De-escalating Locoregional Therapy for Axillary Micrometastases in Breast Cancer: How Much is Too Much?

BACKGROUND: The applicability of modern prospective data on adjuvant radiotherapy (RT) fields in patients with micrometastases is limited because many trials occurred prior to routine measurement of nodal metastasis size and modern sentinel lymph node evaluation techniques. We aimed to determine prognostic factors for patients with micrometastases and evaluate the impact of adjuvant RT on disease outcomes. PATIENTS AND METHODS: Patients diagnosed with pathologic T1-T3 N1mi breast cancers between 2004-2015 were identified. Cox proportional hazards methods were used to determine characteristics predictive of locoregional recurrence (LRR). Tumor and treatment-specific factors were further evaluated using log-rank statistics to compare rates of LRR-free survival. RESULTS: This analysis included 156 patients. On multivariable analysis, grade 3 histology (HR 10.84, 95% CI 2.72-43.21) and adjuvant RT (HR 0.22, 95% CI 0.06-0.81) were independent predictors of LRR. Among patients with grade 1-2 histology, 5-year LRR-free survival was 98.8% in patients who received adjuvant RT versus 100% in patients who did not receive adjuvant RT (P = .82). Among patients with grade 3 histology, 5-year LRR-free survival was 90.1% in patients who received adjuvant RT versus 53.0% in patients who did not receive adjuvant RT (P = .025), and 100% in patients receiving comprehensive nodal irradiation versus 76.7% in patients receiving whole breast irradiation or no RT (P = .045). CONCLUSION: Patients with grade 3 micrometastases are at substantial risk for LRR. Adjuvant RT, including comprehensive nodal irradiation, should be strongly considered in these women.

Delayed Tracheostomy in a Patient With Prolonged Invasive Mechanical Ventilation due to COVID-19.

Coronavirus disease 2019 (COVID-19) can cause acute respiratory distress syndrome (ARDS) that is associated with high mortality among patients requiring invasive mechanical ventilation. We present a case of a 56-year-old male with hypertension and obesity who presented with chest pain from COVID-19. The patient required endotracheal intubation due to worsening hypoxia and remained intubated for 33 days. Tracheostomy placement was delayed in part due to persistent COVID-19 positive testing until hospital day 37. The patient required a total of 52 days in the ICU prior to discharge to a rehabilitation facility. This case highlights the extensive resources needed for critically ill patients with COVID-19 and the long duration that patients may test positive for the virus after onset of symptoms. It also raises questions about the timing and safety of tracheostomy placement among those patients requiring mechanical ventilation from COVID-19.

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides.

ß-Amyloid peptide (Aß) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer's disease. Compounds that bind to Aß, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein-protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aß. We have taken a different approach, by designing Aß-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aß-binding site on TTR, suppressed Aß aggregation into fibrils and protected neurons against Aß toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aß, redirects Aß toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.