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Objectives This study investigated the treatment pattern and the rate of bleeding complications in real-world practice in cancer-associated venous thromboembolism (CT) patients. Methods We used the Korean Health Insurance Review and Assessment Service database (2014–2018). Among patients with venous thromboembolism, patients with concomitant malignancy diagnostic codes were categorized as CT, while all others were categorized as non-CT. Treatments were categorized as direct oral anticoagulant (DOAC), parenteral anticoagulant (PAC), warfarin, and mixed anticoagulants. Results We identified 27,205 CT and 57,711 non-CT patients. DOACs were the most frequently used anticoagulants. The proportion of patients treated with PAC was higher in CT than in non-CT patients (35.7 vs. 19.5%; p Conclusion Five years after their introduction into clinical practice, DOACs have become the most prescribed anticoagulant in Korea. In our patient population, bleeding complications occurred more frequently in CT than in non-CT, especially in patients treated with DOACs.

Thrombopoietin receptor agonists (TPO-RAs) are a reliable second-line immune thrombocytopenia (ITP) treatment. Despite an increase in use of TPO-RAs, the treatment pattern among adults with ITP is not well understood.From January 2015 to December 2018, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database.Of the total 3885 adult patients with ITP, 1745 (44.9%) required treatment, with a median follow-up duration of 31.4 months (range, 0.1-59.8 months). Of these, 46.5% and 36.6% continued treatment for more than 6 months and more than 12 months, respectively. Corticosteroids were the most common first-line therapy. Of the treated patients, 83 (4.8%) received TPO-RAs (eltrombopag, 86.7%; romiplostim, 13.3%). The median age of the group treated with TPO-RAs was 62 years, 62.6% were female, and the median time from first diagnosis to initial TPO-RA treatment was 12.5 months (range, 0.4-48.0 months). A total of 52 (62.7%) patients received TPO-RAs as a second-line treatment for ITP. Splenectomy was performed in 19 patients (22.9%) before initiation of TPO-RAs. When clinical efficacy was analyzed before and during TPO-RA use, there was a significant decrease in platelet transfusion and a tendency toward reduced bleeding events.This population-based study is the first to describe the treatment pattern of TPO-RAs for ITP among patients in Korea.

PURPOSE Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). METHODS Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. RESULTS A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7 months, respectively, for PFS (p = 0.009), and median 21.1 months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. CONCLUSION Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The aim of this study was to investigate the effects of baseline plasma AREG levels in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy. Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The clinical findings were further validated using an in vitro model of CRC. Among 35 patients, the progression-free survival (PFS) was significantly inferior in patients with high AREG than in those with low AREG levels: 10.9 vs. 24.2 months, respectively (p = 0.008). However, after failure of first-line chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months; p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p

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Myeloproliferative neoplasms are rare at a young age, and few reports have described the disease characteristics and outcomes in this group. This study aimed to elucidate the clinical course of essential thrombocythemia (ET) and polycythemia vera (PV) in children and young adults aged

PURPOSE: Acute palliative care units (APCUs) are inpatient services in tertiary hospitals that provide intensive symptom management and assist in hospital discharge for transitions to hospice care. We aimed to analyze the clinical outcomes of operating an APCU at a comprehensive cancer center. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 1,440 consecutive patients admitted to the APCU and analyzed demographic and clinical information, discharge outcomes, symptom assessments using the Edmonton Symptom Assessment System, spiritual distress, and financial distress. RESULTS: The median age of patients was 67.0 (range, 23-97) years, and 41% were female. The most common primary cancer types were lung (21.9%), hepatopancreatobiliary (14.1%), and colorectal cancers (12.9%). The median length of stay was 8.0 days (range, 1-60 days), and 31.0% of patients died in the APCU. Death in the APCU showed a significant decrease over time, and overall inpatient death in oncology wards did not increase after APCU opening. In total, 44.7% of patients were discharged to government-certified hospice centers. The proportion of patients discharged to certified hospice centers increased from 32.2% in 2015 to 62.4% in 2018. Among 715 patients with a follow-up evaluation 1 week after admission, Edmonton Symptom Assessment System symptom scores, spiritual distress, and financial distress showed statistically significant improvements compared with the baseline symptom scores ( P < .001). This improvement was limited to patients who did not die in the APCU. CONCLUSION: Patients with advanced cancer admitted to the APCU may experience significant improvements in distressing symptoms. The majority of patients requiring transition to hospice were successfully transferred to certified hospice centers. The percentage discharged alive improved over time.

Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. In the present study, gene expression profiling was performed to provide more information on ENKTL molecular signature and offer a rationale for further investigation of prognostic markers in ENKTL. NanoString nCounter Analysis encompassing 133 target genes was used to compare gene expression levels of 43 ENKTL tumor samples. The majority of the patients were under 60 years of age (79.1%); 32 (74.4%) patients had nasal type ENKTL and 23 patients (53.5%) had intermediate/high risk ENKTL based on the prognostic index for natural killer cell lymphoma (PINK). The median follow-up was 15.9 months and the median overall survival (OS) was 16.1 months (95% CI 13.0–69.8). EGR1 upregulation was consistently identified in the localized stage with a low risk of prognostic index based on the PINK. Among the six significantly relevant genes for EGR1 expression, high expression levels of genes, including CD59, GAS1, CXCR7, and RAMP3, were associated with a good survival prognosis. The in vitro test showed EGR1 modulated the transcriptional activity of the target genes including CD59, GAS1, CXCR7, and RAMP3. Downregulation of EGR1 and its target genes significantly inhibited apoptosis and decreased chemosensitivity and attenuated radiation-induced apoptosis. The findings showed EGR1 may be a candidate for prognostic markers in ENKTL. Considerable additional characterization may be necessary to fully understand EGR1.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.

Purpose YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and Methods Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC.Results In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2– MBC patients irrespective of tamoxifen sensitivity.

A new bicyclic macrolide, hamuramicin C (

Introduction Direct oral anticoagulants (DOACs) have the potential to increase bleeding due to drug-drug interactions (DDIs). In the present study, the risk of bleeding was evaluated when drugs with potential DDIs were simultaneously prescribed with DOACs. Materials and methods The present study included patients with non-valvular atrial fibrillation (AF) and venous thromboembolism (VTE) who were newly prescribed DOACs between January 2014 and December 2016. Results The study included 115,362 patients with AF or VTE who were newly administered DOACs (median age, 73 years, range, 19–108 years; males, 53.0%; AF, 81.9%). A total of 7001 any bleeding (6.1%) and 2283 major bleeding (2.0%) events occurred with DOAC prescriptions. Based on multiple logistic regression analysis, the number of DDIs was significantly associated with bleeding events independent of CHA2DS2-VASc score and Charlson Comorbidity Index (CCI). The rates of exposure to DDI drugs associated with any bleeding and major bleeding were 56.7% and 66.1%, respectively. The most common DDI drugs showed similar distributions in any or major bleeding; non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, diltiazem, and amiodarone were frequently prescribed. Conclusions Physicians prescribing DOACs for AF or VTE should be aware of the increasing risk of bleeding associated with drugs having potential DDIs regardless of comorbidities.

Background The aim of this study was to estimate the incidence of and risk factors for Pneumocystis pneumonia (PCP) infection in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Methods The medical records of 739 DLBCL patients who received R-CHOP between May 2004 and January 2019 were retrospectively evaluated. Patients were divided into two groups: those who received primary PCP prophylaxis (prophylaxis group) and those who did not (control group). The incidence rate of PCP in each group was calculated, and risk factors for PCP were evaluated in the control group. Results Baseline characteristics were significantly different between the two groups. Compared to the 602 patients who did not receive prophylaxis, the prophylaxis group (n = 137) had poor prognostic factors of older age, high lactate dehydrogenase (LDH) levels, advanced Ann Arbour stage, and high International Prognostic Index (IPI) risk scores. None of the patients receiving PCP prophylaxis developed PCP, while the incidence of PCP in the control group was 8.1% (definite cases 5.5% and probable cases 2.7%). Out of the 49 patients who developed PCP, 10 patients (20.4%) were admitted to the intensive care unit, and the PCP-related death rate was 16.3% (8/49). Conclusion This study showed that PCP prophylaxis is highly effective against PCP infection and may help guide prevention of PCP during R-CHOP treatment in DLBCL patients.

Entrectinib, an oral pan-TRK, ALK, and ROS1 inhibitor is approved as a first-line treatment for NTRK-rearranged solid tumors and ROS1-rearranged non-small cell lung cancer (NSCLC). It has demonstrated clinical efficacy for patients harboring the relevant gene rearrangement in both systemic and intracranial disease, regardless of the tumor type.In this review, the authors analyzed data from preclinical and clinical studies, the characteristics of entrectinib compared to those of other relevant inhibitors (currently available and/or under investigation), and the emerging resistance mechanisms. The authors then provide the readers with their future perspectives.Entrectinib has been well studied across many tumor types, including NSCLC with ALK, ROS1, and NTRK rearrangements. The drug has demonstrated favorable properties with oral administration, prolonged response duration, high intracranial efficacy, and a favorable toxicity profile. However, with acquisition of resistance and the development of newer generation TKIs, the optimal place for entrectinib in the landscape of targeted therapies for NSCLC warrants further validation.

Non-small cell lung cancer (NSCLC) poses a great threat to human health. DNA methylation abnormalities play a central role in the development and outcome of most human malignancies, providing potential biomarkers for diagnosis and prognosis. Iroquois homeobox 1 (IRX1) can act as a tumor suppressor or promoter depending on the tumor microenvironment, and its role in lung cancer is still controversial. The purpose of this study was to investigate the biological role and prognostic value of IRX1 in NSCLC. We examined the methylation status of IRX1 promoter in 146 tumors from patients with NSCLC using pyrosequencing and analyzed the association between methylation status and overall patient survival. A total of 37 cases (25.3%) showed IRX1 methylation-positive tumors when compared with matched normal tissues. No association between IRX1 expression level and methylation status was found in lung cancer cell lines. IRX1 methylation significantly correlated with smoking status and TP53 mutation. Patients with IRX1 methylation showed significantly longer survival than patients without methylation (log-rank P = 0.011). In a multivariate analysis of prognostic factors, IRX1 methylation in tumor samples was an independent prognostic factor (adjusted hazard ratio = 0.35, 95% confidence interval 0.17–0.73, P = 0.005). These results suggest that IRX1 promoter methylation may be a tumor-associated event and an independent predictor of survival advantage in patients with NSCLC. Further large-scale studies are needed to confirm these findings.

Cancer stem cells (CSCs) have been implicated in the growth and progression of several types of human cancer. The technology to derive and establish CSCs in vitro could be a critical tool for under...

Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with

This study aimed to examine the effects of vinpocetine on atopic dermatitis (AD) by administering it via oral, intraperitoneal, and topical routes to HR-1 hairless mice. AD was induced in the mice for five weeks with ovalbumin, and vinpocetine was administered twice daily through each route of administration for two weeks after the induction of AD. Vinpocetine (20, 10, and 2 mg/kg) was administered by oral, intraperitoneal, and topical routes, respectively. The administration of vinpocetine suppressed the increase in serum immunoglobulin (Ig) E and IgG1 levels and the production of interleukin (IL)-4 and IL-13-cytokines linked to T helper 2 cells in skin tissue. In addition, the invasion of inflammatory cells, including eosinophils, into the skin tissue was reduced, and changes in skin structure were also suppressed. These results show the potential for the use of vinpocetine in patients with AD and even for targeted treatment against PDE. In most of the experiments, symptom relief in the groups receiving oral and topical vinpocetine was slightly superior to that in the group receiving vinpocetine intraperitoneally. In particular, topical application of vinpocetine was found to be the most effective route when considering the dose of vinpocetine used in each route.

Trastuzumab deruxtecan (T-DXd, DS-8201), an anti-HER2 antibody-drug conjugate, has shown significant clinical benefits in HER2+ metastatic breast cancer patients. In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated an objective response of 60.9% and median progression-free survival of 16.4 months, laying the foundation for accelerated approval in HER2+ metastatic breast cancer patients who have received two or more prior anti-HER2-based regimens in the metastatic setting. Moreover, T-DXd exhibited promising antitumor efficacy against HER2-low-expressing metastatic breast cancer. Its distinctive side effect was pneumonitis, with a 13.6% incidence. It is approved in the US with boxed warnings for interstitial lung disease and embryo-fetal toxicity. This review focuses on preclinical, pharmacokinetic and pharmacodynamic data on T-DXd and clinical evidence of its antitumor activity (both as monotherapy and in combination) and tolerability in metastatic breast cancer.Lay abstract Breast cancer can be grouped based on its HR and HER2 status. For patients with HER2+ breast cancer, treatments that fight HER2 portion are adopted. Trastuzumab deruxtecan (DS-8201) is a new drug that consists of two parts: a cytotoxic drug and anti-HER2 antibody. It can selectively target HER2-expressing tumor cells. In a recent clinical trial, trastuzumab deruxtecan demonstrated tumor shrinkage in six of ten patients. The time to increase in tumor size or death was 16 months. Its antitumor effect was also demonstrated in low-HER2-expressing breast cancer. Approximately 13% of patients experience lung inflammation following trastuzumab deruxtecan treatment. In these cases, the drug should be promptly halted and the doctor can start steroid therapy.

Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0–1, 49.4% in category 2–3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22–55.27, P P

The psychosocial health of mother is crucial for healthy prenatal period and early childhood. We investigated the prevalence and risk factors of maternal depression during pregnancy and postpartum among women who participated in a home visitation program in Seoul, South Korea (Seoul Healthy First Step Project, SHFSP).We analyzed 80,116 women who participated in the SHFSP, which was launched by Seoul metropolitan government in 2013, and defined peripartum depression as a score ≥ 10 on the Korean version of the Edinburgh Postnatal Depression Scale (EPDS). Sociodemographic factors and psychosocial health status were evaluated through a standardized questionnaire completed by participants upon program registration. We calculated the prevalence of women at risk for peripartum depression and evaluated associated factors by multivariable logistic regression analysis.Prevalence of women at risk for peripartum depression was 17.7% (prepartum depression: 14.2%, postpartum depression: 24.3%). Younger maternal age, low income (OR 2.40, 95% CI 2.03-2.84), disability (2.61, 1.96-3.47), single parenthood (3.27, 2.69-3.99), and smoking (2.02, 1.44-2.83) increased the peripartum depression risk. Furthermore, experience of stress, change, or loss over the past 12 months (3.36, 3.22-3.50), history of treatment for emotional issues (2.47, 2.27-2.70), experience of child abuse (1.91, 1.74-2.11), and domestic violence (2.25, 1.81-2.80) increased the risk for peripartum depression, whereas having helpers for the baby (0.62, 0.58-0.67), having someone to talk with (0.31, 0.27-0.35), and considering oneself confident (0.30, 0.29-0.31) decreased the risk.Policies to reduce and manage peripartum depression should be strengthened, with a focus on high-risk pregnant and puerperal women.

Background Conjunctival myeloid sarcoma (MS) as an isolated presentation of acute myeloid leukemia (AML) relapse is rare. Here, we report a case of unilateral conjunctival MS revealed as a sign of AML relapse. Case presentation A 50-year-old man with a history of AML in remission visited our clinic presenting with a left conjunctival injection persisting for 1 month. Diffuse subconjunctival thickening with conjunctival vascular engorgement was observed. Ultrasound biomicroscopy revealed a hyper-reflective, thickened conjunctiva in his left eye. During the incisional biopsy, the lesion was strongly attached to the underlying sclera; histopathologic examination revealed infiltration of leukemic blasts. The relapse of AML was confirmed by a successive bone marrow biopsy. The ocular lesion disappeared after allogeneic peripheral blood stem cell transplantation (PBSCT) and concomitant salvage radiotherapy on the left eye. The patient has remained in remission for 3 years after allogeneic PBSCT. Conclusions Incidental conjunctival lesions can indicate AML relapse in patients treated earlier for AML. An ophthalmologist may have a role in the early detection of AML when a patient presents with an atypical conjunctival lesion.

Anecdotal evidence suggests that the severity of coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is likely to be distinguished by variations in loss of smell (LOS). Thus, we conducted a meta-analysis of 45 articles that include a total of 42,120 COVID-19 patients from 17 different countries to demonstrate that severely ill or hospitalized COVID-19 patients have a lesser chance of experiencing LOS than non-severely ill or non-hospitalized COVID-19 patients (odds ratio = 0.527 [95% CI 0.373–0.744; p

Background In-hospital cardiopulmonary resuscitation (CPR) is one of undesirable situations. We tried to identify and characterize a potentially avoidable CPR in cancer patients who were hospitalized in hematology and oncology wards. Methods A potentially avoidable CPR was determined based on chemotherapy setting, disease status and clinical situation at the time when a cardiopulmonary arrest occurred, by using a consensus-driven medical records review of two physicians. Results One hundred thirty-seven patients among 12,437 patients hospitalized at hematology and oncology wards between March 2003 and June 2015 (1.1%) underwent a CPR. Eighty-eight patients (64.2%) were men. The majority of patients with a CPR had lung cancer (41, 29.9%), hematologic malignancy (24, 17.5%), stomach cancer (23, 16.8%) or lymphoma (20, 14.6%). A potentially avoidable CPR was identified in 51 patients (37.2%). In a multivariate analysis, advanced diseases and certain tumor types (e.g., lung cancer, lymphoma) were significant risk factors for a potentially avoidable CPR. Of patients who received a potentially avoidable CPR, 29 patients (56.9%) did not have a do-not-resuscitate documentation. A first return of spontaneous circulation rate (ROSC) and in-hospital survival rate (IHSR) were much lower in patients with a potentially avoidable CPR than those with a CPR that was not avoidable (ROSC: 39.2% vs 53.5%, P = 0.106; IHSR: 2.0% vs 12.8%, P = 0.032, respectively). Conclusions A potentially avoidable CPR was common at hematology and oncology wards. A potentially avoidable CPR frequently occurred in advanced diseases and certain tumor types. Furthermore, cancer patients who received a potentially avoidable CPR showed the worse prognosis.

Background/aims Seasonal variation is an environmental factor proposed to affect the incidence of venous thromboembolism (VTE). However, VTE seasonal variation is not well studied in Asian populations, which have different genetic determinants of VTE compared to Westerners. The present study aimed at investigating seasonal variation of VTE occurrence and the effect of various demographic factors (i.e., age, sex, and co-morbidities) on variation. Methods VTE seasonal variation was evaluated in 59,626 index cases (from January 2009 to December 2013) in the Korean Health Insurance Review and Assessment Service database. We quantified and compared VTE occurrence across four seasons, and additionally assessed monthly through a chronobiological analysis. Results VTE incidence varied both seasonally and monthly, with new cases peaking in the winter (January and February) and the lowest incidence in the summer (August and September). After adjusting for sex, age, type of VTE, and combined cancer diagnosis, winter remained a significant independent factor driving VTE incidence. Additionally, seasonal variation was prominent in patients aged 60 years or older and in patients with pulmonary embolism, but not so prominent in patients of aged less than 60 years and patients with deep vein thrombosis. Conclusion Seasonal variation was a weak but independent contributor to VTE incidence in a Korean population diagnosed from 2009 to 2013, especially in those individuals with old age or suffering from a pulmonary embolism.

Purpose Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. Materials and methods Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. Results Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progressionfree survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response. Conclusion The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.

Background: Peripheral T cell lymphoma (PTCL) is a heterogeneous entity with poor survival. We evaluated the neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and platelet count as new prognostic factors for PTCL. Patients and Methods: We retrospectively analyzed 77 patients with PTCL initially treated with anthracycline-based chemotherapy. Survival curves were compared between groups with different initial NLR (iNLR), end-point NLR (eNLR), initial ALC, and platelet counts. Cox regression was used to analyze the risk factor for survival. Results: Patients with a higher eNLR (≥3), lymphopenia (< 1,000/μL), and thrombocytopenia (< 150 K/μL) had an inferior progression-free survival (PFS) and overall survival (OS) compared to their counterparts, while a higher iNLR (≥3) was predictive of a shorter OS but not PFS. Among these, thrombocytopenia was an independent poor prognostic factor for both PFS and OS, with a hazard ratio of 2.42 (p = 0.012) for PFS and 4.21 (p = 0.006) for OS. The presence of thrombocytopenia further stratified patients with a worse prognosis within overlapping risk-groups by the prognostic index for PTCL. Conclusions: Our study showed that thrombocytopenia at diagnosis was an independent prognostic factor for survival in patients with PTCL.

In 2019, the South Korean government established a plan to develop home visitation services for pregnant women and women with children below the age of 24 months and expand the services nationwide. Therefore, a national survey was needed to provide relevant information for the policy decision of whether to implement universal home visitation services by nurses for families with young children. To determine home visitation service needs in South Korea, 804 women who were pregnant or had children below the age of 24 months were selected as survey participants through stratified random sampling by region reflecting geographical distribution in numbers of births. Of them, 614 responded to survey questionnaires delivered via email. After excluding surveys with too short of a response time, extreme values, and incomplete answers, 500 participants’ responses were analyzed. Participants indicated whether they supported the provision of home visitation services and whether they were willing to utilize home visitation services. The survey also elicited responses regarding the level of needs for individual service items that could be delivered by nurses during home visits. The fieldwork was conducted by a consulting and research firm. The differences in whether respondents supported nurse home visitation services and intended to use nurse home visitation services according to mothers’ characteristics were examined using the chi-square test. In total, 88.0% of survey participants supported nurse home visitation services, and 81.2% indicated that they intended to receive the services. Most pregnant women and women with children below the age of 24 months responded positively to the various prenatal or postpartum services that nurses could provide during home visits. The percentages of support for the services and intention to use services were generally high among subgroups according to mothers’ characteristics. Therefore, universal home visitation services by nurses during pregnancy and in the postnatal period would be received well by Korean women.

Resveratrol can inhibit cell proliferation and metastasis and induce apoptosis. However, the mechanisms of action through which resveratrol inhibits the abnormal proliferation of prostate stromal cells, causing prostatic hyperplasia, have not been fully elucidated. Here, we evaluated the inhibitory effects of resveratrol on cell° proliferation associated with prostatic hyperplasia using WPMY-1 cells. Our results showed that resveratrol inhibited the proliferation of WPMY-1 cells via the induction of G0/G1-phase cell cycle arrest, which was caused by downregulated expression of cyclins and cyclin-dependent kinases regulated by increased p21WAF1 and p27KIP1 expression level. In addition, resveratrol treatment suppressed the phosphorylation of phosphatidylinositol 3-kinase/AKT and extracellular signal-regulated kinase 1/2. The expression levels of molecular markers affecting prostate development were also reduced by treatment with resveratrol. Finally, resveratrol attenuated the binding activity of the transcription factor nuclear factor-κB in WPMY-1 cells, and accelerated apoptotic cell death via intrinsic cascade pathway. These results indicate that resveratrol may be useful for the prevention or treatment of prostatic hyperplasia.

Background: CD30 is frequently expressed in Epstein-Barr virus (EBV)-infected lymphoid cells and overexpressed in EBV-positive lymphomas. This open-labeled, multi-center, and investigator-initiated phase-II study evaluated the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas (NCT02388490). Methods: Twenty-five patients with relapsed or refractory EBV-positive lymphomas having CD30-positivity (≥ 1% of tumor cells) were administered with 1.8 mg/kg brentuximab vedotin intravenously every 3 weeks up to 16 cycles until disease progression. The primary endpoint was objective response rate and toxicities, duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Findings: Twenty-two patients (88%), median age of 65 years, were EBV-positive mature T/NK cell neoplasms (angioimmunoblastic T-cell lymphoma, n = 10; EBV-positive peripheral T-cell lymphoma, unspecified, n = 5; extranodal NK/T-cell lymphoma, nasal type, n = 4; and others, n = 3). Most patients (90%) had initial stage III/IV and 15 (60%) received ≥2 prior regimens. The objective response rate was 48% (90% CI, 31·0% to 64·3%; 12 of 25 patients), including five complete responses (20%) and seven partial responses (28%). Median DoR, PFS and OS were 10·1, 6·1, and 15·6 months, respectively. Common adverse events were peripheral neuropathy (48%), neutropenia (40%), thrombocytopenia (20%), and rashes (16%). Grade 3 and 4 adverse events were neutropenia (20%), thrombocytopenia (12%), and anemia (8%). Interpretation: Brentuximab vedotin is active and well tolerated in patients with relapsed or refractory EBV-positive and CD30-positive lymphomas. Trial Registration: (NCT02388490) Funding Statement: Takeda Pharmaceuticals Co. Ltd and Korea Health Industry Development Institute. Declaration of Interests: TMK received a research grant from AstraZeneca-KHIDI outside this work. DWK received travel and accommodation support for advisory board meeting attendance from Amgen and Daiichi-Sankyo outside this work. All other authors declare no competing interests. Seoul National University Hospital received grants from Alpha Biopharma, Amgen, Astrazeneca/Medimmune, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan. Ethics Approval Statement: The study was approved by the institutional review board at each participating site and written informed consent was obtained.

Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.

Clonorchiasis caused by Clonorchis sinensis is endemic in East Asia; approximately 15 million people have been infected thus far. To diagnose the infection, serodiagnostic tests with excellent functionality should be performed. First, 607 expressed sequence tags encoding polypeptides with a secretory signal were expressed into recombinant proteins using an in vitro translation system. By protein array-based screening using C. sinensis-infected sera, 18 antigen candidate proteins were selected and assayed for cross-reactivity against Opisthorchis viverrini-infected sera. Of the six antigenic proteins selected, four were synthesized on large scale in vitro and evaluated for antigenicity against the flukes-infected human sera using ELISA. CsAg17 antigen showed the highest sensitivity (77.1%) and specificity (71.2%). The sensitivity and specificity of the bacterially produced CsAg17-28GST fusion antigen was similar to those of CsAg17 antigen. CsAg17 antigen can be used to develop point-of-care serodiagnostic tests for clonorchiasis., Author summary Human clonorchiasis is a parasitic disease caused by the Chinese liver fluke, Clonorchis sinensis. Humans are infected through eating raw freshwater fishes carrying C. sinensis metacercariae, the encysted larvae. They excyst in the duodenum, move into the liver via bile duct and grow to adult worms. Excretory-secretory products of the worm damage the liver causing various inflammatory pathological changes and may lead to bile duct cancer. Although there exists an anthelmintic choice praziquantel to kill the fluke, emphasis is placed on early diagnosis and prevention before the infection becomes disease. Microscopic stool examination is the standard diagnostic method but is cumbersome and time consuming. Blood serum antibodies from clonorchiasis patients could provide a simple and fast diagnosis. However, antibody detecting diagnostics developed so far have a low specificity and sensitivity. In the present study we selected 607 antigenic candidate proteins from the genomic database and synthesized them through an integrated high-throughput proteogenomic tools. We identified several antigenic proteins and evaluated their diagnostic potential for clonorchiasis. One of them, CsAg17, showed a high sensitivity and specificity. This antigen deserves development of point-of-care serodiagnostics for C. sinensis infections.

PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G0/G1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial–mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells.

Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of nivolumab therapy for ESCC patients. ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed. Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1–22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval [CI] 1.8–2.3) and 7.4 (95% CI 4.8–10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 [95% CI 1.8–13.1] vs. 1.9 [1.4–2.3] months, P = 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration. Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.

Background Scoliosis is a spine abnormal deviation, which is an idiopathic disorder among children and adolescents. As a matter of the fact, distribution of loads on the patient’s spine and load-carrying capacity of the vertebral column are both random variables. Therefore, the probabilistic approach may consider as a sophisticated method to deal with this problem. Method Reliability analysis is a probabilistic-based approach to consider the uncertainties of load and resistance of the vertebral column. The main contribution of this paper is to compare the reliability level of a normal and scoliosis spinal. To do so, the numerical analyses associated with the inherent random parameters of bones and applied load are performed. Then, the reliability indices for all vertebrae and discs are determined. Accordingly, as the main innovation of this paper, the system reliability indices of the spinal column for both normal and damaged backbone systems are represented. Results Based on the required reliability index for normal spinal curvature the target system reliability level for scoliosis disorder is proposed. Conclusion Since the proposed target reliability index is based on the strength limit state of the vertebral column, it can be considered as a reliability level for any proposed treatment approaches.

Background We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC). Methods We created two cohorts of patients diagnosed with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests. Results One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio [HR]: 0.53 [0.22–1.29], p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 [0.08–0.57], p = 0.001) than low/negative/unknown PD-L1 expression (n = 8). Conclusion PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.

Objective Asthma is a chronic inflammatory disease that can lead to severe problems with the respiratory system. This study aimed to evaluate the suppression of allergic airway inflammation of an asthma murine model by 3-isobutyl-1-methylxanthine (IBMX), which is a non-specific cyclic nucleotide phosphodiesterase (PDE) inhibitor. Methods Allergic lung inflammation was evoked by ovalbumin (OVA) alone or co-exposure with lipopolysaccharide (LPS) in a murine asthma model. Results Compared with the OVA alone-treated control, co-exposure with LPS significantly enhanced allergic inflammatory responses in airway hyperresponsiveness and pathologic changes of the asthmatic mouse lung. Specifically, LPS enhanced allergic asthma through the increase of monocyte chemoattractant protein (MCP)-1 release. However, IBMX significantly suppressed specific airway resistance and tidal volume, the infiltration of eosinophils and mast cells into the lung, the levels of serum immunoglobulin (Ig)E and IgG1, and the release of Th2 cytokines (interleukin (IL)-4, IL-13, and MCP-1). IBMX attenuated the aggravation of inflammation by inhibiting MCP-1, and inhibited the infiltration of eosinophils and the production of Th2 cell-associated inflammatory mediators. Conclusion These results demonstrate the therapeutic potential of targeting the regulation of PDE activity in an aggravated chronic allergic asthmatic response after bacterial infection.

OBJECTIVES For patients with locally advanced oesophageal cancer, improved complete pathological response after neoadjuvant chemoradiation (nCRT) and the detrimental effects on the quality of life related to oesophagectomy have led to the need for a reliable method to select patients who have achieved complete pathological response and do not need surgery. The reliability of 18F-fluorodeoxyglucose positron emission–computed tomography (PET-CT) for predicting the pathological response after nCRT was evaluated. METHODS Patients with locally advanced oesophageal cancer who were treated with nCRT and oesophagectomy from July 2010 to February 2017 were analysed. On the post-nCRT PET-CT, a complete metabolic response was defined as all tumourous lesions demonstrating maximum standardized uptake value (SUVmax) ≤2.5. To minimize the effect of radiation-induced oesophagitis, complete metabolic response was also defined as no viable lesion distinguishable from the background with diffuse uptake. The sensitivity, specificity, positive predictive value and negative predictive value were analysed for SUVmax, [X]ΔSUVmax and %ΔSUVmax. RESULTS A total of 158 patients with oesophageal squamous cell carcinoma were analysed. The rate of complete pathological response was 27.8%, and that of complete metabolic response was 7.6%. The sensitivity, specificity, positive predictive value and negative predictive value based on SUVmax ≤2.5 and visual normalization were 95%, 14%, 74% and 50%, respectively. Analysis for [X]ΔSUVmax and %ΔSUVmax using the optimal cut-off values determined by the receiver operating characteristic curves did not show an improved predictive efficacy. CONCLUSIONS PET-CT is not a reliable tool for predicting pathological response. Patients diagnosed with resectable oesophageal cancer who underwent neoadjuvant therapy should not be exempt from surgery based on PET-CT results.

We aimed to compare 30-day readmission after medical-surgical hospitalization for people who experience imprisonment and matched people in the general population in Ontario, Canada. We used linked population-based correctional and health administrative data. Of people released from Ontario prisons in 2010, we identified those with at least one medical or surgical hospitalization between 2005 and 2015 while they were in prison or within 6 months after release. For those with multiple eligible hospitalizations, we randomly selected one hospitalization. We stratified people by whether they were in prison or recently released from prison at the time of hospital discharge. We matched each person with a person in the general population based on age, sex, hospitalization case mix group, and hospital discharge year. Our primary outcome was 30-day hospital readmission. We included 262 hospitalizations for people in prison and 1,268 hospitalizations for people recently released from prison. Readmission rates were 7.7% (95%CI 4.4-10.9) for people in prison and 6.9% (95%CI 5.5-8.3) for people recently released from prison. Compared with matched people in the general population, the unadjusted HR was 0.72 (95%CI 0.41-1.27) for people in prison and 0.78 (95%CI 0.60-1.02) for people recently released from prison. Adjusted for baseline morbidity and social status, hospitalization characteristics, and post-discharge health care use, the HR for 30-day readmission was 0.74 (95%CI 0.40-1.37) for people in prison and 0.48 (95%CI 0.36-0.63) for people recently released from prison. In conclusion, people recently released from prison had relatively low rates of readmission. Research is needed to elucidate reasons for lower readmission to ensure care quality and access.

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.

PURPOSE Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications. MATERIALS AND METHODS We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival. RESULTS The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1‒negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar's test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival. CONCLUSION Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

Epidermal growth factor receptor (EGFR)‒tyrosine kinase inhibitors (TKIs) are effective clinical therapeutics for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib, a thirdgeneration EGFR TKI, has proven effective against T790M mutations. However, the vast majority of patients acquire resistance following successful treatment. A 59-year-old female patient with metastatic NSCLC developed resistance after 43 weeks of osimertinib. CancerSCAN of the metastatic liver lesion revealed a EGFR C797G mutation at an allele frequency of 72%, a preexisting T790M mutation (73%) in cis and an exon 19 deletion (87%). Another 53-year-old female patient developed systemic progression after 10 months of osimertinib. CancerSCAN of the lung biopsy identified an EGFR L718Q mutation at an allele frequency of 7%, concomitant PIK3CA E545K (12.90%) and preexisting EGFR L858R (38%), but loss of the T790M mutation. The heterogeneity of osimertinib resistance mechanisms warrants further investigation into novel or combination agents to overcome the rare acquired resistances.

Non-small cell lung cancer (NSCLC) with oncogenic driver mutations such as EGFR or ALK has a high predilection for brain metastases (BMs) compared to unselected patients. Historically, whole brain radiotherapy (WBRT) was adopted widely for patients with BM. More recently, stereotactic radiosurgery (SRS) has become a standard approach for patients with 1 - 4 metastatic brain lesions. However, data on overall survival benefit with WBRT/SRS compared to target agents are conflicting, with a significant compromise of loss of neurocognitive function. Newer target agents with improved CNS efficacy have challenged the use of early radiotherapy in NSCLC patients with oncogenic driver mutations. Optimal treatment approach and timing of radiotherapy remain unclear, especially under the various clinical contexts. The purpose of this review is to summarize the available data on the possible benefits and risks of early radiotherapy for oncogenic-driven NSCLC patients with brain metastases. Clinical decisions should consider both intracranial efficacy and patient quality of life, given that patients are surviving long enough to experience the long-term consequences of radiation therapy.

Introduction The epidemiology of immune thrombocytopenia (ITP) is not well characterized in an Asian population. Materials and methods From July 2010 to June 2014, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database. Results The overall incidence rate of ITP was 5.3 per 100,000 person-years (95% CI: 5.1–5.5). The overall incidence rate ratios of children under 15 years old to adults and females to males were 3.8 (95% CI: 3.7–3.9) and 1.3 (95% CI: 1.2–1.4), respectively. Of the total 10,814 patients, 3388 patients (31%) needed treatment for ITP; of these, 54% continued treatment for more than three months. First-line therapy consisted of corticosteroids (CS) in 42%, immunoglobulin (IVIg) in 35%, CS with IVIg in 19%, and other immunosuppressive agents (ISA) in 4%. Among treated patients, 75% of adults and 33% of children continued treatment for more than three months. After three months, the most frequently used drug was CS alone in 63% of patients. Only 104 patients underwent splenectomy; of these, 51% received salvage treatment after a median of one month after surgery (range: 0–27). The proportion of patients who received platelet transfusions of 12 units or more per month for at least two consecutive months was significantly higher among patients treated for more than three months compared with patients who completed treatment within three months. Conclusions This population-based study is the first to describe the incidence of ITP and its treatment reality for patients in Korea.

We analyzed adverse events (AEs) in 201 chronic phase CML patients treated with nilotinib (n = 120) or dasatinib (n = 81) as first- or second-line therapy. The dasatinib group had significantly higher grade 3–4 AEs compared to the nilotinib group (22 vs. 54%, p

This study aimed to elucidate patterns of disease transformation to secondary myelofibrosis (SMF) or secondary acute myeloid leukemia (SAML) and the development of second primary malignancies in South Korean patients with BCR-ABL1-negative myeloproliferative neoplasms (MPNs). By using nationwide public health care insurance claims data, we identified and analyzed 7454 patients with MPNs who were newly diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF) from 2008 to 2016 and used the data to appropriately trace the disease course. Transformation to SMF or SAML was rare in patients with ET and PV, but patients with PMF had an 8-year cumulative incidence of SAML of 21.4%. Patients with PV or ET had an 8-year cumulative incidence of second primary solid tumors of ∼14%. Patients with MPNs had a 2 times higher risk of developing second primary solid tumors than that of the general South Korean population. Compared with patients with PMF, patients with SMF had a similar overall survival with a lower risk of developing SAML. The use of ruxolitinib did not increase the risk of developing B-cell lymphoma over a median follow-up period of 16.2 months. Disease transformation to SMF or SAML was rare in patients with ET or PV, but SAML was common in patients with PMF. South Korean patients with MPNs had a significantly higher risk of developing second primary solid tumors than that of the general population, particularly for kidney, prostate, brain, liver, and lung cancers.

Objective Since the first discovery of rearranged during transfection (RET) fusion in lung adenocarcinoma in 2011, two tyrosine kinase inhibitors, namely vandetanib and cabozantinib, are currently available. Despite favorable outcomes in systemic control, the intracranial therapeutic response remains insufficient. In this study, the clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with RET rearrangements were analyzed. Methods Patients with NSCLC harboring RET fusion who received treatment between January 2006 and January 2018 were analyzed. RET rearrangement was identified by FISH or NGS. Results A total of 59 patients were identified. About half of the patients were female (47.5%) and never smokers (50.9%). Most patients had adenocarcinoma (89.8%). A total of 17 patients (28.8%) had an intracranial lesion at the initial diagnosis of stage IV disease, and 11 additional patients (18.6%) developed intracranial metastases during follow-up. The median time to development of intracranial metastases was 19.0 months (95% CI: 9.6–28.5), resulting in a >60% cumulative incidence of brain metastasis at 24 months. The systemic efficacy of pemetrexed-based regimens was favorable with progression-free survival of 9.0 (95% CI: 6.9–11.2) and OS of 24.1 (95% CI: 15.2–33.0) months. The median progression-free survival for vandetanib and immunotherapy was 2.9 (95% CI: 2.0–3.8) and 2.1 (95% CI: 1.6–2.6) months, respectively. Conclusions Given the likelihood of RET-rearranged NSCLC progressing to intracranial metastases and the absence of apparent clinical benefit of currently available targeted or immunotherapeutic agents, development of novel treatment with higher selectivity and better penetration of the blood–brain barrier remains a priority.

Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to the parent cell line, whereas A549 and NCI-H460 did not show this change. The pan-HER inhibitor afatinib inhibited this alternative signaling pathway, resulting in a superior cytotoxic effect in pemetrexed-resistant NCI-H3122 cell lines compared to that in the parental cells line. Conclusion: The activation of EGFR-HER2 contributes to the acquisition of resistance to pemetrexed in EML4-ALK rearranged non-small cell lung cancer. However, the inhibition of this alternative survival signaling pathway with RNAi against EGFR-HER2 and with afatinib overcomes this resistance.