Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

Ammonia and nitrous oxide emissions from a commercial broiler house.

Complex variation in gas emissions from animal facilities has been shown in recent research reports. Uncertainties in these emission estimates are driving research activities concerning different animal species across the globe. Greenhouse gas (NO and CO) and NH concentrations were measured in a modern, tunnel-ventilated, commercial broiler house in Mississippi during five flocks (spanning approximately 1 yr). These were flocks 9 through 13 on reused pine shavings litter, representing litter reuse beyond 2 yr. Gas concentrations obtained from a photoacoustic multigas analyzer were coupled with ventilation measurements of air flow through the house to develop NH and NO emission rates. Ammonia emission during a flock (43 d) averaged approximately 14.8 ± 9.8 kg d in the commercial house (equivalent to 23.5 g bird marketed or 0.54 g bird d). Nitrous oxide emission averaged 2.3 ± 1.7 kg d in the house (equivalent to 3.64 g bird marketed or 0.085 g bird d). Emission rates increased with time from Day 1 to Day 43 and reached average values on Day 23 and 24 for NH and NO. Even with extended litter reuse, estimates of NH emissions from the broiler house agree well with recently published research that reused litter in eight or fewer flocks. This is important information for farmers who may not be able to afford to replace the litter with fresh bedding material annually.

Optimization of phosphorus precipitation from swine manure slurries to enhance recovery.

Laboratory experiments were conducted using magnesium chloride (MgCl2 x 6H2O, 64% solution) to force the precipitation of phosphorus and reduce the concentration of soluble phosphorus (PO4(3-)) in two swine wastes. One of the swine wastes tested contained a high concentration of PO4(3-) (initially approximately 1,000 mg/L), and the other swine waste tested contained a low concentration of PO4(3-) (initially approximately 230 mg/L). The precipitation reactions were performed to determine the required reaction time, pH, magnesium addition rate and seed material for future precipitate recovery work. For the high and low concentration waste, a 10-minute reaction time at a pH of 8.6 was sufficient to remove 98 and 96% of the PO4(3-) from solution. A molar ratio of Mg2+:PO4(3-) of 1.6:1 was determined to be effective for PO4(3-) removal from both the low and high strength wastes. At a molar ratio of 1.6:1, the PO3- in the high concentration waste was reduced from 590 to 12 mg/L. In the low concentration waste, the PO4(3-) concentration was reduced from 157 to 15 mg/L. Seeding the reaction did not significantly enhance the recovery process.

Laboratory and in-situ reductions of soluble phosphorus in swine waste slurries.

Laboratory and field experiments were conducted using magnesium chloride (MgCl2) to force the precipitation of struvite (MgNH4PO4 x 6H2O) and reduce the concentration of soluble phosphorus (SP) in swine waste. In laboratory experiments, reductions of SP of 76% (572 to 135 mg P l(-1)) were observed in raw swine manure after addition of magnesium chloride (MgCl2) at a rate calculated to provide a 1.6:1 molar ratio of magnesium (Mg) to total phosphorus. Adjusting the pH of the treated manure to pH 9.0 with sodium hydroxide (NaOH) increased SP reduction to 91% (572 to 50 mg P l(-1)). X-ray diffraction of the precipitate recovered from swine waste slurry treated only with MgCl2 confirmed the presence ofstruvite. The molar N:P:Mg ratio of the recovered precipitate was 1:1.95:0.24, suggesting that compounds in addition to struvite were formed. In a field experiment conducted in a swine manure holding pond, a 90% reduction in SP concentration was observed in approximately 140,000 l of swine manure slurry treated before land application with 2,000 l MgCl2 (64% solution) at ambient slurry temperatures ranging from 5 to 10 degrees C.