The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation.

Somatic mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a decisive factor for the therapeutic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The stability of mutant EGFR is maintained by various regulators, including heat shock protein 90 (Hsp90). The C terminus of Hsc70-interacting protein (CHIP) is a Hsp70/Hsp90 co-chaperone and exhibits E3 ubiquitin ligase activity. The high-affinity Hsp90-CHIP complex recognizes and selectively regulates their client proteins. CHIP also works with its own E3 ligase activity independently of Hsp70/Hsp90. Here, we investigated the role of CHIP in regulating EGFR in lung adenocarcinoma and also evaluated the specificity of CHIP's effects on mutant EGFR. In HEK 293T cells transfected with either WT EGFR or EGFR mutants, the overexpression of CHIP selectively decreased the expression of certain EGFR mutants (G719S, L747_E749del A750P and L858R) but not WT EGFR. In a pull-down assay, CHIP selectively interacted with EGFR mutants and simultaneously induced their ubiquitination and proteasomal degradation. The expressions of mutant EGFR in PC9 and H1975 were diminished by CHIP, while the expression of WT EGFR in A549 was nearly not affected. In addition, CHIP overexpression inhibited cell proliferation and xenograft's tumor growth of EGFR mutant cell lines, but not WT EGFR cell lines. EGFR mutant specific ubiquitination by CHIP may provide a crucial regulating mechanism for EGFR in lung adenocarcinoma. Our results suggest that CHIP can be novel therapeutic target for overcoming the EGFR TKI resistance.

Recurrent Eosinophilic Pneumonia Associated with Mesalazine Suppository in a Patient with Ulcerative Colitis.

Mesalazine suppositories are widely used to treat ulcerative colitis and have a guaranteed safety profile, but although rare, they can cause pulmonary toxicity. A 35-year-old woman with ulcerative colitis was diagnosed to have acute eosinophilic pneumonia after 29 days of oral mesalazine use and improved after mesalazine and corticosteroid were withdrawn. Reintroduction of mesalazine suppositories resulted in acute eosinophilic pneumonia recurrence after 28 days. Mesalazine re-administration (even via a different route) in patients with a history of mesalazine-induced eosinophilic pneumonia should be undertaken cautiously, because eosinophilic pneumonia may recurrence.

The quality of dying and death for patients in intensive care units: a single center pilot study.

BACKGROUND: To identify the necessary care for dying patients in intensive care units (ICUs), we designed a retrospective study to evaluate the quality of dying and death (QODD) experienced by the surrogates of patients with medical illness who died in the ICU of a tertiary referral hospital. METHODS: To achieve our objective, the authors compared the QODD scores as appraised by the relatives of patients who died of cancer under hospice care with those who died in the ICU. For this study, a Korean version of the QODD questionnaire was developed, and individual interviews were also conducted. RESULTS: Sixteen people from the intensive care group and 23 people from the hospice care group participated in the survey and completed the questionnaire. The family members of patients who died in the ICU declined participation at a high rate (50%), with the primary reason being to avoid bringing back painful memories (14 people, 87.5%). The relatives of the intensive care group obtained an average total score on the 17-item QODD questionnaire, which was significantly lower than that of the relatives of the hospice group (48.7±15.5 vs. 60.3±14.8, P=0.03). CONCLUSIONS: This work implies that there are unmet needs for the care of dying patients and for the QODD in tertiary hospital ICUs. This result suggests that shared decision making for advance care planning should be encouraged and that education on caring for dying patients should be provided to healthcare professionals to improve the QODD in Korean ICUs.

Pleural or pericardial metastasis: A significant factor affecting efficacy and adverse events in lung cancer patients treated with PD-1/PD-L1 inhibitors.

BACKGROUND: Immunotherapy is a new paradigm for the treatment of non-small-cell lung cancer (NSCLC), and targeting the PD-1 or PD-L1 pathway is a promising therapeutic option. Although PD-1/PD-L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes. METHODS: We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD-1/PD-L1 inhibitors between January 2016 and February 2018. RESULTS: The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; P = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; P = 0.002) and grade 3-5 adverse events (52.2% vs. 25.0%; P = 0.046). CONCLUSION: Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis.

Progression-free survival: an important prognostic marker for long-term survival of small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is an extremely aggressive tumor with a poor clinical course. Although many efforts have been made to improve patients' survival rates, patients who survive longer than 2 years after chemotherapy are still very rare. We examined the baseline characteristics of patients with long-term survival rates in order to identify the prognostic factors for overall survivals. METHODS: A total of 242 patients with cytologically or histologically diagnosed SCLC were enrolled into this study. The patients were categorized into long- and short-term survival groups by using a survival cut-off of 2 years after diagnosis. Cox's analyses were performed to identify the independent factors. RESULTS: The mean patient age was 65.66 years, and 85.5% were males; among the patients, 61 of them (25.2%) survived longer than 2 years. In the multivariate analyses, CRP (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.25-6.06; p=0.012), TNM staging (HR, 3.29; 95% CI, 1.59-6.80; p=0.001), and progression-free survival (PFS) (HR, 11.14; 95% CI, 2.98-41.73; p<0.001) were independent prognostic markers for poor survival rates. CONCLUSION: In addition to other well-known prognostic factors, this study discovered relationships between the long-term survival rates and serum CRP levels, TNM staging, and PFS. In situations with unfavorable conditions, the PFS would be particularly helpful for managing SCLC patients.