Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Effectiveness and safety of salmeterol in nonspecialist practice settings.

STUDY OBJECTIVES: To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice settings. DESIGN: A randomized, double-blind, 6-month, parallel-group study involving 253 centers. SETTING: Primarily nonspecialist practices (n = 232). PATIENTS: A total of 911 subjects (417 men; 494 women) who met American Thoracic Society asthma criteria were enrolled and randomized to treatment with either twice-daily salmeterol aerosol (50 microg; n = 455) or matching placebo twice daily (n = 456). Both groups were allowed to take salbutamol as needed. All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study. MEASUREMENTS AND RESULTS: The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization, emergency department visit, or use of prednisone during the treatment period. A total of 712 subjects competed the study. There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups (20.8% vs 20.9%, respectively; p = 0.935; power > 88%). Peak expiratory flow was significantly higher in the salmeterol group (398 L/min vs 386 L/min for placebo; p < 0.01). Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo (p < 0.001). The proportion of subjects sleeping through the night was significantly higher in the salmeterol group (74%) as compared to placebo (68%; p = 0.028). CONCLUSIONS: Salmeterol treatment is effective in subjects typically cared for in the primary-care setting and does not increase the frequency of severe exacerbations.

Associations between physical examination, laboratory, and radiographic findings and outcome and subsequent racing performance of foals with Rhodococcus equi infection: 115 cases (1984-1992).

OBJECTIVE: To determine whether physical examination, laboratory, or radiographic abnormalities in foals with Rhodococcus equi infection were associated with survival, ability to race at least once after recovery, or, for foals that survived and went on to race, subsequent racing performance. DESIGN: Retrospective study. ANIMALS: 49 Thoroughbreds and 66 Standardbreds admitted to 1 of 6 veterinary teaching hospitals between 1984 and 1992 in which R equi infection was positively diagnosed. PROCEDURE: Results of physical examination, laboratory testing, and thoracic radiography were reviewed. Indices of racing performance were obtained for foals that recovered and eventually raced and compared with values for the US racing population. RESULTS: 83 (72%) foals survived. Foals that did not survive were more likely to have extreme tachycardia (heart rate > 100 beats/min), be in respiratory distress, and have severe radiographic abnormalities on thoracic radiographs at the time of initial examination than were foals that survived. Clinicopathologic abnormalities were not associated with whether foals did or did not survive. Forty-five of the 83 surviving foals (54%) eventually raced at least once, but none of the factors examined was associated with whether foals went on to race. Racing performance of foals that raced as adults was not significantly different from that of the US racing population. CLINICAL IMPLICATIONS: R equi infection in foals is associated with a decreased chance of racing as an adult; however, foals that eventually go on to race perform comparably to the US racing population.

Frequency dependence of forced oscillatory respiratory mechanics in horses with heaves.

The effect of measurement frequency on respiratory mechanics was investigated in six horses with reversible allergic airway disease. Total respiratory impedance was measured at 1.5, 2.0, 3.0, and 5.0 Hz by using the forced oscillation technique with the horses in remission, after acute antigenic challenge producing clinical heaves, and with heaves but after the administration of 2 mg fenoterol by inhalation. The slopes of the magnitude (magnitude of Zrs) and real part (R) of total respiratory impedance over the frequency range 1.5-3 Hz changed significantly after antigenic challenge and fenoterol. The ratio of R at 2 Hz to R at 3 Hz, however, discriminated better among the three conditions. Compliance and resonant frequency (calculated by using a three-element model) changed significantly after antigenic challenge and fenoterol, but inertance did not. We concluded that horses with heaves showed frequency dependence of R and (magnitude of Zrs) at frequencies up to 3 Hz and that parameters derived from a three-element model were useful indicators of small airway obstruction in the horse.

Pulmonary function measurements during repeated environmental challenge of horses with recurrent airway obstruction (heaves).

OBJECTIVES: To evaluate the degree of reproducibility in clinical variables, blood gas measurements, and lung function variables, and the changes in these variables caused by exposure to moldy hay in naturally sensitized and control horses. PROCEDURE: The magnitude of variation in arterial blood gas and pulmonary function measurements were evaluated in a model of naturally acquired heaves. Horses with heaves and similarly aged control horses were studied prior to moldy hay challenge and again after the horses with heaves manifested clinical signs of airway obstruction. This cycle of testing was repeated 3 times to determine the variation of the before and after challenge measurements. Variables evaluated for repeatability included: clinical score; arterial O2 and CO2 tensions; pulmonary function variables, such as breathing rate (f), tidal volumes, and flow rates; lung resistance (RL); dynamic compliance; and work of breathing (Wb). RESULTS: Before challenge, significant differences observed between control horses and horses with heaves included clinical score, expiratory flow rate at near-end expiration, RL, and Wb. After exposure to moldy hay, variables measured in control horses were largely unchanged. However, in the afflicted horses, significant changes were observed for clinical score, arterial O2 and CO2 tensions, breathing rate, peak tidal inspiratory and expiratory flow rates, dynamic compliance, RL, and Wb, compared with prechallenge values and with control horses' postchallenge values. Analysis of the data revealed few statistically significant differences between repeats of challenges. CONCLUSION: Horses afflicted with heaves manifest airway obstruction that can be measured in repeatable fashion.

Effect of 5-hydroxytryptamine type-2 receptor blockade on pulmonary function in calves with experimentally induced Pasteurella haemolytica pneumonia.

OBJECTIVE: To evaluate a 5-hydroxytryptamine type-2 receptor antagonist, metrenperone (MET), in alleviating respiratory distress associated with experimentally induced Pasteurella haemolytica pneumonia in feedlot calves. DESIGN: Double-blind controlled clinical trial. ANIMALS: 30 healthy 6- to 8-month-old Hereford-type calves (250 to 450 kg). PROCEDURE: Initial measurements were made of rectal temperature (RT), arterial blood gas (ABG) tensions, and pulmonary mechanics. Calves were then infected with P haemolytica in logarithmic phase of growth by intratracheal inoculation. 18 hours later, determination of RT and ABG tensions, and pulmonary function testing were repeated and calves were selected for inclusion in the study on the basis of having 2 of the following: respiratory rate > 50 breaths/min, RT > 40 C, or PaO2 > 20 mm of Hg below the baseline value. MET (0.1 mg/kg of body weight, IM) or an equivalent vehicle dose was then administered. RT, ABG, and pulmonary mechanics measurements were repeated at 0.5, 1, 2, 3, 4, 6, 12, and 24 hours after treatment. Calves were then euthanatized, and gross necropsy scoring and histologic examination were performed on the lungs. RESULTS: Infection with P haemolytica caused significant increases in RT and respiratory rate, and reduction in PaO2, PaCO2, and tidal volume 18 hours after inoculation. MET-treated calves and significantly reduced rectal temperature between 1 and 12 hours, compared with vehicle-treated calves. In addition, MET-treated calves had reduced respiratory rate with concomitantly increased tidal volume between 0.5 and 2 hours after treatment, compared with vehicle-treated calves. Necropsy revealed acute lobar bronchopneumonia in all 30 calves, but there was no difference in necropsy score between treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: MET may have an antipyretic effect on calves with pneumonia caused by P haemolytica. Its influence on pulmonary mechanics was minimal however, and it did not induce lung lesions in the short term.

Respiratory mechanics of horses measured by conventional and forced oscillation techniques.

Respiratory mechanics were compared using conventional and forced oscillation techniques in six conscious horses and a mechanical model of the equine respiratory system. The parameters calculated from conventional airflow and esophageal pressure measurements were pulmonary resistance and dynamic compliance. The impedance of the respiratory system was measured at 1, 2, and 3 Hz with the forced oscillation technique, and respiratory system resistance, compliance, inertance, and resonant frequency were calculated. Pulmonary resistance was 1.0 +/- 0.3 cmH2O.l-1.s, and pulmonary dynamic compliance was 2.4 +/- 0.6 l/cmH2O. With the use of the forced oscillation system, respiratory resistance was 1.61 +/- 0.50 cmH2O.l-1.s at 1 Hz, compliance was 0.195 +/- 0.075 l/cmH2O, inertance was 0.026 +/- 0.0095 cmH2O.l-1.s2, and resonant frequency was 2.40 +/- 0.25 Hz. Data collected from a model of the respiratory system showed a close correlation between resistance and compliance measured with the two systems. This study demonstrates that the forced oscillation technique is a useful method for noninvasive measurement of respiratory mechanics in horses.

The rapid and effective administration of a beta 2-agonist to horses with heaves using a compact inhalation device and metered-dose inhalers.

The purpose of the study was to administer therapeutic aerosol generated by metered-dose inhalers to horses exhibiting clinical signs of heaves using a compact inhalation device developed for human medicine. It was fitted to a custom face mask in order to study the effect of an inhaled beta 2-agonist, fenoterol. Pulmonary function testing was performed on six horses following an acute exacerbation of heaves, characterized by tachypnea, wheezes, crackles, and spasmodic cough. Horses inhaled fenoterol in 1 mg increments administered as one 200 microgram puff every 5-10 s with the recording of data 5 min after the cessation of drug inhalation. A significant effect of fenoterol was shown for maximum change in transpulmonary pressure, dynamic compliance, lung resistance, and work of breathing, and the wheezes and crackles disappeared when auscultation was performed at the end of the test. This study demonstrates a novel, highly effective method for the rapid administration of inhaled medication in horses.

Evaluation of a guarded bronchoscopic method for microbial sampling of the lower airways in foals.

A novel method to reduce contamination of the bronchoscope during microbial sampling of the lower airways of foals was evaluated. Methylene blue (MB) was used as a nasopharyngeal dye marker to assess the relative contamination from the upper airways of bronchoalveolar lavage (BAL) specimens obtained by standard bronchoscopy (SB) and a "guarded" bronchoscopic method (GB). For GB, a clear sterile cellulose sheath was fitted over the bronchoscope in an effort to protect the endoscope tip and channel from contamination. Methylene blue was detected visually in seven of eight BAL samples from foals following SB, but in none of the samples recovered by GB (p less than 0.001). Significantly less MB was detected in BAL by spectrophotometry in the GB group as well (p less than 0.02). The GB was next employed to study the microbial flora in the lower airways of healthy weaned foals (n = 30). Bacteria were isolated from 29 of 30 (97%) BAL samples, and in moderate or large numbers from 26 of 30 (87%) of the foals. Potential pathogens, including Bordetella bronchiseptica, Streptococcus zooepidemicus, Staphylococcus aureus, Mycoplasma felis and Streptococcus pneumoniae, were cultured from the lower airways of foals. In conclusion, the bronchoscope and bronchoalveolar lavage specimens were readily contaminated by a dye marker placed in the nasopharynx of foals, and the degree of contamination was significantly reduced by sheathing the endoscope. This contamination during bronchoscopy may obscure the interpretation of isolates from BAL specimens from foals, which may possess a bacterial flora in the lower airways without cytological evidence of inflammation.