Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort.

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. SIGNIFICANCE: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483.

A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis.

BACKGROUND: Plasma-derived bovine thrombin is used as a topical agent to improve surgical hemostasis, but development of antibodies to bovine hemostatic proteins has been associated with increased bleeding and thrombotic complications. Recombinant human thrombin could reduce the risk of these complications. STUDY DESIGN: The objective of this randomized, double-blind, comparative trial was to compare the efficacy, safety, and antigenicity of recombinant human thrombin (rhThrombin) and bovine thrombin as adjuncts to hemostasis in liver resection, spine, peripheral arterial bypass, and dialysis access surgery. Blinded study drug was applied topically to bleeding sites with an absorbable gelatin sponge. The primary efficacy end point was time to hemostasis, summarized as the incidence of hemostasis within 10 minutes. Safety analyses were conducted for 1 month after operation, and the development of antibodies to rhThrombin or to the bovine product was evaluated. RESULTS: Four hundred one patients completed this trial. Hemostasis was achieved at the time-to-hemostasis evaluation site within 10 minutes in 95% of patients in each treatment group. Overall complications, including operative mortality, adverse events, and laboratory abnormalities, were similar between groups. Forty-three (21.5%) patients receiving bovine thrombin developed antibodies to the product; three patients (1.5%; p < 0.0001) in the rhThrombin group developed antibodies to rhThrombin. None of the three patients who developed antirhThrombin antibodies had abnormal coagulation laboratory results or bleeding, thromboembolic, or hypersensitivity events. CONCLUSIONS: Results of this trial suggest that rhThrombin has comparable efficacy, a similar safety profile, and is considerably less immunogenic than bovine thrombin when used for surgical hemostasis.

Protecting the privacy of third-party information: recommendations for social and behavioral health researchers.

In psychosocial and health-behavioral research, we often request that research participants provide information on significant individuals in their lives, so-called "third parties". Recently there has been a greater recognition of privacy issues and risks in research pertaining to third parties. Reaction on the part of USA federal regulatory authorities to one study [Amber, D. (2000). Case at vcu bring ethics to forefront. , 14, 1], which attempted to collect survey data about the psychiatric history of respondents' parents, has generated such concern and caution that longstanding practices for the collection of social determinants of health data are being questioned and are at risk of being disallowed by Institutional Review Boards (IRBs). In this paper, we consider third party research rights and risks from the perspective of social and behavioral scientists. Focusing on research about health and quality of life, we first discuss the rationale for research methods that elicit contextual information about family members, friends, co-workers, and other social contacts. Second, we discuss the matter of 'privacy' and its central role in the current third party rights and risks dialogue. Next, we describe ways to effectively manage third-party information, building upon current recommendations by the Office for Human Research Protections (OHRP) and Botkin's [(2001). Protecting the privacy of family members in survey and pedigree research. Journal of the American Medical Association, 285(2), 207-211] treatment of the matter for survey and pedigree research. Lastly, we discuss the implications of applying these data collection and management strategies in social and behavioral research. We assert that these recommendations protect the rights of, and minimize the risks to, third parties without impeding social and behavioral health research.

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.

Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study.

Recombinant adeno-associated serotype 2-based vectors (rAAV2) possess a number of theoretical advantages for cystic fibrosis (CF) gene therapy because they elicit little or no inflammatory response and generally result in stable expression. rAAV2 vectors expressing the cystic fibrosis transmembrane conductance regulator (CFTR) gene have previously been shown to mediate stable correction of the CF defect in CF bronchial epithelial cells and stable expression of CFTR in rabbit and nonhuman primate models. Here we report the results of the first trial initiated with rAAV in humans, a phase I study in 25 adult and adolescent CF patients with mild to moderate lung disease. Doses of the rAAV-CFTR vector (tgAAVCF) ranging from 3 x 10(1) to 1 x 10(9) replication units (RU), which is equivalent to approximately 6 x 10(4) to 2 x 10(12) DNase resistant particles (DRP), were administered to one side of the nose and to the superior segment of the lower lobe of the right lung. Several adverse events were noted prior to and/or after vector delivery, but most of them appeared to be related to the endogenous CF lung disease or a result of the bronchoscopic procedures. Only one of the serious events was judged to be possibly vector-related (based on temporal association), and this event was a pulmonary exacerbation very similar to several others experienced by the same subject in the three months preceding vector delivery. Vector shedding was minimal throughout the study, and serum-neutralizing antibodies were detected after vector delivery to subjects in the highest dosage cohorts. Gene transfer as measured by DNA polymerase chain reaction (PCR) was not observed until cohort 10 in nasal and bronchial epithelia. Sporadic low-level copy numbers suggested gene transfer of anywhere from 0.002 copies per cell up to 0.5 copies per cell was possible; however, DNA PCR was positive in lungs prior to direct dosing suggesting aspiration from the nasal dosing. These data indicate the need for continued evaluation of rAAV-CFTR vectors in additional clinical trials.

A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies.

tgAAVCF, an adeno-associated cystic fibrosis transmembrane conductance regulator (CFTR) viral vector/gene construct, was administered to 23 patients in a Phase II, double-blind, randomized, placebo-controlled clinical trial. For each patient, a dose of 100,000 replication units of tgAAVCF was administered to one maxillary sinus, while the contralateral maxillary sinus received a placebo treatment, thereby establishing an inpatient control. Neither the primary efficacy endpoint, defined as the rate of relapse of clinically defined, endoscopically diagnosed recurrent sinusitis, nor several secondary endpoints (sinus transepithelial potential difference [TEPD], histopathology, sinus fluid interleukin [IL]-8 measurements) achieved statistical significance when comparing treated to control sinuses within patients. One secondary endpoint, measurements of the anti-inflammatory cytokine IL-10 in sinus fluid, was significantly (p < 0.03) increased in the tgAAVCF-treated sinus relative to the placebo-treated sinus at day 90 after vector instillation. The tgAAVCF administration was well tolerated, without adverse respiratory events, and there was no evidence of enhanced inflammation in sinus histopathology or alterations in serum-neutralizing antibody titer to adeno-associated virus (AAV) capsid protein after vector administration. In summary, this Phase II trial confirms the safety of tgAAVCF but provides little support of its efficacy in the within-patient controlled sinus study. Various potentially confounding factors are discussed.