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Abstract DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab’s clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs β-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

Abstract Background Oligoprogression is an emerging issue in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, the surgical treatment for central nervous system (CNS) oligoprogression is not widely discussed. We investigated the outcomes of craniotomy with adjuvant whole-brain radiotherapy (WBRT) and subsequent therapies for CNS oligoprogression in patients with EGFR-mutated NSCLC. Methods NSCLC patients with CNS oligoprogression were identified from a tertiary medical center. The outcomes of surgery with adjuvant WBRT or WBRT alone were analyzed, along with other variables. Overall survival and progression-free survival were analyzed using the log-rank test as the primary and secondary endpoints. A COX regression model was used to identify the possible prognostic factors. Results Thirty-seven patients with CNS oligoprogression who underwent surgery or WBRT were included in the study after reviewing 728 patients. Twenty-one patients underwent surgery with adjuvant WBRT, and 16 received WBRT alone. The median overall survival for surgery and WBRT alone groups was 43 (95% CI 17–69) and 22 (95% CI 15–29) months, respectively. Female sex was a positive prognostic factor for overall survival (OR 0.19, 95% CI 0.06–0.57). Patients who continued previous tyrosine kinase inhibitors (OR 3.48, 95% CI 1.06–11.4) and induced oligoprogression (OR 3.35, 95% CI 1.18–9.52) were associated with worse overall survival. Smoking history (OR 4.27, 95% CI 1.54–11.8) and induced oligoprogression (OR 5.53, 95% CI 2.1–14.7) were associated with worse progression-free survival. Conclusions Surgery combined with adjuvant WBRT is a feasible treatment modality for CNS oligoprogression in patients with EGFR-mutated NSCLC. Changing the systemic-targeted therapy after local treatments may be associated with improved overall survival.

Abstract Background Some prospective studies have shown that second‐generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non‐small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second‐line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. Methods Patients with EGFR‐mutated advanced‐stage NSCLC who received first‐line EGFR‐TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second‐line chemotherapy were enrolled. We compared progression‐free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan–Meier and log‐rank tests. Results In total, 209 (54.8%) patients had a negative T790M mutation test and received second‐line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. Conclusion This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.

Abstract Tracheopathia osteochondroplastica (TO) is a rare and benign condition. It typically manifests as multiple osteocartilaginous nodules in the submucosa of the central airway. TO‐related clinical symptoms and physical signs are nonspecific. The bronchoscopic examination is helpful in establishing the diagnosis. Treatment for TO is mostly conservative and symptom‐oriented. The prognosis of TO is generally good, although cases of associated airway stenosis have been reported. In this case report, we describe the clinical, imaging, and histological features, and videoed bronchoscopic findings, of a middle‐aged male patient with incidentally diagnosed TO.

Abstract Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical–regulatory factors for the entrance protein of SARS-CoV-2, angiotensin–converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman’s r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019–1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb–/– mice; however, exogenous ROS increased the ACE2 in Cybb–/– AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS–induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.

Abstract The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial–mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan–Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results.

Non-radiative traps and structures are present on the graphene quantum dots doped with nitrogen and functionalized with amino groups (amino-N-GQDs) and multiple crystalline layers because of cross-link-enhanced emission. Secondary and tertiary amines, which are potential fluorophores, have also been observed on the polyethylenimine (PEI) coating of amino-N-GQDs. Cross-linked PEI coating reduced rotation and vibration, thereby enhancing the photoluminescence quantum yield (PL QY). Introduced nitrogen atoms from N dopants, amino-functionalized groups and PEI, as well as sulfur from polystyrene sulfonate (PSS) enhanced the cooperative effect on the properties of heteroatom-doped materials among electrons captured by new surface states. This enhanced radiative recombination and subsequently enhanced PL QY, therefore, surface conjugation improved the amino-N-GQD surfaces by increasing the quantum confinement of their emissive energy, evidenced by the increased PL QY of amino-N-GQD-PSS-PEI (or amino-N-GQD-polymer composites). In some situations, the maximum available power required for delivery to the two-photon imaging plane without damaging tissues limits imaging depth but the additional brightness provided by amino-N-GQD-polymer composites in this study extended the maximum imaging depth to 240 μm. Amino-N-GQD-polymer composites had favorable two-photon properties under two-photon excitation (self-developed femtosecond Ti–sapphire laser optical system; power: 23.93 nJ pixel−1, 160 scans, approximately 1.09 s of total exposure time; excitation wavelength: 980 nm, near-infrared-II region), indicating that cells treated with amino-N-GQD-polymer composites and the anti-epidermal growth factor receptor antibody can achieve two-photon luminescence with 1/81 of the power required for similar-intensity two-photon autofluorescence (1938.33 nJ pixel−1 with 800 scans, total exposure time of ∼5.44 s). The materials can serve as contrast agents for the non-invasive detection of biological specimens and interior tissues using a two-photon excitation wavelength in the near-infrared region.

Background: Invasive pulmonary aspergillosis (IPA) can negatively impact cancer patients’ survival. It remains uncertain whether IPA’s impact on patient outcomes varies by treatment approach in advanced lung cancer. Objectives: To explore the association between IPA and outcomes in patients with advanced lung cancer receiving different treatments. Design: A retrospective cohort study. Methods: We enrolled patients with advanced-stage lung cancer between 2013 and 2021 at a college hospital in Taiwan and used the 2021 European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium consensus for IPA diagnosis. Multivariable logistic regression was used to identify the IPA risk factors. We compared overall survival (OS) and postgalactomannan (GM) test survival between the IPA and control groups using multivariable Cox proportional hazards regression and the Kaplan–Meier method with propensity score matching (PSM). Results: Among 2543 patients with advanced-stage lung cancer, 290 underwent a GM test, of which 34 (11.7%) were diagnosed with IPA. Patients undergoing chemotherapy (HR = 4.02, p = 0.027) and immunotherapy [hazard ratio (HR) = 3.41, p = 0.076] tended to have IPA. Compared to the control group, the IPA group had shorter median OS (14.4 versus 9.9 months, p = 0.030) and post-GM test survival (4.5 versus 1.9 months, p = 0.003). IPA was associated with shorter OS (log-rank p = 0.014 and 0.018 before and after PSM, respectively) and shorter 1-year and 2-year survival post-GM test (HR = 1.65 and 1.66, respectively). Patients receiving chemotherapy or immunotherapy had a shorter post-GM test survival if they had IPA. Conclusions: IPA tended to be diagnosed more frequently in patients receiving chemotherapy or immune checkpoint inhibitors. Patients diagnosed with IPA are associated with shorter survival. Larger cohort studies are needed to verify the observations.

Abstract Tumor resection could increase treatment efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). This study aimed to retrospectively analyze patients with advanced EGFR-mutant NSCLC from a Taiwanese tertiary center and receiving EGFR-TKI treatment with or without tumor resection. A total of 349 patients were enrolled. After propensity score matching, 53 EGFR-TKI treated patients and 53 EGFR-TKI treated patients with tumor resection were analyzed. The tumor resection group showed improved progression-free survival (PFS) (52.0 vs. 9.8 months; hazard ratio [HR] = 0.19; p

Although combination therapy including chemotherapy and immune checkpoint inhibitors (ICIs) improves overall survival (OS) of patients with non-small-cell lung cancer (NSCLC), there is a higher incidence of adverse events and treatment discontinuation. Since programmed death-ligand 1 (PD-L1) could not serve as a predictive biomarker, we investigated the neutrophil-to-lymphocyte ratio (NLR) as a predictive biomarker. In our previous research, we demonstrated that a low NLR could predict survival benefits when patients with high PD-L1 expression (> 50%) received chemoimmunotherapy as opposed to immunotherapy alone. In this current study, our objective is to evaluate this predictive capacity in patients with low PD-L1 expression (< 50%). A total of 142 patients were enrolled, 28 receiving combination therapy and 114 receiving chemotherapy alone. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Patients who received combination therapy had significantly better PFS and OS than those who received monotherapy. In the subgroup of patients with low NLR, those who received combination therapy exhibited extended PFS and OS with clinical significance, which was also confirmed by multivariate Cox regression analysis. Our study demonstrates the potential use of NLR as a biomarker for predicting survival benefits when receiving combination therapy with chemotherapy and ICIs in patients with advanced NSCLC and low PD-L1 expression.

Background: A comprehensive study of respiratory pathogens was conducted in an area with a low prevalence of COVID-19 among the adults quarantined at a tertiary hospital. Methods: From March to May 2020, 201 patients suspected lower respiratory tract infection (LRTI) were surveyed for etiologies by multiplex polymerase chain reaction (PCR: FilmArray TM Respiratory Panel) test combination with cultural method, viral antigen detection and serologic surveys. Results: Total 201 patients tested with FilmArray TM Respiratory Panel were enrolled, of which 68.2% had sputum bacterial culture, 86.1% had pneumococcus and Legionella urine antigen test. Their median age was 72.0 year-old with multiple comorbidities, and 11.4% were nursing home residents. Bacteria accounted for 59.7% of identified pathogens. Atypical pathogens were identified in 31.3% of total pathogens, of which viruses accounted for 23.9%. In comparison to patients with bacterial infection, patients with atypical pathogens were younger (median= 77.2 vs 67.1, years, P = 0.017) and had shorter length of hospital (8.0 vs 4.5, days, P = 0.007). Conclusions: Patients with LRTI caused by atypical pathogens was indistinguishable from those with bacterial pathogens by clinical manifestations or biomarkers. Multiplex PCR providing rapid diagnosis of atypical pathogens enhance patient care and decision making when rate of sputum culture sampling was low in quarantine ward during pandemic.

Background/Purpose: Cytomegalovirus (CMV) viremia is associated with a higher mortality rate and prolonged intensive care unit (ICU) stay for critically ill patients. CMV infection causes transient but substantial immunosuppression for transplant recipients, increasing risk of fungal infection. The association between CMV viremia and invasive pulmonary aspergillosis (IPA) for critically ill patients is still unknown. Methods: We retrospectively analyzed patients received bronchoalveolar lavage (BAL), galactomannan test, influenza survey and blood CMV viral load test in ICUs of a university hospital between April 2017 and May 2020. Independent risks for IPA were analyzed by multivariable logistic regression. Results: A total of 136 patients were included. Twenty-one patients had IPA, 48 patients had CMV viremia and 22 patients had influenza. In a multivariable logistic regression model, patients with CMV viremia or influenza had higher IPA risk (adjusted odds ratio, 3.98 and 8.72; 95% CI, 1.26–12.60 and 2.64–28.82; p value = 0.019 and

Abstract Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician’s discretion based on patient’s request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy.

Background/Purpose: Early detection and timely quarantine measures are necessary to control disease spread and prevent nosocomial outbreaks of Coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the impact of a quarantine strategy on patient safety and quality of care. Methods: This retrospective cohort study enrolled patients admitted to the quarantine ward in a tertiary hospital in southern Taiwan. The incidence and causes of acute critical illness, including clinical deterioration and unexpected complications during the quarantine period, were reviewed. Further investigation was performed to identify risk factors for acute critical illness during quarantine. Results: Of 320 patients admitted to the quarantine ward, more than two-thirds were elderly, and 37.8% were bedridden. During the quarantine period, 68 (21.2%) developed acute critical illness, which more commonly occurred among patients older than 80 years and with a bedridden status, nasogastric tube feeding, or dyspnea symptoms. Bedridden status was an independent predictor of acute critical illness. Through optimization of sampling for COVID-19 and laboratory schedules, both the duration of quarantine and the proportion of acute critical illness among bedridden patients during quarantine exhibited a decreasing trend. There was no COVID-19 nosocomial transmission during the study period. Conclusion: The quarantine ward is a key measure to prevent nosocomial transmission of COVID-19 but may carry a potential negative impact on patient care and safety. For patients with multiple comorbidities and a bedridden status, healthcare workers should remain alert to rapid deterioration and unexpected adverse events during quarantine.

Abstract Background Although epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) have been the standard treatment for advanced EGFR‐mutant adenocarcinoma, the effects of upfront EGFR‐TKI use in unresectable stage III EGFR‐mutant adenocarcinoma remain unexplored. Here, we conducted a retrospective study to compare different treatment strategies in these patients. Methods From October 2010 to June 2019, patients with unresectable stage III adenocarcinoma who received treatment at a tertiary referral center were enrolled. Patients were classified into three groups: EGFR‐mutant adenocarcinoma treated with concurrent chemoradiotherapy (group 1) or EGFR‐TKI (group 2) and EGFR wild‐type adenocarcinoma treated with concurrent chemoradiotherapy (group 3). Progression‐free survival, progression‐free survival‐2, and overall survival were estimated and compared using Kaplan–Meier and log‐rank tests. Results A total of 92 patients were enrolled; 10, 40, and 42 patients were assigned to groups 1, 2, and 3, respectively. Patients with EGFR mutations who received upfront EGFR‐TKIs had significantly longer progression‐free and overall survival than those who received upfront concurrent chemoradiotherapy (hazard ratio 0.33 vs. 0.34, p = 0.006 vs. 0.031) according to a Cox model adjusted for possible confounders. Moreover, upfront concurrent chemoradiotherapy did not lead to higher survival rates in patients with EGFR mutations than in those with EGFR wild‐type adenocarcinoma (progression‐free survival; hazard ratio 0.37, p = 0.036; overall survival; hazard ratio 0.35, p = 0.080) by Cox regression analysis. Conclusion This current study suggests that EGFR‐TKIs is a better choice for patients with unresectable stage III EGFR‐mutant adenocarcinoma. However, further randomized studies are required to validate the results.

Abstract C‐ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement has been detected in patients with advanced non‐small cell lung cancer (NSCLC). Although ROS1 tyrosine kinase inhibitors (TKIs) provide a survival benefit for patients with ROS1‐rearranged advanced NSCLC, subsequent therapy remains limited. Small cell transformation is an important mechanism of drug resistance in epidermal growth factor receptor‐mutant NSCLC. However, its significance in mediating ROS1 resistance has not been determined yet. Here, we present the case of a 63‐year‐old man with ROS1‐rearranged advanced NSCLC who had disease progression with small cell transformation of the mediastinal lymph node after 8 months of treatment with crizotinib. More importantly, fluorescence in situ hybridization of post‐progression tumor biopsy demonstrated retention of ROS1 rearrangement. Tissue biopsy remains indispensable for patients who acquire resistance to ROS1 TKIs.

Background: Recent study showed that the combination of erlotinib and bevacizumab had better disease control than erlotinib monotherapy in patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, there is lack of real-world evidence for this therapeutic regimen. We aimed to compare outcomes between patients with EGFR mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) and bevacizumab and those treated with EGFR-TKI alone in a real-world setting. Methods: Patients with advanced EGFR-mutant NSCLC who received first-line EGFR-TKI in a tertiary referral center from October 1, 2013 to December 31, 2019 were retrospectively analyzed. We performed 1:2 propensity score-matching: one EGFR-TKI and bevacizumab recipient with two patients who received EGFR-TKI alone. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan–Meier method. The prognostic factors were analyzed using Cox proportional hazards regression analysis. Results: Total 313 patients were enrolled. After propensity score matching, 45 patients who received first-line EGFR-TKI and bevacizumab and 89 patients who received EGFR-TKI alone were analyzed. The combination group showed improved PFS (17.0 vs. 11.0 months; hazard ratio [HR] = 0.48; p = 0.002) compared to the monotherapy group. In subgroup analysis of patients with an L858R mutation, the combination group showed longer PFS (23.1 vs. 10.7 months; HR = 0.40; p = 0.011) and OS (not reached vs. 40.6 months; HR = 0.27; p = 0.040) than the EGFR-TKI monotherapy group. Conclusion: Our data suggest that the combination of EGFR-TKI and bevacizumab could improve PFS in patients with EGFR-mutant NSCLC. In patients harboring L858R mutation, the combination therapy provides better OS than TKI alone.

Abstract Tyrosine kinase inhibitors (TKIs) are the standard treatment for epidermal growth factor receptor (EGFR)‐mutant advanced‐stage non‐small cell lung cancer (NSCLC). However, TKIs can cause some severe adverse events, which are more prevalent within first‐generation EGFR‐TKI use than with second‐generation inhibitors. Herein, we report a case of a patient with advanced‐stage EGFR‐mutant NSCLC who developed drug reaction with eosinophilia and systemic symptoms (DRESS) after receiving treatment with afatinib. The patient was successfully rechallenged with erlotinib, without manifestations of skin rash in the following 6 months. Hence, erlotinib may be considered a potential substitute for other EGFR‐TKIs following DRESS occurrence.

Telisotuzumab vedotin is a MET-targeting antibody–drug conjugate that has demonstrated a good treatment response in patients with EGFR wild-type MET-overexpressing non-squamous non-small cell lung cancer. However, patients have been reported to acquire resistance to this drug, and the subsequent therapy has not been standardized. Here, we present a case of a 56-year-old woman diagnosed with KIF5B-MET fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.

Abstract Left ventricular (LV) global peak systolic longitudinal strain (GLS) is a sensitive measurement for detecting subtle LV systolic dysfunction and a powerful prognostic predictor. However, the clinical implication of LV GLS in lymphoma patients receiving cancer therapy remains unknown. We prospectively enrolled 74 lymphoma patients (57.9 ± 17.0 years old, 57% male). We performed echocardiographic studies after the 3rd and 6th cycles and 1 year after chemotherapy and a cardiopulmonary exercise test upon completion of 3 cycles of anticancer therapy. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥ 15% relative reduction in GLS value from baseline. The primary outcome was a composite of all-cause mortality and heart failure events. Thirty-six patients (49%) had CTRCD (LV GLS: baseline vs. after 3rd cycle of therapy: 20.1 ± 2.6 vs. 17.5 ± 2.3%, p

Abstract Background Few studies have compared the efficacy of the irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), afatinib, with that of reversible EGFR‐TKIs. Therefore, this study assessed the effectiveness of afatinib, erlotinib, and gefitinib in terms of OS (overall survival) and progression‐free survival (PFS) in EGFR mutation‐positive advanced non‐small cell lung cancer (NSCLC) patients. Methods Patients with EGFR mutation‐positive advanced NSCLC who sought treatment from December 2013 to June 2018, at a tertiary referral center were retrospectively analyzed. These patients were treated with afatinib or a reversible EGFR‐TKI (erlotinib or gefitinib) until disease progression, intolerable adverse events, or death. The Kaplan‐Meier and log‐rank tests were then used to compare the OS and PFS of the patients. We further analyzed the survival differences among the subgroup of patients without brain metastases. Results Of the 363 patients enrolled, 134 and 229 received first‐line afatinib and first‐line reversible EGFR‐TKI, respectively. Those given afatinib had better OS (39.3 vs. 26.0 months; HR 0.65, P = 0.033) and PFS (14.1 vs.11.2 months; HR 0.58, P

Background: Critically compromised by upper airway anatomical impaired properties, obstructive sleep apnea (OSA) can be categorized into different phenotypic traits, mainly including oropharyngeal muscle dysfunction. The upper airway muscle strength training was targeted on oropharyngeal muscle dysfunction by re-educating the oropharyngeal muscles to maintain the upper airway patency. OSA was characterized with multilevel collapsibility of the upper airway; however, the programs are still inconsistent and the effects are unknown. Therefore, the purpose of this study was to investigate the effects of a comprehensive physical therapy on OSA. Methods: Fifteen subjects with newly diagnosed moderate or severe OSA (AHI ≥ 15) were randomized into intervention and control groups. The intervention group underwent a 12-week-intervention of hospital based physical therapy, while the control group was kept on waiting for 12 weeks. Polysomnography (PSG) data, oropharyngeal and respiratory muscle performance were measured before and after intervention. Results: In intervention group (n = 8), AHI was significantly improved (from 46.96 ± 19.45 to 32.78 ± 10.78 events/h, p = 0.017); in control group (n = 7), AHI was significantly increased (from 35.77 ± 17.49 to 42.96 ± 17.32 events/h, p = 0.043). While the control group remained no change between pre- and post- intervention, the intervention group demonstrated that other PSG outcomes significantly improved, including arousal index (46.04 ± 18.9 versus 32.98 ± 8.35/h), mean SpO2 (92.88 ± 2.1 versus 94.13 ± 1.46%), and oxygen desaturation index (ODI) (31.13 ± 19.48 versus 20.57 ± 7.83/h). Conclusion: This comprehensive physical therapy can be prescribed for the significant clinical improvement on sleep apnea for the patients with moderate and severe OSA.

BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy.

Introduction: Patients with stage III NSCLC represent a very heterogenous group that requires different treatment strategies, especially in patients with N2 (2 nearby lymph nodes having cancer)-positive NSCLC and unresectable EGFR-mutant NSCLC. This real-world study may provide more insights into treatment decisions. Methods: The KINDLE study is a large, multinational real-world observational study that assessed different treatment strategies in patients with stage III NSCLC. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using Kaplan-Meier and log-rank testing. Patients were classified on the basis of disease stage, resectability, and treatment modalities. Results: The Taiwan subgroup enrolled 200 patients. The median PFS and OS values were similar among patients with stage IIIA and stage IIIB disease, but were significantly better in patients who were deemed as a resectable disease than in those who were deemed as an unresectable disease. In patients with N2-positive NSCLC, patients who underwent surgery had better PFS, but not OS, than patients administered with chemoradiotherapy (CRT) (PFS 13.4 vs. 7.3 mo, hazard ratio [HR] = 0.18, p < 0.001; OS 32.4 vs. 22.0 mo, HR = 0.64, p = 0.215). Among patients with unresectable EGFR-mutant NSCLC, OS was significantly poorer after upfront EGFR–tyrosine kinase inhibitors (TKI) than after upfront CRT with sequential EGFR-TKI (27.4 vs. 49.0 mo, HR = 3.09, p = 0.03). Conclusions: Our study suggests that surgery could be added as part of therapy for patients with stage III N2-positive NSCLC. Moreover, upfront CRT with sequential EGFR-TKI seems to be appropriate for stage III unresectable EGFR-mutant NSCLC. Further randomized studies are needed to validate these results.

The use of immune checkpoint inhibitors (ICIs) has provided overall survival (OS) benefits in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, studies comparing ICIs monotherapy with combination therapy either with chemotherapy or radiotherapy in programmed death-ligand 1 high expressors remain limited. This study aimed to retrospectively compare the treatment efficacy of the therapies by studying 47 patients with treatment-naïve advanced NSCLC who received ICI monotherapy (n = 28) or combination therapy either with chemotherapy or radiotherapy (n = 19). Progression-free survival (PFS) and OS were estimated using the Kaplan–Meier method and compared using log–rank tests. It was observed that patients who received combination therapy had a better PFS than monotherapy, but no such significant benefit was observed in OS. The difference in PFS was higher in the subgroup of patients with low neutrophil-to-lymphocyte ratio (NLR) than in the high-NLR patient subgroup. This study suggests that pembrolizumab in combination with chemotherapy or radiotherapy could provide a significant benefit in PFS, especially in patients with treatment-naïve advanced NSCLC with low NLR. Furthermore, our study also demonstrates the potential use of NLR as a biomarker for prediction of treatment outcomes in patients with advanced NSCLC receiving combination therapy.

Targeted therapy with combined dabrafenib and trametinib has been proven to provide clinical benefits in patients with NSCLC with a BRAF V600E mutation. Nevertheless, the treatment strategy for patients with NSCLC with BRAF non-V600E mutations remains limited. Here, we present a patient with NSCLC with a BRAF K601E mutation, a class II BRAF mutation, who had a durable response to targeted therapy with combined dabrafenib and trametinib.

Abstract Background Osimertinib yields significant tumor responses and durations of progression‐free survival (PFS) in patients with acquired T790M mutations. However, the evidence supporting liquid biopsy‐guided treatment is still limited. This study examined the real‐world benefits of osimertinib in patients with tissue or plasma T790M mutations. Methods From January 2016 to June 2018, a total of 183 non‐small‐cell lung cancer patients were enrolled. The presence of the T790M mutation was assessed by either tissue or plasma. The PFS, overall survival, and tumor response rates of the patients were calculated and compared with those of previous clinical trials. Results T790M mutations were detected in 51.5% of the patients, including 64 of 140 (45.7%) who underwent liquid biopsies and 23 of 29 (79.3%) who underwent tumor biopsies. After excluding those in clinical trials, 46 patients received osimertinib, including 33 with positive plasma and 13 with positive tissue results for T790M mutations. The median PFS was 11.3 months (interquartile range: 5.2‐NR) in all the T790M‐positive patients and 10.1 months (interquartile range: 5.9‐NR) in the plasma T790M‐positive patients. The overall survival, meanwhile, was not reached, whereas the one‐year survival rate was 66.1% in all the patients and 61.4% in those who were plasma T790M‐positive. The objective response rate and disease control rate were 37.8% and 91.9% in all the patients and 34.6% and 92.3% in the plasma T790M‐positive group, respectively. Using a Cox proportional hazards regression, we determined that male gender was a poor prognostic factor for PFS. Conclusions In this retrospective real‐world analysis, it was determined that both tissue and plasma T790M mutations can be used to guide treatment with osimertinib. Similar disease control rates and survival durations were observed in comparison to those of phase 3 clinical trials.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear. Materials and methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for 5 Y group. Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and

In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Primary effusion lymphoma (PEL) is a rare subtype of non‐Hodgkin's lymphoma. PEL is closely related in pathogenesis to human herpesvirus 8 (HHV‐8) and typically occurs in patients with significant immunodeficiency. Cases of PEL in patients without either HIV infection or transplantation have been reported from HHV‐8‐endemic areas, but very rarely from the Asia‐Pacific region. In this case series, we describe the clinical and immunohistochemical presentations of four patients in southern Taiwan who were diagnosed with HHV‐8‐related PEL. All four patients were HIV‐negative and had not received organ transplantation. To our knowledge, this is the first authentic report of HIV‐unrelated PEL from the ethnically Chinese population. Considering the non‐specific clinical manifestations, the pivotal roles of specific assays for correct diagnosis, and the dismal prognosis of PEL, it is important for clinicians to include PEL as one of the differential diagnosis when approaching HIV‐uninfected patients with unexplained exudative body cavity effusion.

This study delineated the characteristics of 24 (11.2%) culture-positive, influenza-associated pulmonary aspergillosis (IAPA) patients out of 215 patients with severe influenza during 2016–2019 in a medical center in southern Taiwan. Twenty (83.3%) patients did not have EORTC/MSG-defined host factors. The mean time from influenza diagnosis to Aspergillus growth was 4.4 days, and 20 (83.3%) developed IAPA within seven days after influenza diagnosis. All patients were treated in intensive care units and all but one (95.8%) received mechanical ventilation. Aspergillus tracheobronchitis was evident in 6 (31.6%) of 19 patients undergoing bronchoscopy. Positive galactomannan testing of either serum or bronchoalveolar lavage was noted in all patients. On computed tomography imaging, IAPA was characterized by peribronchial infiltrates, multiple nodules, and cavities superimposed on ground-glass opacities. Pure Aspergillus growth without bacterial co-isolation in culture was found in 17 (70.8%) patients. A. fumigatus (15, 62.5%), A. flavus (6, 25.0%), and A. terreus (4, 16.7%) were the major causative species. Three patients had mixed Aspergillus infections due to two species, and two had mixed azole-susceptible and azole-resistant A. fumigatus infection. All patients received voriconazole with an all-cause mortality of 41.6%. Of 14 survivors, the mean duration of antifungal use was 40.5 days. In conclusion, IAPA is an early and rapidly deteriorating complication following influenza that necessitates clinical vigilance and prompt diagnostic workup.

Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase inhibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we profiled EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells’ sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefitinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC.

Introduction: Brain metastases (BM) are common in advanced non-small cell lung cancer (NSCLC), and the prognosis is poor with few therapeutic options. This study evaluated the efficacy of three epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in preventing and treating BM in patients with EGFR mutation-positive advanced NSCLC. Methods: Patients with EGFR mutation-positive advanced NSCLC who visited a tertiary referral center from 1 December 2013 to 30 November 2017 were analyzed retrospectively. They received gefitinib, erlotinib, or afatinib until disease progression, death, or intolerable adverse events. The cumulative incidence of subsequent BM of initial non-BM patients, progression-free survival (PFS), and overall survival (OS) of the BM and non-BM patients were estimated and compared using the Kaplan–Meier and log-rank tests. Results: 306 NSCLC patients were enrolled, with 116, 75, and 115 receiving first-line gefitinib, erlotinib, and afatinib, respectively. The afatinib group had a better PFS [12.7 versus 9.8 months; hazard ratio (HR) 0.59, p = 0.001] and OS (39.1 versus 22.0 months; HR 0.64, p = 0.035) than the gefitinib group. Afatinib tended to provide better BM prevention than gefitinib (BM cumulative incidence, HR 0.49; 95% confidence interval 0.34–0.71, p

Previous studies have demonstrated the association between EGFR mutations and distant metastasis. However, the association for subsequent brain metastasis (BM) in stages I-III non-small cell lung cancer (NSCLC) patients remains inconclusive. We conducted a retrospective analysis to clarify the impact of EGFR mutations on the incidence of BM and associated survival in patients with stage I-III NSCLC. A total of 491 patients screened for EGFR mutations were retrospectively enrolled. Brain MRI or CT was used to detect the BM. Cumulative incidence of subsequent BM and overall survival (OS) after diagnosis of BM were estimated by the Kaplan-Meier method and compared using log-rank test. We performed Cox proportional hazard regression for predictors of subsequent BM and determinants of OS after BM. The cumulative incidence of BM seemed higher in patients harboring EGFR mutations than those without EGFR mutations although it did not reach statistical significance (hazard ratio [HR] = 1.75, 95% confidence interval [CI] = 0.73~1.81). After adjusting possible confounders, including age, smoking, stage, and tumor size, EGFR mutation became one of the predictors for subsequent BM (HR = 1.89, 95% CI = 1.12~3.17, p = 0.017). Though there was no statistical difference in survival after BM between patients with EGFR mutations and wild-type EGFR (median survival: 17.8 vs. 12.2 months, HR = 0.79, 95% CI = 0.45-1.40), patients with EGFR 19 deletion (Del) tended to have a longer survival after BM than the non-EGFR 19 Del group (median survival: 29.4 vs. 14.3 months, HR 0.58, 95% CI = 0.32-1.09, p = 0.089). In conclusion, our data suggested EGFR mutation to be one of the predictors for subsequent BM in stage I-III patients. Given the small sample size, more studies are warranted to corroborate our results.