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Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.

Background MenACWY-CRM (Menveo ® ; GlaxoSmithKline) and MenACWY-TT (Nimenrix ® ; Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited. Methods The reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12–15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement. Results A total of 202 children aged 12–15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high. Conclusion Despite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified.

The quadrivalent meningococcal glycoconjugate vaccine MenACWY-CRM is licensed for children from 2 months of age as a 4-dose series. This study assessed the immunogenicity of a 3-dose MenACWY-CRM vaccination series in infants, compared with the 4-dose series, and evaluated the impact of MenACWY-CRM concomitant administration on immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13).Overall, 751 healthy infants (age: 55-89 days) were randomized to receive 3 or 4 doses of MenACWY-CRM (2/4/12 or 2/4/6/12 months of age, respectively) with PCV13 + routine vaccinations (ACWY3 and ACWY4 groups, respectively) or PCV13 + routine vaccinations only (routine group). Immunological noninferiority of the 3-dose versus 4-dose MenACWY-CRM vaccination series was evaluated at 13 months of age for serogroups CWY; noninferiority of immune responses to PCV13 serotypes for concomitant administration of MenACWY-CRM and PCV13 was evaluated at 7 and 13 months of age.At 13 months, 88%-100% of subjects in groups ACWY3 and ACWY4 achieved seroprotective bactericidal antibody titers against serogroups ACWY; noninferiority criteria for the 3-dose versus 4-dose MenACWY-CRM vaccination series were met. At 7 months, noninferiority criteria were met for all PCV13 serotypes except for serotypes 3 and 5 (group ACWY3) and 19A (group ACWY4). At 13 months, noninferiority criteria were met for all PCV13 serotypes for both ACWY groups.After completion of either MenACWY-CRM vaccination series, most subjects achieved seroprotective titers against serogroups ACWY, with the 3-dose series being noninferior to the 4-dose series for serogroups CWY, and no interference with immune responses against PCV13 serotypes was observed (NCT01214837).

In a primary study, healthy adolescents received 2 doses (months 0/2) of 1 of the 4 investigational meningococcal ABCWY vaccine formulations, containing components of licensed quadrivalent glycoconjugate vaccine MenACWY-CRM, combined with different amounts of recombinant proteins (rMenB) and outer membrane vesicles (OMV) from a licensed serogroup B vaccine, or 2 doses of rMenB alone or 1 dose of MenACWY-CRM then a placebo.This phase 2 extension study evaluated antibody persistence up to 10 months after the 2-dose series and the immunogenicity and safety of a third dose (month 6). Immune responses against serogroups ACWY and serogroup B test strains were measured by serum bactericidal assay with human complement.At month 12, antibody persistence against serogroups ACWY in all 2-dose MenABCWY groups was at least comparable with the 1-dose MenACWY-CRM group. Bactericidal antibodies against most serogroup B test strains declined by month 6, then plateaued over the subsequent 6 months, with overall higher antibody persistence associated with OMV-containing formulations. A third MenABCWY vaccine dose induced robust immune responses against vaccine antigens, although antibody levels 6 months later were comparable with those observed 5 months after the 2-dose series. All investigational MenABCWY vaccines were well tolerated.Two or three doses of investigational MenABCWY vaccines elicited immune responses against serogroups ACWY that were at least comparable with those after 1 dose of MenACWY-CRM. After either vaccination series, investigational MenABCWY vaccine formulations containing OMV had the highest immunogenicity against most serogroup B test strains. No safety concerns were identified in this study.

Cryoablation is a well-established technique to treat fibroadenomas. Pilot studies suggest this could be an effective non-surgical treatment for breast cancer. American College of Surgeons Oncology Group Z1072 is a phase II trial exploring the effectiveness of cryoablation in the treatment of breast cancers. The primary endpoint of Z1072 was the rate of complete tumor ablation, defined as no remaining invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) on pathologic examination of the targeted lesion. A secondary objective was to evaluate the negative predictive value of magnetic resonance imaging (MRI) to determine residual IBC or DCIS. Eligible patients included those with unifocal invasive ductal breast cancer ≤2 cm, with

Persistence of bactericidal antibodies following vaccination is extremely important for protection against invasive meningococcal disease, given the epidemiology and rapid progression of meningococcal infection. We present an analysis of antibody persistence and booster response to MenACWY-CRM, in adolescents, children and infants, from 7 clinical studies. Immunogenicity was assessed using the serum bactericidal assay with both human and rabbit complement. Post-vaccination hSBA titers were high, with an age- and serogroup-specific decline in titers up to 1 y and stable levels up to 5 y The waning of hSBA titers over time was more pronounced among infants and toddlers and the greatest for serogroup A. However, rSBA titers against serogroup A were consistently higher and showed little decline over time, suggesting that protection against this serogroup may be sustained. A single booster dose of MenACWY-CRM administered at 3 to 5 y induced a robust immune response in all age groups.

Background Given the broad age range across which the quadrivalent meningococcal conjugate vaccine MenACWY-CRM is used, coadministration with routine vaccines should be evaluated across age groups for possible immunologic interference and impact on vaccine reactogenicity and safety. Methods We summarize data from a large population of infants, adolescents and international travelers from 10 phase 3 or 4 clinical studies to evaluate coadministration of MenACWY-CRM with commonly administered vaccines. Noninferiority analyses of immune responses were performed across studies and age groups for each vaccine. Reactogenicity and safety were also assessed. Results In infants, MenACWY-CRM coadministered with routine vaccines did not reduce immune responses to diphtheria, tetanus, poliovirus, hepatitis B, Haemophilus influenzae type b, pneumococcal conjugate, measles-mumps-rubella, varicella or pertussis antigens. Noninferiority criteria were not met for some pneumococcal conjugate serotypes at 7 months of age, but no consistent trends were observed. In adolescents, coadministration did not reduce immune responses to tetanus, diphtheria and human papilloma virus vaccine antigens. Noninferiority criteria for pertussis antigens were not uniformly met in infant and adolescent studies, although the clinical relevance is unclear. In adults, coadministration did not reduce immune responses to hepatitis A/B, typhoid fever, yellow fever, Japanese encephalitis and rabies antigens. Immune responses to MenACWY-CRM were not impacted by coadministration of commonly administered vaccines. Coadministration did not increase frequencies of postvaccination adverse events in any age group. Conclusions With no clinically relevant vaccine interactions or impact on vaccine reactogenicity or safety, these results support the coadministration of MenACWY-CRM with routine vaccines in all age groups.

BACKGROUND We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children. METHODS In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1. RESULTS One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups. CONCLUSIONS The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

Background This study compared the surgical results of 2 localization methods—cryo-assisted localization (CAL) and needle-wire localization (NWL)—in patients undergoing breast lumpectomy for breast cancer. Methods A total of 310 patients were treated in an institutional review board–approved study with 18 surgeons at 17 sites. Patients were randomized 2:1 to undergo either intraoperative CAL or NWL. A cryoprobe was inserted under ultrasound guidance in the operating room and an ice ball created an 8- to 10-mm margin around the lesion. The palpable ice ball then was dissected. NWL was placed according to institutional practice and resection was performed in a standard fashion. Surgical margins, complications, re-excisions, tissue volume, procedure times, ease of localization, specimen quality, and patient satisfaction were evaluated. Positive margins were defined as any type of disease present 1 mm or less from any specimen edge. Results Positive margin status did not differ between the 2 groups (28% vs. 31%). The volume of tissue removed was significantly less in the CAL group (49 vs. 66 mL, P = .002). Re-excisions were similar in both groups. CAL was superior in ease of lumpectomy, quality of specimen, acute surgical cosmesis, short-term cosmesis, patient satisfaction, and overall procedure time for the patient. CAL had a lower invasive positive margin rate (11% vs. 20%, P = .039) but a higher observed ductal carcinoma in situ–positive margin rate (30% vs. 18%, approaching statistical significance, P = .052). Conclusions CAL is a preferred alternative to standard wire localization because it provides a palpable template, removes less tissue and improves cosmesis, decreases overall procedure time, and is more convenient for the patient and surgeon.

Background A meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM. Methods A total of 484 healthy 10–25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters. Results Seroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90–92% vs. 73%; C: 93–95% vs. 63%; W: 80–84% vs. 65%; and Y: 90–92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported. Conclusions Both investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified.

To the Editor: In 1959, coyotes (Canis latrans) were found in only 3 Massachusetts towns, but by 2007, their population was estimated at 10,000 and they were present throughout the state, except on the islands of Martha’s Vineyard and Nantucket (1). The coyote is highly adaptable and readily tolerates living near humans (2). Because the raccoon rabies virus (RRV) variant is endemic to Massachusetts and spillover into the coyote population occurs (3), coyotes are a potential source of rabies exposure for humans. Rabies in coyotes has emerged in Massachusetts at the same time that coyote and human populations have increased. From 1985 through 2008, the Massachusetts Department of Public Health tested coyotes by following the standard direct fluorescent antibody testing protocol published by the Centers for Disease Control and Prevention (4). Of the 111 coyotes submitted for rabies testing, 4 (3.6%) were unsatisfactory because of decomposed brain tissue. Of the remaining 107 coyotes, 10 (9.0%) were found to be rabid; strain typing confirmed all 10 to have had spillover RRV. Within each county, the time between the first identification of RRV in an animal and finding a rabid coyote within that county ranged from 558 to 4,857 days; median was 2,799 days. The long time before spillover from raccoon to coyote was detected suggests that coyotes might avoid rabid reservoir animals. The time lag may also be the result of the distinct ecologic niches of these animals; coyotes are the top predators in ecosystems, and raccoons are only 1 of several mesocarnivores. The public health rabies surveillance system in the United States is passive and relies on interaction of humans or domestic animals with rabies vector species (5). Because a rabid wild animal would go untested if a human or domestic animal had not had potentially infectious contact with it, the 10 coyotes with confirmed rabies likely represented only some portion of all rabid coyotes in Massachusetts during the study period. Among 97 nonrabid coyotes, 7 had reportedly been in contact with humans and domestic animals. Among the 10 rabid coyotes, 4 were reported to have been in contact with humans and domestic animals. The coyotes in contact with both were 8.6× more likely to be rabid than were those in contact with only 1 or the other (p

Objective The aim of this prospective study was to assess the intermediate- (6 months) and longer-term (12 months) follow-up of patients with breast fibroadenomas treated by cryoablation in community-based practice settings. Methods The FibroAdenoma Cryoablation Treatment (FACT) registry was created to systematically collect procedural and follow-up data for patients with fibroadenomas treated by cryoablation without subsequent excision. This report summarizes the experience from 55 different practice settings across the United States. Baseline and follow-up clinical data at 6 months and 12 months were tabulated for all patients. Results Data from 444 treated fibroadenomas were analyzed. The mean tumor diameter was 1.8 cm. Before cryoablation, 75% of fibroadenomas were palpable by the patient. Follow-up at 6- and 12-month intervals revealed palpability of the treated site in 46% and 35%, respectively. When fibroadenomas were grouped by size, for lesions ≤2 cm, residual cryoablation induce changes were visible by ultrasound in 35% of patients at 6 months. The treatment area was palpable in 31% of cases at this time. Visibility by ultrasound was 27%, and palpability was 28% at 12 months follow-up in these patients with smaller fibroadenomas. For lesions >2 cm, residual cryoablation induce changes were visible by ultrasound in 39% of the patients at 6 months. The treatment area was palpable in 78% of the cases at the same time. Visibility by ultrasound was 32%, and palpability was 59% at 12 months follow-up. Patient satisfaction with the procedure was rated as high at 91% and 88% at 6 and 12 months follow-up, respectively. Conclusions Before implementing this technique, patients should be apprised of the likely persistence of a palpable mass of the treated site for a prolonged period that will reabsorb over time. Palpability of the treated site persists for a substantially longer period of time for lesions greater than 2 cm in diameter. For patients with a fibroadenoma smaller than 2 cm, complete resolution can be expected in two thirds and three quarters of the patients at 6 and 12 months, respectively. We will continue to follow these patients to better define the length of time and factors influencing the resolution of the treatment induced physical and radiographic findings.