Jae Young Moon

Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance.

The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cells dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.

Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma.

Clinical Practice Guideline of Acute Respiratory Distress Syndrome

There is no well-stated practical guideline for mechanically ventilated patients with or without acute respiratory distress syndrome (ARDS). We generate strong (1) and weak (2) grade of recommendations based on high (A), moderate (B) and low (C) grade in the quality of evidence. In patients with ARDS, we recommend low tidal volume ventilation (1A) and prone position if it is not contraindicated (1B) to reduce their mortality. However, we did not support high-frequency oscillatory ventilation (1B) and inhaled nitric oxide (1A) as a standard treatment. We also suggest high positive end-expiratory pressure (2B), extracorporeal membrane oxygenation as a rescue therapy (2C), and neuromuscular blockage for 48 hours after starting mechanical ventilation (2B). The application of recruitment maneuver may reduce mortality (2B), however, the use of systemic steroids cannot reduce mortality (2B). In mechanically ventilated patients, we recommend light sedation (1B) and low tidal volume even without ARDS (1B) and suggest lung protective ventilation strategy during the operation to lower the incidence of lung complications including ARDS (2B). Early tracheostomy in mechanically ventilated patients can be performed only in limited patients (2A). In conclusion, of 12 recommendations, nine were in the management of ARDS, and three for mechanically ventilated patients.

Spontaneous regression in advanced squamous cell lung carcinoma.

Spontaneous regression of malignant tumors is rare especially of lung tumor and biological mechanism of such remission has not been addressed. We report the case of a 79-year-old Korean patient with non-small cell lung cancer, squamous cell cancer with a right hilar tumor and multiple lymph nodes, lung to lung metastasis that spontaneously regressed without any therapies. He has sustained partial remission state for one year and eight months after the first histological diagnosis.

Lesser Toxicities of Belotecan in Patients with Small Cell Lung Cancer: A Retrospective Single-Center Study of Camptothecin Analogs

Purpose. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC). This study compared the toxicities and efficacies of belotecan and topotecan monotherapies in patients with SCLC. Methods. We retrospectively reviewed data from 94 patients with SCLC (with or without prior chemotherapy) who were treated using belotecan monotherapy (n = 59, 188 cycles) or topotecan monotherapy (n = 35, 65 cycles) between September 2003 and December 2011. Results. Thrombocytopenia occurred during 42% and 61.5% of the belotecan and topotecan cycles, respectively (p = 0.007). Significant differences between belotecan and topotecan were also observed for grade 4/5 lung infection (3.2% versus 10.8%, resp.; p = 0.003), all-grade headache (3.2% versus 10.8%, resp.; p = 0.017), and grade 4/5 increased liver enzymes (0.5% versus 4.6%, resp.; p = 0.023). The median TTPDs, CSSs, and OSs were 14 months and 11.6 months (p = 0.646), 10 months and 7 months (p = 0.179), and 34.5 months and 21.4 months (p = 0.914) after belotecan and topotecan monotherapy, respectively. Conclusions. Belotecan monotherapy may be safer than topotecan monotherapy in SCLC patients. And in terms of efficacy, belotecan could be comparable to topotecan monotherapy.

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 CHIPs 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 xenografts 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.

Promising effects of 3rd line cyclophosphamide, adriamycin and vincristine (CAV) and 4th line ifosfamide and carboplatin chemotherapy in refractory small cell lung cancer.

Third and fourth line chemotherapy agents are not helpful in the setting of extensive stage small cell lung cancer (SCLC). We describe the case of a 43‐year‐old Korean patient with T4N3M1b extensive stage SCLC who responded remarkably well to treatment and experienced a prolonged progression‐free survival (PFS) period following treatment with fourth line ifosfamide and carboplatin after experiencing disease progression with three previous regimens. Additionally, third line cyclophosphamide, doxorubicin (Adriamycin), and vincristine demonstrated long‐term PFS periods.

Ethics in the Intensive Care Unit

The intensive care unit (ICU) is the most common place to die. Also, ethical conflicts among stakeholders occur frequently in the ICU. Thus, ICU clinicians should be competent in all aspects for ethical decision-making. Major sources of conflicts are behavioral issues, such as verbal abuse or poor communication between physicians and nurses, and end-of-life care issues including a lack of respect for the patients autonomy. The ethical conflicts are significantly associated with the job strain and burn-out syndrome of healthcare workers, and consequently, may threaten the quality of care. To improve the quality of care, handling ethical conflicts properly is emerging as a vital and more comprehensive area. The ICU physicians themselves need to be more sensitive to behavioral conflicts and enable shared decision making in end-of-life care. At the same time, the institutions and administrators should develop their processes to find and resolve common ethical problems in their ICUs.

Diagnostic usefulness of the GenoType MTBDRplus assay for detecting drug-resistant tuberculosis using AFB smear-negative specimens with positive TB-PCR result

Abstract Background The aim of this study was to evaluate the diagnostic accuracy of the GenoType MTBDRplus assay in detecting drug-resistant tuberculosis (DR-TB) by using acid-fast bacilli (AFB) smear-negative specimens with positive TB-PCR results. Methods The MTBDRplus assay was performed with 2 different categories of 117 samples, including AFB smear-positive specimens (nu2009=u200953) and AFB smear-negative specimens (nu2009=u200964), which exhibited positive TB-PCR results, at a single institution. The results were retrospectively compared with the results of the phenotypic drug susceptibility test (DST), for reference. Results A total of 105 tests were finally analyzed. Of these, 54 tests were conducted using AFB smear-negative specimens with positive TB-PCR results. The MTBDRplus assay for these 54 samples demonstrated a sensitivity of 100%, specificity of 98%, positive predictive value (PPV) of 75%, and negative predictive value (NPV) of 100% in detecting rifampicin resistance. With these same species, the sensitivity, specificity, PPV, and NPV values for the MTBDRplus assay were 83.3%, 97.9%, 83.3%, and 97.9%, respectively, for the detection of isoniazid resistance. The overall correlation between the MTBDRplus assay and phenotypic DST demonstrated excellent agreement for detection of rifampicin resistance (κu2009=u20090.847) and for detection of INH resistance (κu2009=u20090.812), respectively. Conclusions The MTBDRplus assay can be used effectively even on AFB smear-negative specimens from TB patients, when the TB-PCR is positive. This result might help clinicians to manage patients with suspected DR-TB in difficult situations.

Spontaneous regression of non‐small cell lung cancer that progressed after multiple chemotherapies: A case report

Spontaneous regression (SR) of cancer is defined as a complete or partial, temporary or permanent disappearance of all or at least some relevant parameters of malignant disease with inadequate or no treatment. SR of cancer is an extremely rare phenomenon. We report a case of a 67‐year‐old man who experienced SR of non‐small‐cell lung cancer (NSCLC), which progressed after fifth‐line chemotherapy and regressed after chemotherapy ceased. Surprisingly, the primary tumor size continued to decrease for more than 13 months and his general condition markedly improved after discontinuation of the chemotherapy. To our knowledge, this is the first report of SR in a patient with NSCLC that was not responsive to a fifth round of chemotherapy.