondestruction, and is considered to be effective for some difficult situations such as aged fingerprint deposits or those exposed to environmental extremes. In fact, a portable electrostatic generator can be easily accessible in a local forensic technology laboratory, which is already widely used in the visualization of footwear impressions. In this study, a modified version of this electrostatic apparatus is proposed for latent fingerprint development and has shown great potential in visualizing fingerprints on metallic surfaces such as cartridge cases. Results indicate that this experimental arrangement can successfully develop aged latent fingerprints on metal surfaces, and we demonstrate its effectiveness compared with existing conventional fingerprint recovery methods.

The Effectiveness of Trace DNA Profiling-A Comparison Between a U.S. and a U.K. Law Enforcement Jurisdiction.

Recovery, profiling, and speculative searching of trace DNA (not attributable to a body fluid/cell type) over a twelve-month period in a U.S. Crime Laboratory and U.K. police force are compared. Results show greater numbers of U.S. firearm-related items submitted for analysis compared with the U.K., where greatest numbers were submitted from burglary or vehicle offenses. U.S. multiple recovery techniques (double swabbing) occurred mainly during laboratory examination, whereas the majority of U.K. multiple recovery techniques occurred at the scene. No statistical difference was observed for useful profiles from single or multiple recovery. Database loading of interpretable profiles was most successful for U.K. items related to burglary or vehicle offenses. Database associations (matches) represented 7.0% of all U.S. items and 13.1% of all U.K. items. The U.K. strategy for burglary and vehicle examination demonstrated that careful selection of both items and sampling techniques is crucial to obtaining the observed results.