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Purpose Literature is scarce regarding cancer care utilization during the massive outbreak of coronavirus disease 2019 (COVID-19) in the Republic of Korea. We investigated functional impairments in mental health and their relationships with depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization among cancer patients in the COVID-19 pandemic era.Materials and Methods We used an online survey with questions related to the disturbances faced by patients with cancer in utilizing healthcare services in the pandemic era. Current mental health status was assessed using the Work and Social Adjustment Scale (WSAS), Stress and Anxiety to Viral Epidemics-6 (SAVE-6) scale, Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI), Brief Resilience Scale (BRS), Cancer-Related Dysfunctional Beliefs about Sleep Scale (C-DBS), and Fear of COVID-19 over Cancer (FCC).Results Among the 221 responders, 95 (43.0%) reported disruptions in healthcare service utilization during the COVID-19 pandemic. Logistic regression analysis revealed that functional impairment in the mental health of these patients was expected due to disruptions in healthcare service utilization, high levels of depression, anxiety regarding the viral epidemic, fear of COVID over cancer, and low resilience. Mediation analysis showed that patient resilience and cancer-related dysfunctional beliefs about sleep partially mediated the effects of viral anxiety on functional impairment.Conclusion In this pandemic era, patients with cancer experience depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization, which may influence their functional impairments in mental health.

Purpose This study aimed to confirm the decision-making patterns for life-sustaining treatment and analyze medical service utilization changes after enforcement of the Life-Sustaining Treatment Decision-Making Act. Materials and methods Of 1,237 patients who completed legal forms for life-sustaining treatment (hereafter called the life-sustaining treatment [LST] form) at three academic hospitals and died at the same institutions, 1,018 cancer patients were included. Medical service utilization and costs were analyzed using claims data. Results The median time to death from completion of the LST form was three days (range, 0 to 248 days). Of these, 517 people died within two days of completing the document, and 36.1% of all patients prepared the LST form themselves. The frequency of use of the intensive care unit, continuous renal replacement therapy, and mechanical ventilation was significantly higher when the families filled out the form without knowing the patient's intention. In the top 10% of the medical expense groups, the decision-makers for LST were family members rather than patients (28% patients vs. 32% family members who knew and 40% family members who did not know the patient's intention). Conclusion The cancer patient's own decision-making rather than the family's decision was associated with earlier decision-making, less use of some critical treatments (except chemotherapy) and expensive evaluations, and a trend toward lower medical costs.

The advent of receptor tyrosine kinase inhibitors (RTKi) are important contributions to treat NSCLC patients harboring genetic aberration effectively. Nevertheless, the emergence of acquired or intrinsic RTKi resistance by other RTK activation bypass finally limits their efficacy. First of all, in this study, we identified MED12 mutation in TKI-resistant NSCLC cells based-on NGS analysis. Although MED12 was known to controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling reportedly, we additionally found that MED12 mutation activates not only TGF-beta receptor not also other ones, such as EGFR, meaning that blocking TGF-beta receptor or EGFR alone may not effective to overcome MED12 mutation-induced RTKi resistance. To overcome the RTKi resistance in NSCLC harboring MED12 mutation, we elaborated the two downstream signaling of RTK in MED12 knock-out NSCLC cells and observed that PI3K/AKT signaling is downregulated but MEK/ERK signaling is upregulated. We observed that only MEK inhibitor (MEKi), not PI3K/mTOR inhibitor, shows effective anti-cancer effect. Therefore, we explored why MEKi alone is effective in RTKi resistant NSCLC cells harboring MED12 mutation and presented that MED12 mutation directly suppressed activation of YAP via blocking a large mediator complex of MED12, MED13, CDK8 and CCNC, thereby increasing PTEN expression by inhibition of miR-29 expression. Increased PTEN inhibits reactivation of PI3K/AKT pathway. In conclusion, we first identified that MED12 mutation induces RTKi resistance though activating other RTKs, such as TGF-beta receptor or EGFR, and blocks PI3K/AKT pathway via dysregulation of YAP/PTEN/AKT interaction. Therefore, among two downstream signaling of RTK, activated MEK/ERK pathway can be a definitive target enough to overcome RTKi resistant NSCLC patients harboring MED12 mutation and MEKi could be a primary treatment option for resistant patients harboring MED12 mutation among NSCLC patients with repetitive recurrence of RTKi resistance by another RTK activation bypass. Citation Format: Hyun-Min Ryu, Deokhoon Kim, Shinkyo Yoon, Ho-Su Lee, Eunjin Lee, Chang Hoon Lee, Wanlim Kim, Seyoung Seo, Kyung Hae Jung, Sook Ryun Park, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. RTK inhibitor resistance in NSCLC harboring MED12 mutation is overcome by only blocking MEK signaling, not AKT due to mutated MED12-induced YAP-PTEN dysregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 424.

Background/aim Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS). Patients and methods We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients. Results SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX. Conclusion S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.

Background: We evaluated the safety and efficacy of direct oral anticoagulants (DOACs) versus subcutaneous dalteparin for cancer-associated venous thromboembolism (CA-VTE) in patients with advanced upper gastrointestinal (GI) tract, hepatobiliary, or pancreatic cancer. Methods: This was a multicenter, randomized, open-label, phase II trial in five centers. Patients randomly received rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily)/apixaban (10 mg twice daily for the first 7 days, then 5 mg twice daily) or dalteparin (200 IU/kg once daily for the first month, then 150 IU/kg once daily). Randomization was stratified by the Eastern Cooperative Oncology Group Performance Status, primary cancer type, active chemotherapy, and participating centers. The primary endpoint was the rates of clinically relevant bleeding (CRB) in the full analysis set (FAS). Results: A total of 90 patients were randomly assigned to the DOAC (n = 44) and dalteparin groups (n = 46) in FAS. CRB and major bleeding (MB) rates were 34.1% and 13.0% (p = 0.018) and 18.2% and 4.3% (p = 0.047) for the DOAC and dalteparin groups, respectively. Time to CRB and MB was higher in the DOAC group than in the dalteparin group (hazard ratio [HR] 2.83; p = 0.031 and HR 4.32; p = 0.064). Cancer involvement at the GI mucosa was also a significant risk factor for CRB. Recurrent CA-VTE occurred in 2.3% and 2.2% of patients given DOAC and dalteparin, respectively (p = 1.000). Conclusion: DOAC therapy further increased the risk of bleeding compared with dalteparin in patients with active advanced upper GI tract, hepatobiliary, or pancreatic cancer, suggesting that extra caution should be taken when selecting anticoagulants for CA-VTE.

Background This study was conducted to compare the reported adverse event (AE) profiles and unexpected use of medical services during chemotherapy between before and after the healthcare reimbursement of AE evaluation in patients with cancer. Patients and Methods Using the electronic medical record database system, extracted patients with breast, lung, gastric, and colorectal cancers receiving neoadjuvant or adjuvant chemotherapy between September 2013 and December 2016 at four centers in Korea were matched using the 1:1 greedy method: pre‐reimbursement group (n = 1084) and post‐reimbursement group (n = 1084). Unexpected outpatient department (OPD), emergency room (ER) visit, hospitalization rates, and chemotherapy completion rates were compared between the groups. Results The baseline characteristics were well‐balanced between the groups. By chemotherapy cycle, hospitalization (1.8% vs. 2.3%; p = 0.039), and ER visit rates (3.3% vs. 3.9%; p = 0.064) were lower in the post‐reimbursement group than that in the pre‐reimbursement group. In particular, since cycle 2, ER visit and hospitalization rates were significantly lower in the post‐reimbursement group than those in the pre‐reimbursement group (2.6% vs. 3.3%; p = 0.020 and 1.4% vs. 2.0%; p = 0.007, respectively), although no significant differences were observed during cycle 1. The OPD visit rates were similar between both groups, regardless of cycles. The post‐reimbursement group had a higher proportion of patients who completed chemotherapy as planned than the pre‐reimbursement group (93.5% vs. 90.1%; p = 0.006). Post‐reimbursement group had more AEs reported, including alopecia, fatigue, diarrhea, anorexia, and peripheral neuropathy, during cycle 1 than the pre‐reimbursement group, which significantly decreased after cycle 2. Conclusion The introduction of healthcare reimbursement for AE evaluation may help physicians capture and appropriately manage AEs, consequently, decreasing hospital utilization and increasing chemotherapy completion rates.

Brachial plexopathy in cancer patients is a rare but significant complication that causes pain and disability of the upper extremities. Clinical features of breast cancer patients with metastatic brachial plexopathy (MBP) have not been studied. We aimed to investigate the characteristics of MBP in breast cancer patients. We retrospectively reviewed medical records of patients with breast cancer with MBP who visited Asan Medical Center from 2000 to 2016; we enrolled 44 patients. We comprehensively reviewed the characteristics, range of metastatic lymph nodes, initial symptoms, location, and severity of brachial plexus injury by electrodiagnostic study, radiologic findings, and associated complications. The mean age of patients with MBP was 51.9 ± 9.3 years; 25% were diagnosed with stage IV breast cancer at initial diagnosis. Weakness was the most common initial symptom of MBP (52.3%). Most patients showed limitation of shoulder range of motion and pain; 66% of patients exhibited malignant lymphedema. Forty-one patients were evaluated by electromyography; upper nerve trunk involvement (22.0%) was more frequent than lower nerve trunk involvement (9.8%). Nineteen patients underwent brachial plexus MRI, and supraclavicular area (SCA) metastasis was most frequent (57.9%). Sixteen patients were examined by both brachial plexus MRI and electromyography; patients with SCA metastasis exhibited significantly more frequent malignant lymphedema (p = 0.019) and upper nerve trunk involvement (p = 0.035), compared with patients with non-SCA metastasis. Our study revealed clinical features of MBP in breast cancer patients. Additional diagnostic evaluation focused on metastasis or aggravated metastatic tumor is needed when breast cancer patients are diagnosed with brachial plexopathy.

Objective To investigate the clinical significance of MET gene amplification in patients with gastric cancer in the palliative setting. Methods MET amplification was assessed using fluorescence in situ hybridization (FISH) in 50 patients and quantitative polymerase chain reaction (qPCR) in 326 patients; 259 patients treated with first-line fluoropyrimidine and platinum were included for survival analysis. Results The results of FISH and qPCR indicated that the c-MET/CEP7 ratio was correlated with gene copy number. The optimal cutoff value for the copy number using qPCR to detect MET gene amplification with FISH was 5 (κ=0.778, P5 detected by qPCR. MET-amplified gastric cancer was associated with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≥2 (33.3% vs. 10.5% P=0.007), peritoneal metastasis (76.2% vs. 46.2%, P=0.008), and elevated bilirubin levels (28.6% vs. 7.3%, P=0.006). The median overall survival (OS) and progression-free survival (PFS) were 11.9 and 5.6 months, respectively. MET-amplified gastric cancer was not associated with survival outcomes [hazard ratio (HR)=0.68, 95% confidence interval (95% CI): 0.35−1.32, P=0.254 for PFS; HR=0.68, 95% CI: 0.35−1.32, P=0.251 for OS]. Conclusions qPCR can be used to detect MET gene amplification. MET amplification was not a predictor of poor prognosis in patients with metastatic or unresectable gastric cancer.

PurposeHeat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.Materials and MethodsWe established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.ResultsWe identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.ConclusionThe synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer prognosis in various cancer types. However, ICIs may trigger accelerated tumor progression, regarded as hyperprogressive disease (HPD), in certain patients, and it is still challenging to define HPD. We aimed to investigate the landscape of HPD and the prognostic value of its different definitions in advanced solid cancer patients treated with ICIs. Methods: We conducted a multicenter, prospective cohort study for solid cancer patients receiving ICIs. Among them, only unresectable or metastatic cancer patients were included in this analysis. Tumor response was evaluated according to RECIST 1.1. In patients who showed progressive disease (PD) by RECIST 1.1 at the first tumor evaluation, HPD was defined according to the following three criteria: A) tumor growth kinetics (TGK) ratio (TGKpost-ICI/TGKpre-ICI >=2, B) >=10mm increase in sum of target lesion (SUMtarget)and at least one of the following two criteria - 1) >=40% increase in SUMtarget or 2) >=20% increase in SUMtarget and the appearance of new lesions in at least two different organs, C) TGK ratio >=2 and >50% increase in SUMtarget. The discriminatory ability of three definitions in terms of overall survival (OS) were evaluated by the chi-square, C-statistics, and prediction error with integrated Brier score. Results: A total of 427 patients were included; head and neck (n=22, 5.2%), lung (n=173, 40.5%), breast (n=8, 1.9%), gastrointestinal tract (n=99, 23.2%), hepatobiliary pancreas (n=57, 13.3%), genitourinary (n=56, 13.1%), melanoma (n=5, 1.2%), and others (n=7, 1.6%). Incidences of HPD were 4.9%, 14.8%, and 11.5% in definition A, B, C, respectively. The incidence of HPD was relatively low (2.7%-9.5%) in non-small cell lung cancer compared to other cancer types (10.1%-21.5% in esophagogastric cancer, 3.9%-21.6% in hepatobiliary pancreas cancer, and 5.5%-22.5% in genitourinary cancer). Median OS was the worst for patients with HPD, which ranged from 4.8 months to 4.9 months according to definition A-C. After multivariate analysis adjusting for cancer types, ICIs types, and the number of prior anti-cancer therapy, each definition remained a significant factor for OS (P Conclusions: Incidences of HPD appear to be various according to its definitions and cancer types. Given that the RECIST-based definition B not requiring pre-ICI imaging, showed similar discriminatory ability to predict dismal OS compared to TGK-based ones, it may be the most feasible and convenient measure to capture HPD in daily clinical practice. Citation Format: Jwa Hoon Kim, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, Ji-Youn Han, Il-Hwan Kim, Sang-We Kim, Dae Ho Lee, Jae Lyun Lee, Jae Cheol Lee, Chang-Min Choi, Changhoon Yoo, Shinkyo Yoon, Jae Ho Jeong, Seyoung Seo, Sun Young Kim, Jin-Hee Ahn, Sook Ryun Park. Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5209.

6018 Background: Salivary gland cancers (SGCs) are relatively rare, accounting for 1-6% of all neoplasms of the head and neck, have diverse disease course with respect to origin and pathology. Salivary duct carcinoma (SDC) is the most aggressive tumor subtype of primary SGC, showing high rates of local recurrence and distant metastases. In regard to previous studies which reported a high prevalence of HER2 positivity in SDCs, we conducted a single-arm, phase II study to evaluate the antitumor activity and safety of Herzuma (a trastuzumab biosimilar which demonstrated an equivalent efficacy to reference trastuzumab) in combination with docetaxel anhydrous (Nanoxel) in patients with HER2-positive advanced SDCs. Methods: Eligible patients had histologically confirmed HER2-positive (defined as IHC≥2+ and/or FISH HER2/CEN17 ratio ≥2.0) recurrent/metastatic SDC, or subtypes of SGC that were pathologically similar to SDC (excluding ACCs). They received Herzuma (8mg/kg i.v. loading dose, followed by 6mg/kg i.v.) and Nanoxel (75mg/m2 i.v.) every 3 weeks. The primary endpoint was the investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. The calculated sample size was 43 patients for H1 of ORR ≥40%. Safety was evaluated by CTCAE v4.0. Results: A total of 43 patients were enrolled. Patient characteristics included: median age 60 (range 35–81); 86% male; 84% ECOG1; 84% SDC, 9% adenocarcinoma, 2% high grade mucoepidermoid carcinoma, and 5% other subtypes. Confirmed ORR was seen in 67% (95% CI, 52–81). No patient had a complete response as their BOR, 29 (67%) had a partial response, 11 (26%) had stable disease, 1 (2%) had progressive disease, and 2 (5%) were unevaluable. The DCR was 93% (95% CI, 81–99). The median PFS and OS were 8.2 months (95% CI, 6.7–9.7) and 23.3 months (95% CI, 19.9–26.7), respectively. Thirty-eight (88%) patients experienced a treatment-related AE (TRAE), with 15 (35%) patients experiencing ≥grade 3 TRAE including: neutropenia (10), febrile neutropenia (4), anemia (1), sepsis (1), anaphylaxis (1), decreased LVEF (1). There were no treatment-related deaths. Conclusions: The study met the primary endpoint of ORR. Herzuma and Nanoxel combination therapy demonstrated a promising treatment outcome in patients with HER2-positive recurrent/metastatic SDC. Clinical trial information: NCT03614364.

Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS).We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients.SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX.S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients.

Anti-PD-1/PD-L1 immunotherapy, as a treatment for many tumors, has shown good efficacy. However, responses to immunotherapy did not always occur or last long., i.e. primary or acquired resistance, even tumors were PD-L1 positive. Several oncogenic pathways, including PI3K/AKT activation by PTEN loss and NF-κB activation, induce PD-L1 expression and PD-L1 inhibitor-resistance. They also induce expression of CCL2, an inhibitory chemokine that blocks T cell tracking into the tumor by binding to CCR2 on the T cell surface. In this study, we showed that transglutaminase 2 (TG2), a post-translational modification enzyme, induced ubiquitin-proteasome dependent degradation of tumor suppressors including PTEN and IκBα by peptide cross-linking, inducing CCL2 as well as PD-L1 expression via PI3K/AKT and NF-κB activation. It also induced PD-L1 inhibitor-resistance because CCL2 was expressed despite increased PD-L1, which was blocked by PD-L1 inhibitor. We also revealed that inhibition of TG2, instead of PD-L1, restored T cell-dependent killing effect by blocking expression of both PD-L1 and CCL2 in PD-L1(+) triple negative breast cancer (TNBC) cells. In addition, the TG2-expressing TNBC patient group showed higher PD-L1 expression incidence than did the TG2-negative TNBC patient group. In conclusion, TG2 induces primary PD-1/PD-L1 inhibitor-resistance by inducing CCL2 expression. TG2 blockade can be utilized as an excellent therapeutic strategy to overcome PD-L1 inhibitor-resistance in PD-L1(+) TNBC patients. Our study suggested that PD-L1 expression alone might not always be a predictive biomarker for PD-L1(+) TNBC, but TG2 could be a useful predictive marker to select PD-L1 inhibitor-resistant TNBC patients.

OBJECTIVE Given the rarity of the disease, the post-resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection. METHODS We retrospectively analyzed the outcomes of 20 patients with resectable pancreatic ACC who underwent surgery. RESULTS Altogether 20 patients were included in the study, with a median age of 57 years and a male predominance. There were eight pure ACC, 10 mixed acinar–neuroendocrine carcinomas and two mixed acinar–ductal adenocarcinomas. Among the 15 patients who were staged histologically, 3, 8 and 4 were at stages IB, IIA and IIB, respectively. Eleven patients received adjuvant chemotherapy (5-fluorouracil-based [n = 9]; gemcitabine [n = 1]; etoposide plus cisplatin [n = 1]). In a median follow-up period of 27.1 months, disease recurred in 10 patients, most commonly in the liver (90%). Median recurrence-free survival and overall survival were 16.9 months and 75.0 months, respectively. Elevation of cancer antigen 19-9 (CA19-9), lymph node metastasis and neural invasion were significantly associated with poor overall survival (P = 0.007, P = 0.027 and P = 0.016, respectively). CONCLUSIONS Compared with ductal adenocarcinoma, resectable pancreatic ACC has a favorable prognosis after surgery. Considering that distant metastasis is the most common pattern of recurrence, further studies are necessary to define the role of adjuvant chemotherapy for improving survival outcomes.

Background/Aim: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer. Patients and Methods: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. Results: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Conclusion: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks.

Background: Although non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutations shows dramatic responsiveness to EGFR-TKI, some of them still showed primary resistance. The loss of PTEN and NF-κB activation have known to contribute to intrinsic EGFR-TKI resistance in EGFR mutant lung cancer. Interestingly, Transglutaminase 2 (TG2) was well known to down-regulate PTEN and IκBα (NF-kB inhibitor) levels in tumor cells. Therefore, we investigated whether TG2 plays a role in the resistance and what kind of mechanisms involves in that resistance. Methods: We have established de novo and ectopic TG2 over-expressing EGFR mutant NSCLC cell lines. Subsequently, we have elaborated the resistance to EGFR-TKI therapy in these TG2-over-expressing cells. We have tried to investigate whether TG2 inhibitor could restore EGFR-TKI sensitivity with EGFR inhibitors in vitro and in vivo. Then, we evaluated TG2 expression in two intrinsic and eight sensitive clinical cases. Findings: The higher TG2 expression and lower PTEN and IκBα expression were evident in the intrinsic EGFR-TKI resistant NSCLC. EGFR-TKI sensitive NSCLC cells, harboring EGFR mutations, that stably expressed TG2 had reduced PTEN and IκBα and exhibited EGFR-TKI resistance. TG2 inhibition alone or co-treatment with TG2 inhibitor and EGFR-TKI in intrinsic EGFR-TKI resistant NSCLC cells harboring EGFR mutations overcame EGFR-TKI resistance via PTEN and IκBα restoration. Interpretation: TG2 elicits intrinsic EGFR-TKI resistance via PTEN loss and activation of the NF-κB pathway in NSCLC harboring EGFR sensitizing mutation. Therefore, TG2 may be a useful predictive marker and also be a target for overcoming the resistance. Funding Statement: This manuscript was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1520220) and the PostGenome Technology Development Program [10067758, Business model development driven by clinico-genomic database for precision immuno-oncology] funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). Declaration of Interests: D.H.L. declares honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, ChongKunDang, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm and ST Cube. The other authors declare that they have no conflict of interest. Ethics Approval Statement: Animal procedures were approved by the institutional review board of Asan Medical Center

Additional file 1: Table S1. Characteristics of 89 patients with angiosarcoma.

// Seyoung Seo 1,* , Seong Joon Park 1,* , Min-Hee Ryu 1,* , Sook Ryun Park 1 , Baek-Yeol Ryoo 1 , Young Soo Park 2 , Young-Soon Na 3 , Chae-Won Lee 3 , Ju-Kyung Lee 3 and Yoon-Koo Kang 1 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 3 Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea * Seyoung Seo, Seong Joon Park, Min-Hee Ryu have contributed equally to this study as first authors Correspondence to: Yoon-Koo Kang, email: // Keywords : FGFR2; amplification; advanced gastric cancer; prognosis; quantitative real-time polymerase chain reaction Received : July 20, 2016 Accepted : October 22, 2016 Published : October 27, 2016 Abstract Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival. Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age

// Seyoung Seo 1, * , Jung Yong Hong 1, * , Shinkyo Yoon 1, 7 , Changhoon Yoo 1 , Ji Hyun Park 1 , Jung Bok Lee 2 , Chan-sik Park 3 , Jooryung Huh 4 , Yoonse Lee 4 , Kyung Won Kim 5 , Jin-Sook Ryu 6 , Seok Jin Kim 8 , Won Seog Kim 8 , Dok Hyun Yoon 1 , Cheolwon Suh 1 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Medical Statistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 4 Department of Otorhinolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 5 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 6 Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 7 Department of Hemato-oncology, Bundang Jesaeng Hospital, Gyeonggi-do, Korea 8 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors contributed equally to this work Correspondence to: Cheolwon Suh, email: csuh@amc.seoul.kr Dok Hyun Yoon, email: dhyoon@amc.seoul.kr Keywords: beta 2-microglobulin, diffuse large B-cell lymphoma, rituximab, prognosis, non-Hodgkin lymphoma Received: July 22, 2016 Accepted: October 12, 2016 Published: October 18, 2016 ABSTRACT The prognostic value of serum beta-2 microglobulin for diffuse large B-cell lymphoma (DLBCL) is not well known in the rituximab era. A retrospective registry data analysis of 833 patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was conducted to establish the prognostic significance of serum beta-2 microglobulin at a ≥2.5 mg/L cutoff. Five-year progression-free survival (PFS, 76.1% vs. 41.0%; p < 0.001) and overall survival (OS, 83.8% vs. 49.2%; p < 0.001) were significantly worse in patients with elevated serum beta-2 microglobulin ( n = 290, 34.8%). Furthermore, the five parameters of the International Prognostic Index, accompanying B symptoms, bone marrow involvement and impaired renal function were associated with worse PFS and OS. In multivariate analysis, elevated beta-2 microglobulin was a significant poor prognostic factor for PFS (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.29–2.24; p < 0.001) and OS (HR, 2.0; 95% CI, 1.47–2.75; p < 0.001). In an independent validation cohort of 258 R-CHOP treated patients with de novo DLBCL, elevated beta-2 microglobulin levels remained a significant poor prognostic factor for PFS (HR, 2.03; 95% CI, 1.23–3.32; p = 0.005) and exhibited a strong trend of association with worse OS (HR, 1.64; 95% CI, 0.98–2.75; p = 0.062). The significance of serum beta-2 microglobulin levels as an independent prognostic factor for patients with DLBCL receiving R-CHOP is confirmed.

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib. [BMB Reports 2018; 51(12): 660-665].

Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy. We enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression. At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH−. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4–36.8) months. A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.

Small cell lung cancer (SCLC) cannot be efficiently controlled using existing chemotherapy and radiotherapy approaches, indicating the need for new therapeutic strategies. Although ABT-737, a B-cell lymphoma-2 (BCL-2) inhibitor, exerts anticancer effects against BCL-2-expressing SCLC, monotherapy with ABT-737 is associated with limited clinical activity because of the development of resistance and toxicity. Here, we examined whether combination therapy with ABT-737 and heat shock protein 90 (HSP90) inhibitor NVP-AUY922 exerted synergistic anticancer effects on SCLC. We found that the combination of ABT-737 and NVP-AUY922 synergistically induced the apoptosis of BCL-2-expressing SCLC cells. NVP-AUY922 downregulated the expression of AKT and ERK, which activate MCL-1 to induce resistance against ABT-737. The synergistic effect was also partly due to blocking NF-κB activation, which induces anti-apoptosis protein expressions. However, interestingly, targeting BCL-2 and MCL-1 or BCL2 and NF-κB did not induce the cytotoxicity. In conclusion, our study showed that combination of BCL2 inhibitor with HSP90 inhibitor increased activity in in vitro and in vivo study in only BCL-2 expressing SCLC compared to either single BCL2 inhibitor or HSP inhibitor. The enhanced activity might be led by blocking several apoptotic pathways simultaneously rather than a specific pathway.

More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.

Given the rarity of the disease, the post-resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection.We retrospectively analyzed the outcomes of 20 patients with resectable pancreatic ACC who underwent surgery.Altogether 20 patients were included in the study, with a median age of 57 years and a male predominance. There were eight pure ACC, 10 mixed acinar-neuroendocrine carcinomas and two mixed acinar-ductal adenocarcinomas. Among the 15 patients who were staged histologically, 3, 8 and 4 were at stages IB, IIA and IIB, respectively. Eleven patients received adjuvant chemotherapy (5-fluorouracil-based [n = 9]; gemcitabine [n = 1]; etoposide plus cisplatin [n = 1]). In a median follow-up period of 27.1 months, disease recurred in 10 patients, most commonly in the liver (90%). Median recurrence-free survival and overall survival were 16.9 months and 75.0 months, respectively. Elevation of cancer antigen 19-9 (CA19-9), lymph node metastasis and neural invasion were significantly associated with poor overall survival (P = 0.007, P = 0.027 and P = 0.016, respectively).Compared with ductal adenocarcinoma, resectable pancreatic ACC has a favorable prognosis after surgery. Considering that distant metastasis is the most common pattern of recurrence, further studies are necessary to define the role of adjuvant chemotherapy for improving survival outcomes.

Background Proper evaluation and management of chemotherapy-related toxicity (CRT) is critical to cancer patients. We aimed to assess the clinical utility of STAF in patients with breast cancer receiving chemotherapy. Methods The STAF is a systematic form including common CRT lists and grades to help clinicians to assess CRT comprehensively as opposed to assessing CRT individually by cases. Using data from clinical data warehouse, the CRT profile was analyzed in patients with breast cancer receiving adjuvant or neoadjuvant therapy during two time periods; before (n = 1874) and after (n = 981) using STAF in the clinic at Asan Medical Center. The two cohorts were matched by age and chemotherapy, leaving conventional practice (A; n = 333) and STAF (B; n = 333) groups. The rates of unscheduled hospital utilization (outpatient department [OPD], emergency room [ER] and hospitalization) were compared between group A and B. Results No significant differences were noted in baseline characteristics between the two groups, except for a higher proportion of patients living near the hospital in group A compared to group B (67.0 vs 56.2%; P = 0.004). The completion rate of planned chemotherapy was 96.7% and 97.6% (P = 0.704), and the rate of dose reduction was 12.3% and 10.8% (P = 0.473), respectively, in group A and B. The median dose intensity was lower in group A than group B (0.92 vs. 0.95; P Table . 1788P Unscheduled utilization since cycle 2 of chemotherapy Group A (n = 333, %) Group B (n = 333, %) P OPD 22 (6.6) 11 (3.3) 0.050 ER 56 (16.8) 32 (9.6) 0.006 Hospitalization 42 (12.6) 28 (8.4) 0.077 Conclusions Using the STAF may facilitate to capture CRT in clinical practice and reduce the rates of unscheduled hospital utilization in patients with breast cancer receiving adjuvant or neoadjuvant therapy. Legal entity responsible for the study The authors. Funding Korean Foundation for Cancer Research. Disclosure All authors have declared no conflicts of interest.

e22195Background: Oxaliplatin (OX)-based chemotherapy is known to cause hepatic sinusoidal injury, resulting portal hypertension with splenomegaly (SM). We compared this OX-induced hepatopathy, SM,...

27 Background: Although discordance of HER2 positivity between primary and metastatic lesions was well known, changes of HER2 positivity after chemotherapy have not been studied in gastric cancer (GC). Methods: A total of 48 HER2-positive advanced GC (AGC) patients who were treated with trastuzumab-containing 1stline chemotherapy and had paired biopsies at baseline and after progression were enrolled. Scores of HER2 immunohistochemistry (IHC) were reviewed and in situ hybridization (ISH) was conducted when tissues were available. Results: Thirty-nine patients were treated with capecitabine, cisplatin/oxaliplatin, and trastuzumab (XPT) while the other 9 received XPT plus pertuzumab/placebo. Objective response rate (ORR) was 76% (26 out of 34) and median progression free survival (PFS) and overall survival were 8.3 and 16.3 months, respectively. At baseline, HER2 was positive with IHC 2+ and ISH+ in 5 and with IHC 3+ in 43. Loss of HER2 positivity after progression was observed in 14 (28.6%); 10 with IHC 0 or 1+ and 4 with IHC 2+ but ISH- at 2nd biopsy. HER2 remained positive in the other 34; 4 with IHC2+ and ISH+, and 30 with IHC 3+ at 2nd biopsy. Applying H-score formula, mean scores decreased from 201 to 170 (Wilcoxon test; p=0.047). HER2 genetic heterogeneity (5% to nd biopsy. The mean ratio was changed from 6.5 (1.2-15.8) to 5.0 (0.4-15.2) (paired t-test, p=0.019) and all patients with genetic heterogeneity at 2ndbiopsy showed HER2 negative conversion. Among 13 who received 2ndline T-DM1, 3 showed HER2 negative conversion. Those 3 had no objective response at all and very short PFS (1.2, 1.3 and 3.4 months), whereas the others with stable HER2 status showed 44% of ORR and median PFS of 2.7 (0.4-36.8) months. Conclusions: A substantial portion of initially HER2-positive AGC patients showed HER2 negative conversion with increased HER2 heterogeneity after trastuzumab-containing chemotherapy. Loss of HER2 positivity could be a predicting factor for 2nd line anti-HER2 treatment.

Background Multicentric Castleman's disease (CD) is commonly associated with poor prognosis, and well-known prognostic factors are scarce. We performed a retrospective analysis to define the clinical features and prognostic factors for patients with multicentric CD. Methods Between 1990 and 2013, 32 patients with multicentric CD were identified from the database of the Asan Medical Center, Seoul, Korea. Clinicopathologic data were collected by reviewing the medical records. With the exclusion of 4 patients because of unknown human immunodeficiency virus infection status, 28 human immunodeficiency virus-negative patients with multicentric CD were included in this analysis. Results Most of the patients were male (76%) and had a median age of 54 years. Hyaline vascular variant was the most common subtype (N=11, 39%). Hepatosplenomegaly (61%), fever (39%), edema (29%), and ascites (18%) were the most frequently reported symptoms and signs at diagnosis. With a median follow-up of 67 months, the 5-year overall survival (OS) was 77%. Patients with extravascular fluid accumulation (i.e., peripheral edema, ascites, and/or pleural effusions) were significantly associated with a poor survival rate (5-year OS, 94% vs. 56%; P=0.04). The extent of disease involvement was also a significant prognostic factor (5-year OS, 91% for involvement on a single side vs. 73% on both sides of the diaphragm; P=0.03). Other clinicopathologic factors were not significantly associated with patient survival. Conclusion Our findings suggest that the hyaline vascular variant is not a rare subtype of multicentric CD. Extravascular fluid accumulation and disseminated disease involvement seem to be significant prognostic factors.

Background Bone marrow biopsy (BMB) has been recommended for all patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) to detect bone marrow involvement in the staging workup for decades. No clear consensus, however, is reached regarding whether bilateral BMB is required for all patients or unilateral BMB is sufficient. Moreover, a number of studies have reported positron emission tomography combined with computed tomography (PET/CT) to be accurate enough to replace BMB for the detection of bone marrow involvement and the use of PET/CT in place of BMB has been consistently increasing. However reported results assessing the roles of BMB and PET/CT in the staging of the BM have been contradictory and controversial. Therefore, we investigated the difference between unilateral and bilateral BMB in the diagnostic value of DLBCL and how they are respectively correlated to PET/CT findings. Method A registry data set, prospectively collected at a single institution, Asan Medical Center (AMC), was retrospectively reviewed. Bone marrow biopsy and aspirate were performed bilaterally from September 2012 to September 2014 (n=282) and unilaterally from September 2014 to May 2016 (n=279). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET/CT were analyzed. Ann Arbor stage was determined using PET/CT with and without the contribution of BMB, and the proportion of stage IV cases by each method was calculated. Result A total of 561 patients were analyzed and all patients had evaluated BM involvement by PET/CT, of which 282 patients and 279 patients underwent unilateral and bilateral BMB, respectively. Bone marrow involvement was identified in 50 of 282 patients (17.7%) based on bilateral BMB and in 55 of 279 patients (19.7%) on unilateral BMB. In bilateral BMB group, 18 of 50 patients had unilateral involvement of bone marrow. The yield of unilateral BMB was not inferior to that of bilateral BMB. (p=0.547) In bilateral BMB group, PET/CT identified BM involvement by with sensitivity 46%, specificity 86.6%, PPV 42.6%, and NPV 88.2%. In unilateral BMB group, sensitivity 58.2%, specificity 83.9%, PPV 47.1%, and NPV 89.1%. (figure 1,2) BMB did not show statistically significant differences in the contribution to upstaging to stage IV in neither bilateral nor unilateral BMB group (p=0.513). Ann Arbor stage according to diagnostic modality is shown in table 1. Conclusion Unilateral BMB showed a similar yield compared to bilateral BMB and the likelihood of upstaging was also comparable between the two groups. Additionally the NPV of PET/CT was shown to be high as reported in previous studies. Our results suggest that unilateral BMB may replace bilateral BMB in patients with DLBCL whereas unilateral BMB might not be necessary for routine staging procedures in patients without BM involvement in PET/CT findings. Figure 1 (Case distribution of bone marrow status assessed by PET/CT and BM biopsy in patients with bilateral BMB) Figure 1. (Case distribution of bone marrow status assessed by PET/CT and BM biopsy in patients with bilateral BMB) Figure 2 (Case distribution of bone marrow status assessed by PET/CT and BM biopsy in patients with unilateral BMB) Figure 2. (Case distribution of bone marrow status assessed by PET/CT and BM biopsy in patients with unilateral BMB) Table 1 (Ann Arbor stage according to diagnostic modality in both groups of patients.) Table 1. (Ann Arbor stage according to diagnostic modality in both groups of patients.) Disclosures No relevant conflicts of interest to declare.

Background Novel treatment strategies, such as non-anthracycline-based chemotherapy and upfront use of concurrent chemoradiotherapy or radiotherapy have markedly improved the survival outcome of extranodal natural killer/T cell lymphoma (ENKTL). Recently, a new prognostic model, Prognostic Index of Natural killer cell lymphoma (PINK) was proposed for predicting clinical outcomes of ENKTL patients treated with non-anthracycline-based strategies. Elevated serum beta-2 microglobulin (B2M) had been suggested as a potential prognostic predictor for patients with ENKTL, but there was no prognostic model including serum B2M level. We investigated the prognostic role of serum B2M level and suggested a new prognostic index by incorporating serum B2M level into PINK in patients with ENKTL. Methods We retrospectively identified 98 patients who received non-anthracycline-based treatment for newly diagnosed ENKTL in Asan Medical Center between January 2005 to December 2014. Serum beta-2 microglobulin level was measured using a radioimmunoassay kit (Immunotech, Inc., Prague, Czech Republic). The optimal cutoff point of serum beta-2 microglobulin level was estimated using ROC curve analysis. We developed a new prognostic model (PINK-B) with 4 elements of PINK (Age>60 years, Ann arabor Stage ¥²-¥³, distant lymph node involvement, and non-nasal type disease) plus serum B2MG level. We performed a validation analysis of a new prognostic model (PINK-B) in an independent cohort. Result Baseline characteristic were summarized in Table 1. Median B2M value was 2.35 mg/L (range, 1.0-22.0) and the optimal cutoff value of serum B2M level for predicting 3-year overall survival (OS) was ¡Ã2.8 mg/L. Baseline serum B2M elevation (¡Ã2.8 mg/L) was observed in 39 patients (39.8%). In univariate analysis, elevated B2M level (¡Ã2.8 mg/L) was significantly associated with poorer OS (HR=3.83 ;95% CI: 2.06-7.09; p Conclusion We suggest a new version of prognostic index (PINK-B : PINK combined with elevated serum B2M) for ENKTL patients treated with non-anthracycline-based strategies. Table 1 Comparison of baseline characteristics between the training cohort and validation cohort Table 1. Comparison of baseline characteristics between the training cohort and validation cohort Figure 1 overall survival according to PINK, PINK-E, PINK-B in the training cohort Figure 1. overall survival according to PINK, PINK-E, PINK-B in the training cohort Figure 2 overall survival according to PINK, PINK-E, PINK-B in the validation cohort Figure 2. overall survival according to PINK, PINK-E, PINK-B in the validation cohort Disclosures Kim: Celltrion, Inc.: Consultancy, Honoraria.