Clinical Outcomes for Plasma-Based Comprehensive Genomic Profiling Versus Standard-of-Care Tissue Testing in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced nonsquamous non-small cell lung cancer (aNSCLC). The NILE study was a prospective observational study that demonstrated noninferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed nonsquamous aNSCLC. As the cohort has matured, clinical outcomes data can now be analyzed. METHODS: This prospective, multicenter North American study enrolled patients with previously untreated nonsquamous aNSCLC who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis (Guardant360). Patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician's choice of therapy had objective response rates, disease control rate, and time to treatment collected and compared to published outcomes. RESULTS: Among 282 patients, 89 (31.6%) had an actionable biomarker, as defined by NCCN, detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these were treated with an FDA-approved targeted therapy guided by somatic genotyping results (EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) and 17 (52%) achieved a durable response > 6 months and 12 months, respectively. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (18 vs. 31 days, respectively; P = .0008). CONCLUSIONS: cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published targeted therapy outcomes with tissue profiling, even in community-based centers.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).

Biomarker Discovery and Outcomes for Comprehensive Cell-Free Circulating Tumor DNA Versus Standard-of-Care Tissue Testing in Advanced Non-Small-Cell Lung Cancer.

PURPOSE: Treatment guidelines for advanced non-small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC. PATIENTS AND METHODS: Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers (EGFR and ALK) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA. RESULTS: The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue (P < .05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported. CONCLUSION: This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed.

Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer.

PURPOSE: Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non-small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360). RESULTS: Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guideline-recommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51; P < 0.0001). CONCLUSIONS: In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.See related commentary by Meador and Oxnard, p. 4583.

A systematic review and meta-analysis of complications in conversion arthroplasty methods for failed intertrochanteric fracture fixation.

BACKGROUND: Conversion arthroplasty for failed primary fixation of intertrochanteric fractures can be achieved using various methods, including cemented total hip arthroplasty, uncemented total hip arthroplasty, hybrid total hip arthroplasty, and hemiarthroplasty. Complication rates vary between each conversion method. The purpose of this paper is to examine the effect of conversion method on total conversion complication rates. METHODS: We performed a meta-analysis of five studies with sufficient data for analysis. We created a null hypothesis stating that the expected distribution of complications across conversion methods would reflect the distribution of conversion method used for failed primary fixation. Using a z test, we compared proportions of the expected distribution of complications to the observed distribution of complications. RESULTS: A total of 138 cases of conversion arthroplasty with 49 complications were available for analysis. The mean age was 73 (range, 32-96) years. 19 males and 48 females were included, with one study not including patient gender. The mean time from primary fixation failure to conversion was 11 months, and the mean duration of conversion surgery was 132 min. Expected and observed complication rate distributions were as follows: cemented total hip arthroplasty, 6.5% versus 4.1% (p = 0.79); uncemented total hip arthroplasty, 77.5% versus 81.6% (p = 0.69); hybrid total hip arthroplasty, 2.9% versus 2.0% (p = 1); and hemiarthroplasty, 13% versus 12.2% (p = 1). CONCLUSIONS: Our findings suggest that the method of conversion arthroplasty following failed primary intertrochanteric femur fracture fixation does not influence complication rate.

Device design methodology and formulation of a protein therapeutic for sustained release intraocular delivery.

Despite years of effort, sustained delivery of protein therapeutics remains an unmet need due to three primary challenges - dose, duration, and stability. The work presented here provides a design methodology for polycaprolactone reservoir-based thin film devices suitable for long-acting protein delivery to the back of the eye. First, the challenge of formulating highly concentrated protein in a device reservoir was addressed by improving stability with solubility-reducing excipients. Next, predictive correlations between design parameters and device performance were developed to provide a methodology to achieve a target product profile. Prototype devices were designed using this methodology to achieve desired device size, release rate, therapeutic payload, and protein stability, assessed by in vitro studies. Finally, prototype tolerability was established in a non-human primate model. The design methodology presented here is widely applicable to reservoir-based sustained delivery devices for proteins and provides a general device design framework.

Comparative Analysis of Short-Term Postoperative Complications in Outpatient Versus Inpatient Total Ankle Arthroplasty: A Database Study.

Ankle arthritis is a potentially debilitating disease, with approximately 50,000 cases diagnosed annually. One treatment option for these patients is total ankle arthroplasty (TAA). This procedure has historically been performed in the inpatient setting with a 1-2-night postoperative hospital stay. Outpatient surgeries are gaining popularity due to their cost effectiveness, decreased length of hospital stay, and convenience. Therefore it is important to evaluate the safety of specific procedures in the outpatient setting compared with the inpatient setting. This study evaluated the complication rates in inpatient versus outpatient TAA. It analyzed data from the National Surgical Quality Improvement Program for 591 patients who received TAA. Postoperative complication rates were compared between 66 outpatients and 535 inpatients. Frequencies of the following complications were analyzed: wound complications, pneumonia, hematologic complications (pulmonary embolism and deep vein thrombosis), renal failure, stroke, and return to the operating room within 30 days. Unadjusted direct comparisons of the cohorts revealed higher complication rates in the inpatient cohort. Inpatients had higher rates of superficial surgical site infections, deep surgical site infections, number of organ/space surgical site infections, pneumonia occurrences, and return to the operating room, but these differences were not significant. These results showed no significant increase in complication rates in outpatients compared to inpatients. Our results suggest that inpatient and outpatient TAA show similar complication rates. This suggests that outpatient TAA is safe and may be a superior option for certain populations. Further investigation is warranted to verify these conclusions.

Correlation of Appointment Times and Subspecialty With the No-Show Rates in an Orthopedic Ambulatory Clinic.

EXECUTIVE SUMMARY: Unexpectedly missed appointments ("no-shows") cause clinic inefficiency, lost time and revenue, wasted healthcare resources, and provider dissatisfaction. No-shows can be associated with miscommunication, transportation difficulties, employment status, age, race, and socioeconomic status. This study investigates the association between no-show rates and patient, appointment time, and provider characteristics. Data for all scheduled appointments in a single orthopedic multispecialty institution during calendar year 2016 were obtained. Data points included patient age, gender, and race; hour; month; and subspecialty. Chi-square testing was used to compare no-show and kept appointments with respect to patient and appointment characteristics. Logistic regression was used to calculate differences in no-show rates between orthopedic subspecialties. The overall no-show rate was 11.5%. Race, age, and subspecialties were all found to be associated with higher no-show rates. No significant differences were observed for gender, appointment time, or month of appointment. The authors suggest that patients at higher risk of not showing up for scheduled appointments may need extra effort from providers to accommodate the patients' schedules when making appointments, to confirm their appointments a few days before, and/or to incentivize patients to minimize no-shows.

How Would MRI-targeted Prostate Biopsy Alter Radiation Therapy Approaches in Treating Prostate Cancer?

OBJECTIVE: To determine if magnetic resonance imaging (MRI)/ultrasound fusion-targeted prostate biopsy (TB) would lead to increased recommendations of aggressive radiotherapy treatments for higher risk prostate cancer compared to systematic biopsy (SB) results. METHODS: Clinicopathologic data of 533 men who underwent both TB and SB from 2014 to 2017 was analyzed. TB was performed in addition to SB in patients with detection of MRI suspicious lesions. Three patient cohorts were established: (1) biopsy naïve (80/533, 15.0%), (2) active surveillance (185/533, 34.7%), and (3) prior negative biopsy (268/533, 50.3%). Cancer risk categorical criteria were established with recommended radiotherapy treatment for each. Variation of risk classification due to biopsy method for all patients and within each cohort was analyzed using either a chi-squared statistic or Fisher's exact test. McNemar's pairwise analyses were performed for all risk categories between TB and SB to assess the effects of TB on high-risk cancer identification and subsequent radiotherapy recommendations. RESULTS: Number of patients within cancer risk categories (1. "No Cancer or Low-Risk"; 2. "More Favorable Intermediate-Risk"; 3. "Less Favorable Intermediate-Risk"; 4. "High-Risk") varied significantly based on TB and SB pathology among all patients combined (P <.0001), in cohort 2 (P = .0005), and in cohort 3 (P <0.0001). Further, among all patients, TB increased cancer risk classification and correspondingly would result in more aggressive radiotherapy recommendations: "No Cancer or Low-Risk" to "Less Favorable Intermediate-Risk" (30/343, P <0.0001) and "No Cancer or Low-Risk" to "High-Risk" (31/353, P <.0001). CONCLUSION: Among men with prostate cancer, TB commonly led to reclassification to a higher risk group, which is accompanied by more aggressive radiotherapy treatment recommendations when compared with SB findings alone.

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices.

Weight gain prevention among black women in the rural community health center setting: the Shape Program.

BACKGROUND: Nearly 60% of black women are obese. Despite their increased risk of obesity and associated chronic diseases, black women have been underrepresented in clinical trials of weight loss interventions, particularly those conducted in the primary care setting. Further, existing obesity treatments are less effective for this population. The promotion of weight maintenance can be achieved at lower treatment intensity than can weight loss and holds promise in reducing obesity-associated chronic disease risk. Weight gain prevention may also be more consistent with the obesity-related sociocultural perspectives of black women than are traditional weight loss approaches. METHODS/DESIGN: We conducted an 18-month randomized controlled trial (the Shape Program) of a weight gain prevention intervention for overweight black female patients in the primary care setting. Participants include 194 premenopausal black women aged 25 to 44 years with a BMI of 25-34.9 kg/m2. Participants were randomized either to usual care or to a 12-month intervention that consisted of: tailored obesogenic behavior change goals, self-monitoring via interactive voice response phone calls, tailored skills training materials, 12 counseling calls with a registered dietitian and a 12-month YMCA membership.Participants are followed over 18 months, with study visits at baseline, 6-, 12- and 18-months. Anthropometric data, blood pressure, fasting lipids, fasting glucose, and self-administered surveys are collected at each visit. Accelerometer data is collected at baseline and 12-months.At baseline, participants were an average of 35.4 years old with a mean body mass index of 30.2 kg/m2. Participants were mostly employed and low-income. Almost half of the sample reported a diagnosis of hypertension or prehypertension and 12% reported a diagnosis of diabetes or prediabetes. Almost one-third of participants smoked and over 20% scored above the clinical threshold for depression. DISCUSSION: The Shape Program utilizes an innovative intervention approach to lower the risk of obesity and obesity-associated chronic disease among black women in the primary care setting. The intervention was informed by behavior change theory and aims to prevent weight gain using inexpensive mobile technologies and existing health center resources. Baseline characteristics reflect a socioeconomically disadvantaged, high-risk population sample in need of evidence-based treatment strategies. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov NCT00938535.

[The effects of protein stabilizers on aggregation induced by multiple-stresses].

A successful development of therapeutic proteins requires a formulation optimal for long-term storage of the proteins. During storage and shipment, proteins are subjected to multiple stresses. Here we show that ciliary neurotrophic factor (CNTF) readily aggregates upon exposure to mechanical stress such as agitation and elevated temperature at 37 degrees C. Sucrose and lysine or arginine protect CNTF from heat stress, while detergents such as Tween20 and organic solvents such as propylene glycol (PG) are effective against agitation. Combination of the amino acids and PG protected the protein from both stresses. The results suggest the importance of combining additives, against multiple stresses, which may have negative as well as positive influence individually against one particular stress.

Differences in natural ligand and fluoropyrimidine binding to human thymidylate synthase identified by transient-state spectroscopic and continuous variation methods.

Thymidylate synthase (TS) is a central target for the design of chemotherapeutic agents due to its vital role in DNA synthesis. Structural studies of binary complexes between Escherichia coli TS and various nucleotides suggest the chemotherapeutic agent FdUMP and the natural ligand dUMP bind similarly. We show, however, that FdUMP binding to human TS yields a substantially greater decrease in fluorescence than does dUMP. Because the difference in quenching due to ligand binding was approximately two-fold and this difference was not seen when using ecTS, the intriguing result indicated a significant difference in the mode of FdUMP binding to the human enzyme. We compared the binding affinities of dUMP, FdUMP, and TMP to TS from both species and found no significant differences for the individual ligands. Because binding affinities were not different among the ligands, the method of continuous variation was employed to determine binding stoichiometry. Similar to that found for dUMP binding to human and ecTS, FdUMP displayed single site occupancy with both enzymes. These results show that nucleotide binding differences exist for FdUMP and dUMP binding to the human enzyme. The observed differences are not due to differences in stoichiometry or ligand affinity. Therefore, although the crystal structure of human TS with various nucleotide ligands has not been solved, these results show that the differences observed using fluorescence methods result from as yet unidentified differential interactions between the human enzyme and nucleotide ligands.