High flow nasal cannula (HFNC) has been shown to improve extubation outcomes in patients with hypoxemia, but the role of HFNC in weaning patients with chronic obstructive pulmonary disease (COPD) with hypercapnia from invasive ventilation is unclear. We compared the effects of HFNC to noninvasive ventilation (NIV) on postextubation vital signs and arterial blood gases (ABGs) among patients with COPD. Other outcomes included comfort scores, need for bronchoscopy, use of pulmonary medications, and chest physiotherapy. Forty‐two COPD patients who had persistent hypercapnia at extubation were assigned randomly to receive HFNC (22) or NIV (20). Twenty patients in each group were enrolled for per‐protocol analysis with regard to primary outcomes. Vital signs and ABGs before extubation were similar between groups. At 3 hr after extubation, pH in the NIV group was lower than HFNC group (7.42 ± 0.06 vs. 7.45 ± 0.05, p = 0.01). At 24 hr after extubation, patients’ mean arterial pressure (82.97 ± 9.04 vs. 92.06 ± 11.11 mmHg, p = 0.05) and pH (7.42 ± 0.05 vs. 7.46 ± 0.03, p = 0.05) in the NIV group were lower than in the HFNC group. No significant differences were found at 48 hr after extubation. In the HFNC group, comfort scores were better (3.55 ± 2.01 vs. 5.15 ± 2.28, p = 0.02) and fewer patients needed bronchoscopy for secretion management within 48 hr after extubation (2/22 vs. 9/20, p = 0.03). HFNC is a potential alternative to NIV to wean hypercapnic COPD patients with regard to vital signs and ABGs, HFNC improved patients’ comfort and secretion clearance.

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Background This multicenter, open‐label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3‐kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. Materials and Methods Eighty‐nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0‐2. Binimetinib and buparlisib combinations were explored in patients with KRAS‐, NRAS‐, or BRAF‐mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)‐mutant, advanced non‐small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS‐ or BRAF‐mutant ovarian cancer; or advanced non‐small cell lung cancer with KRAS mutation. Results At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF‐mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. Conclusion Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose‐limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. Implications for Practice Because dysregulation of the mitogen‐activated protein kinase (MAPK) and the phosphatidylinositol 3‐kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single‐agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

UBR5 is a nuclear phosphoprotein of obscure functions. Clinical analyses reveal that UBR5 amplifications and overexpression occur in over 20% cases of human breast cancers. Breast cancer patients carrying UBR5 genetic lesions with overexpression have significantly reduced survival. Experimental work in vitro and in vivo demonstrates that UBR5, functioning as an oncoprotein, plays a profound role in breast cancer growth and metastasis. UBR5 drives tumor growth largely through paracrine interactions with the immune system, particularly through inhibiting the cytotoxic response mediated by CD8 + T lymphocytes, whereas it facilitates metastasis in a tumor cell-autonomous manner via its transcriptional control of key regulators of the epithelial-mesenchymal transition, ID1 and ID3. Furthermore, simultaneous targeting of UBR5 and PD-L1 yields strong therapeutic benefit to tumor-bearing hosts. This work significantly expands our scarce understanding of the pathophysiology and immunobiology of a fundamentally important molecule and has strong implications for the development of novel immunotherapy to treat highly aggressive breast cancers that resist conventional treatment.