Increased Tuberculosis Reactivation Risk in Patients Receiving Immune Checkpoint Inhibitor-Based Therapy.

OBJECTIVE: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI). METHODS: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI. RESULTS: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, P = .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, P = .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, P = 0.035) under multivariable Cox regression. CONCLUSION: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection.

bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA).

Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)-engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates, we show that there is considerable flexibility in both the choice of substrate binders (binding positions, scaffold-class) and the E3 ligases. We then identified a highly effective bioPROTAC against an oncology target, proliferating cell nuclear antigen (PCNA) to elicit rapid and robust PCNA degradation and associated effects on DNA synthesis and cell cycle progression. Overall, bioPROTACs are powerful tools for interrogating degradation approaches, target biology, and potentially for making therapeutic impacts.

Real-world effectiveness of second-line Afatinib versus chemotherapy for the treatment of advanced lung squamous cell carcinoma in immunotherapy-naïve patients.

BACKGROUND: Limited treatment options exist for relapsed advanced lung squamous cell carcinoma (SCC), leading to poor outcomes compared with adenocarcinoma. This study aimed to investigate the efficacy of second-line afatinib versus chemotherapy in patients with advanced lung SCC who progressed after first-line chemotherapy. METHODS: In this retrospective, multisite cohort study, we recruited patients with initial locally advanced or metastatic lung SCC from four institutes in Taiwan between June 2014 and October 2020. The primary endpoint of this study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: The present study enrolled 108 patients: 19 received second-line afatinib, and 89 received second-line chemotherapy. The median ages were 71 and 67 years, respectively. PFS was significantly longer among patients who received afatinib than among those who received chemotherapy (median 4.7 months [95% confidence interval (CI), 0.1-7.5] vs. 2.6 months [95% CI, 0.9-6.7]; hazard ratio (HR) 0.53 [95% CI 0.32-0.88], p = 0.013). Compared with the chemotherapy group, OS was longer in the afatinib group but did not reach significance (median 16.0 months [95% CI, 6.1-22.0] vs. 12.3 months [6.2-33.9]; HR 0.65 [95% CI 0.38-1.11], p = 0.112). CONCLUSIONS: Afatinib offered a longer PFS and comparable OS to chemotherapy in advanced lung SCC patients in a real-world setting, it may be considered as a 2nd line alternative treatment choice for immunotherapy unfit advanced lung SCC patients.

COSORE: A community database for continuous soil respiration and other soil-atmosphere greenhouse gas flux data.

Globally, soils store two to three times as much carbon as currently resides in the atmosphere, and it is critical to understand how soil greenhouse gas (GHG) emissions and uptake will respond to ongoing climate change. In particular, the soil-to-atmosphere CO2 flux, commonly though imprecisely termed soil respiration (RS ), is one of the largest carbon fluxes in the Earth system. An increasing number of high-frequency RS measurements (typically, from an automated system with hourly sampling) have been made over the last two decades; an increasing number of methane measurements are being made with such systems as well. Such high frequency data are an invaluable resource for understanding GHG fluxes, but lack a central database or repository. Here we describe the lightweight, open-source COSORE (COntinuous SOil REspiration) database and software, that focuses on automated, continuous and long-term GHG flux datasets, and is intended to serve as a community resource for earth sciences, climate change syntheses and model evaluation. Contributed datasets are mapped to a single, consistent standard, with metadata on contributors, geographic location, measurement conditions and ancillary data. The design emphasizes the importance of reproducibility, scientific transparency and open access to data. While being oriented towards continuously measured RS , the database design accommodates other soil-atmosphere measurements (e.g. ecosystem respiration, chamber-measured net ecosystem exchange, methane fluxes) as well as experimental treatments (heterotrophic only, etc.). We give brief examples of the types of analyses possible using this new community resource and describe its accompanying R software package.

Xeromorphic traits help to maintain photosynthesis in the perhumid climate of a Taiwanese cloud forest.

Previous flux measurements in the perhumid cloud forest of northeastern Taiwan have shown efficient photosynthesis of the endemic tree species Chamaecyparis obtusa var. formosana even under foggy conditions in which leaf surface moisture would be expected. We hypothesized this to be the result of 'xeromorphic' traits of the Chamaecyparis leaves (hydrophobicity, stomatal crypts, stomatal clustering), which could prevent coverage of stomata by precipitation, fog, and condensation, thereby maintaining CO2 uptake. Here we studied the amount, distribution, and composition of moisture accumulated on Chamaecyparis leaf surfaces in situ in the cloud forest. We studied the effect of surface tension on gas penetration to stomata using optical O2 microelectrodes in the laboratory. We captured the dynamics of condensation to the leaf surfaces with an environmental scanning electron microscope (ESEM). In spite of substantial surface hydrophobicity, the mean water film thickness on branchlets under foggy conditions was 80 µm (upper surface) and 40 µm (lower surface). This amount of water could cover stomata and prevent CO2 uptake. This is avoided by the clustered arrangement of stomata within narrow clefts and the presence of Florin rings. These features keep stomatal pores free from water due to surface tension and provide efficient separation of plant and atmosphere in this perhumid environment. Air pollutants, particularly hygroscopic aerosol, may disturb this functionality by enhancing condensation and reducing the surface tension of leaf surface water.

Identification of the two KIT isoforms and their expression status in canine hemangiosarcomas.

BACKGROUND: KIT is a tyrosine kinase growth factor receptor. High expression of KIT has been found in several tumors including canine hemangiosarcoma (HSA). This study investigated the correlation of KIT expression and c-kit sequence mutations in canine HSAs and benign hemangiomas (HAs). RESULTS: Immunohistochemistry (IHC) staining confirmed KIT expression in 94.4 % (34/36) of HSAs that was significantly higher than 0 % in HAs (0/16). Sequencing the entire c-kit coding region of HSAs and normal canine cerebellums (NCCs) revealed GNSK-deletion in exon 9. As for exon 9 genotyping by TA-cloning strategy, GNSK-deletion c-kit accounted for 48.6 % (68/140) colonies amplified from12 KIT-positive HSAs, a significantly higher frequency than 14.1 % (9/64) of colonies amplified from six NCCs. CONCLUSIONS: Due to the distinct expression pattern revealed by IHC, KIT might be used to distinguish benign or malignant vascular endothelial tumors. Moreover, the high incidence of GNSK-deletion c-kit in canine HSAs implicates KIT isoforms as possibly participating in the tumorigenesis of canine HSAs.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7(-) effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.

Development of highly selective Kv1.3-blocking peptides based on the sea anemone peptide ShK.

ShK, from the sea anemone Stichodactyla helianthus, is a 35-residue disulfide-rich peptide that blocks the voltage-gated potassium channel Kv1.3 at ca. 10 pM and the related channel Kv1.1 at ca. 16 pM. We developed an analog of this peptide, ShK-186, which is currently in Phase 1b-2a clinical trials for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. While ShK-186 displays a >100-fold improvement in selectivity for Kv1.3 over Kv1.1 compared with ShK, there is considerable interest in developing peptides with an even greater selectivity ratio. In this report, we describe several variants of ShK that incorporate p-phophono-phenylalanine at the N-terminus coupled with internal substitutions at Gln16 and Met21. In addition, we also explored the combinatorial effects of these internal substitutions with an alanine extension at the C-terminus. Their selectivity was determined by patch-clamp electrophysiology on Kv1.3 and Kv1.1 channels stably expressed in mouse fibroblasts. The peptides with an alanine extension blocked Kv1.3 at low pM concentrations and exhibited up to 2250-fold selectivity for Kv1.3 over Kv1.1. Analogs that incorporates p-phosphono-phenylalanine at the N-terminus blocked Kv1.3 with IC50s in the low pM range and did not affect Kv1.1 at concentrations up to 100 nM, displaying a selectivity enhancement of >10,000-fold for Kv1.3 over Kv1.1. Other potentially important Kv channels such as Kv1.4 and Kv1.6 were only partially blocked at 100 nM concentrations of each of the ShK analogs.

Conformational flexibility in the binding surface of the potassium channel blocker ShK.

ShK is a 35-residue peptide that binds with high affinity to human voltage-gated potassium channels through a conserved K-Y dyad. Here we have employed NMR measurements of backbone-amide (15)N spin-relaxation rates to investigate motions of the ShK backbone. Although ShK is rigid on the ps to ns timescale, increased linewidths observed for 11 backbone-amide (15)N resonances identify chemical or conformational exchange contributions to the spin relaxation. Relaxation dispersion profiles indicate that exchange between major and minor conformers occurs on the sub-millisecond timescale. Affected residues are mostly clustered around the central helix-kink-helix structure and the critical K22-Y23 motif. We suggest that the less structured minor conformer increases the exposure of Y23, known to contribute to binding affinity and selectivity, thereby facilitating its interaction with potassium channels. These findings have potential implications for the design of new channel blockers based on ShK.

Mammography and the risk of thyroid and hematological cancers: a nationwide population-based study.

To investigate the association between thyroid cancer as well as the most radiosensitive hematological cancers and radiation exposure from mammography. This study used information from a random sample of two million persons enrolled in the nationally representative Taiwan National Health Insurance (NHI) Research Database. The exposed group was composed of women aged 18-65 who had undergone diagnostic mammography between 2000 and 2007. The nonexposed control group was composed of women in the NHI database who had never undergone diagnostic mammography. There were 25,362 women in the exposed group and 203,317 women in the nonexposed group. After adjusting for age and comorbidities, the patients who had been exposed to radiation from mammography did not have a significantly higher risk of developing thyroid cancer and hematological cancers (adjusted HR, 1.201; 95% CI, 0.813-1.774 for thyroid cancer and adjusted HR, 1.228; 95% CI, 0.838-1.800 for hematological cancers). The scattered radiation dose delivered by mammography should be cautiously handled, but no additional concerns about the risk of thyroid cancer developing malignancy should be emphasized.

Comparative chest computed tomography findings of non-tuberculous mycobacterial lung diseases and pulmonary tuberculosis in patients with acid fast bacilli smear-positive sputum.

BACKGROUND: Early diagnosis and treatment of nontuberculous mycobacterial lung diseases (NTM-LD) and pulmonary tuberculosis (PTB) are important clinical issues. The present study aimed to compare and identify the chest CT characteristics that help to distinguish NTM lung disease from PTB in patients with acid-fast bacilli (AFB) smear-positive sputum. METHODS: From January 2009 to April 2012, we received 467 AFB smear-positive sputum specimens. A total of 95 CT scans obtained from the 159 patients were analyzed, 75 scans were from patients with PTB and 20 scans from NTM-LD. The typical chest CT findings of mycobacterial diseases were analyzed. RESULTS: In patients with PTB, the prevalence of pleural effusion (38.7% vs. 15.0%; P = 0.047), nodules < 10 mm in size (76.0% vs. 25.0%; P < 0.001), tree-in-bud pattern (81.3% vs. 55.0%; P = 0.021), and cavities (31.1% vs. 5.0%; P = 0.018) were significantly higher than patients with NTM. Of the 20 patients with NTM lung diseases, bronchiectasis and cystic changes were significantly higher than patients with PTB (20.0% vs. 4.0%; P = 0.034). In multivariate analysis, CT scan findings of nodules was independently associated with patients with diagnoses of PTB (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.02-0.30). Presence of bronchiectasis and cystic changes in CT scans was strongly associated with patients with NTM-LD (OR, 33.04; 95% CI, 3.01-362.55). CONCLUSIONS: The CT distinction between NTM-LD and PTB may help radiologists and physicians to know the most likely diagnoses in AFB-smear positive patients and avoid unnecessary adverse effects and the related costs of anti-TB drugs in endemic areas.

Exploring the evolution of T cell function and diversity across different stages of non-small cell lung cancer.

The immune system plays a key role in detecting and fighting cancerous tumors. T cells are a crucial component in both natural and therapeutic cancer immunoediting responses, but it is unclear if they are the primary agents of these processes. In this study, patients with lung lesions detected by CT scan were selected, and their peripheral blood samples were analyzed for T cell population and serum cytokines/chemokines. T cell subtypes (CD3, CD4, CD8, CD27, CD28, CD45, CD45RA, CD57, CCR7, and PD1) and serum cytokines/chemokines (IL-2, IL-6, IL-10, IFN-γ, TGF-ß, TNFα, CXCL1, CXCL9, and CXCL12) were measured by flow cytometry and analysis before surgical resection or other cancer treatments. The frequency of T cell subpopulations in patients with lung cancer (n = 111) corresponded to those seen in patients with T cell exhaustion. As lung cancer progressed, the proportion of effector memory T cells decreased, while the proportion of naive T cells, PD-1, CD57+, CD28+CD27+, CD45RA+, and CD3+CD4+CCR7 increased. Circulating CD8+PD1+ T cells were positively correlated with intra-tumoral PD-L1 expression. Concurrently, serum levels of IL-2, TGF-ß, and CXCL9 decreased, while IL-6, IL-10, IFN-γ, and CXCL12 increased during the progression of lung cancer. In conclusion, T cell dysfunction is associated with cancer progression, particularly in advanced-stage lung cancer, and cancer immunoediting will provide early-stage cancer detection and further therapeutic strategies.

The risk of cataract associated with repeated head and neck CT studies: a nationwide population-based study.

OBJECTIVE: Medical radiation-induced cataracts, especially those resulting from head and neck CT studies, are an issue of concern. The current study aimed to determine the risk of cataract associated with repeated radiation exposure from head and neck CT. MATERIALS AND METHODS: This study used information from a random sample of 2 million persons enrolled in the nationally representative Taiwan National Health Insurance Research Database. Exposed cases consisted of patients with head and neck tumor 10-50 years old who underwent at least one CT between 2000 and 2009. The nonexposed control group was composed of subjects who were never exposed to CT studies but who were matched by time of enrollment, age, sex, history of coronary artery disease, hypertension, and diabetes. RESULTS: There were 2776 patients in the exposed group and 27,761 matched subjects in the nonexposed group. The exposed group had higher overall incidence of cataracts (0.97% vs 0.72%; adjusted hazard ratio [HR], 1.76; 95% CI, 1.18-2.63). Further stratifying the number of CT studies in the exposed group into one or two, three or four, and five or more revealed that cataract incidence increased gradually with increasing frequency of CT studies (0.79%, 0.93%, and 1.45%, respectively) (p=0.001, adjusted for trend). Radiation exposure due to repeated head and neck CT studies was independently associated with an increased risk of developing cataracts when the cumulative CT exposure frequency involved more than four studies (adjusted HR, 2.12; 95% CI, 1.09-4.14). CONCLUSION: Repeated exposure to head and neck CT is significantly associated with increased risk of cataract.

Photoluminescent toroids formed by temperature-driven self-assembly of rhodamine B end-capped poly(N-isopropylacrylamide).

In this paper, self-assembled polymeric toroids formed by a temperature-driven process are reported. Rhodamine B (RhB) end-capped poly(N-isopropylacrylamide) (PNIPAAm) demonstrating a lower critical solution temperature (LCST) is prepared. In a two-phase system, the polymer in the aqueous phase could move to the chloroform phase on raising the temperature above its LCST. This temperature-driven process results in the formation of polymeric toroids in the chloroform phase, and the strategy affords a new pathway to toroidal self-assembly of polymers. Moreover, the photoluminescent behavior of the RhB end-capped PNIPAAm species formed by the process is also studied and discussed.

Investigation the electroplating behavior of self formed CuMn barrier.

The electrical and material properties of Copper (Cu) mixed with [0-10 atomic% manganese (Mn)] and pure Cu films deposited on silicon oxide (SiO2)/silicon (Si) are explored. Cu electroplating on self formed CuMn barrier was investigated with different Mn content. The electrochemical deposition of the Cu thin film onto the electrode using CuMn barrier was investigated. Scanning electron microscopic (SEM) micrographs of copper electroplating on CuMn films were examined, and the copper nucleation behaviors changed with the Mn content. Since the electrochemical impedance spectroscopy (EIS) is widely recognized as a powerful tool for the investigation of electrochemical behaviors, the tool was also used to verify the phenomena during plating. It was found that the charge-trasfer impedance decrease with the rise in the Mn content below 5%, but increase with the rise in the Mn content higher than 5%. The result was corresponded to the surface energy, the surface morphology, the corrosion and the oxidation of the substrate.

High glucose concentration up-regulates the expression of matrix metalloproteinase-9 and -13 in tendon cells.

BACKGROUND: Diabetes mellitus is associated with tendinopathy or tendon injuries. However, the mechanism underlying diabetic tendinopathy is unclear. The purpose of this study was to examine the effects of high glucose concentrations on the activity and expression of matrix metalloproteinases, type I collagen, and type III collagen in tendon cells. METHODS: Tendon cells from rat Achilles tendons were treated with 6 mM, 12 mM, and 25 mM glucose, and then cell proliferation was evaluated by the 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Messenger RNA (mRNA) expression of MMP-2, MMP-8, MMP-9, and MMP-13 and type I and type III collagen was assessed by quantitative real-time polymerase chain reaction (PCR). The enzymatic activity of MMP-2 and MMP-9 was measured by gelatin zymography. RESULTS: The MTT assay results showed that the glucose concentration did not affect tendon cell proliferation. The results of the real-time PCR assay revealed that the mRNA expression of MMP-9 and MMP-13 was up-regulated by treatment with 25 mM glucose, whereas the mRNA expression of type I and III collagen was not affected. Gelatin zymography showed that 25 mM glucose increased the enzymatic activity of MMP-9. CONCLUSIONS: High glucose concentration up-regulates the expression of MMP-9 and MMP-13 in tendon cells, which may account for the molecular mechanisms underlying diabetic tendinopathy.

Abnormal renal resistive index in patients with mild-to-moderate chronic obstructive pulmonary disease.

BACKGROUND: Arterial rigidity and endothelial dysfunction are systemic manifestations of chronic obstructive pulmonary disease (COPD). The decrease in renal vascular resistance in order to adapt the increase in glomerular filtration rate after oral protein loading is known as normal renal functional reserve. We tested the hypothesis that COPD patients, even in those with mild-to-moderate airflow obstruction, are affected by systemic inflammation associated with abnormal renal functional reserve. MATERIALS AND METHODS: The study enrolled 24 current smokers with a cigarette smoking history ≥ 25 pack-years and 8 nonsmokers with normal spirometry as control. Doppler sonography detected the renal resistive index (RRI) before and after oral protein loading to determine the renal functional reserve. Pulmonary function and serum tumor necrosis factor α (TNF-α) levels were analyzed to compare with the renal functional reserve. RESULTS: The smokers were stratified into 3 groups (Group 1: smokers with normal spirometry, Group 2: mild COPD, Group 3: moderate COPD); nonsmokers as Group 4. The baseline RRI levels were similar in Group 1 and Group 4. After protein loading, the RRI elevated in all smoking groups; moreover, Group 3 had the highest RRI and with longer duration than other groups. The smokers with higher serum TNF-α levels had a longer RRI elevation. Multiple linear regression revealed forced expiratory volume in one second (FEV1), serum TNF-α levels and aging were independently predictive factors of impaired renal functional reserve. CONCLUSIONS: A greater impairment in renal functional reserve of COPD patients was correlated with more severe airway obstruction and inflammation.

Synergic Effect of Robot-Assisted Rehabilitation and Antispasticity Therapy: A Narrative Review.

BACKGROUND: Stroke and spinal cord injury are neurological disorders that cause disability and exert tremendous social and economic effects. Robot-assisted training (RAT), which may reduce spasticity, is widely applied in neurorehabilitation. The combined effects of RAT and antispasticity therapies, such as botulinum toxin A injection therapy, on functional recovery remain unclear. This review evaluated the effects of combined therapy on functional recovery and spasticity reduction. MATERIALS AND METHODS: Studies evaluating the efficacy of RAT and antispasticity therapy in promoting functional recovery and reducing spasticity were systemically reviewed. Five randomized controlled trials (RCTs) were included. The modified Jadad scale was applied for quality assessment. Functional assessments, such as the Berg Balance Scale, were used to measure the primary outcome. Spasticity assessments, such as the modified Ashworth Scale, were used to measure the secondary outcome. RESULTS: Combined therapy improves functional recovery in the lower limbs but does not reduce spasticity in the upper or lower limbs. CONCLUSIONS: The evidence supports that combined therapy improves lower limb function but does not reduce spasticity. The considerable risk of bias among the included studies and the enrolled patients who did not receive interventions within the golden period of intervention are two major factors that should be considered when interpreting these results. Additional high-quality RCTs are required.

Factors associated with outcomes of second-line treatment for EGFR-mutant non-small-cell lung cancer patients after progression on first- or second-generation EGFR-tyrosine kinase inhibitor treatment.

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatments for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) patients. However, factors associated with outcomes after progression on first-line therapy are seldom investigated. Materials and methods: From January 2016 to December 2020, we enrolled 242 EGFR-mutant stage IIIB-IV NSCLC patients who progressed on first- or second-generation EGFR-TKI treatments, and 206 of them receive second-line treatments after disease progression. The factors that predict the survival outcomes of different second-line treatments after disease progression were evaluated. Clinical and demographic characteristics, including metastatic sites, neutrophil-to-lymphocyte ratio (NLR) at first-line progression, and second-line treatment regimens, and whether re-biopsied after disease progression or not, were reviewed for outcome analysis. Results: The univariate analysis showed that the PFS was shorted in male patients (p =0.049), patients with ECOG performance state ≥ 2 (p =0.014), former smokers (p =0.003), patients with brain metastasis (p =0.04), second-line chemotherapy or EGFR-TKIs other than osimertinib (p =0.002), and NLR ≥5.0 (p=0.024). In addition, second-line osimertinib was associated with longer OS compared to chemotherapy and other EGFR-TKI treatment (p =0.001). In the multivariate analysis, only second-line osimertinib was an independent predictor of PFS (p =0.023). Re-biopsy after first-line treatment was associated with a trend of better OS. Patients with NLR ≥5.0 at disease progression had shorter OS than patients with NLR <5.0 (p = 0.008). Conclusion: The benefits of osimertinib necessitate that aggressive re-biopsy after progression on first- or second-generation EGFR-TKI treatment is merited for appropriate second-line treatments to provide better outcomes for these patients.

Real world experience on the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis in Taiwan.

Introduction: Randomized controlled trials have demonstrated a reduction in the decline of lung function and a reduced risk of acute exacerbation in patients with idiopathic pulmonary fibrosis treated with the antifibrotic prifenidone. The present study aimed to investigate the real-world effectiveness and safety profile of pirfenidone treatment for patients with IPF in Taiwan. Methods: Between January 1, 2019 and December 31, 2020, we enrolled 50 patients who were newly diagnosed with IPF and had at least 12 months follow-up period after pirfenidone administration. Result: The primary outcome of pharmacologic effect showed that the mean differences in the absolute values of forced vital capacity from baseline were 0.2 liter (n = 36), 0.13 liter (n = 32), 0.04 liter (n = 26), and - 0.004 liter (n = 26) after 3, 6, 9, and 12 months of administration, respectively. A slight improvement in quality of life, including scores of chronic obstructive pulmonary disease assessment test and St. George's respiratory questionnaire scores. The most common adverse effects were gastrointestinal upset and dermatological problems. No new safety concerns were observed in the present study. Conclusion: Our real-world study describe for the first time in Taiwan, the use of pirfenidone over a 12 months period. This drug preserves the lung function and improves quality of life with tolerable side effects.