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Purpose We conducted a nationwide, multicenter, prospective registry study for newly diagnosed patients with peripheral T-cell lymphoma (PTCL) to better define the clinical characteristics, treatment patterns, survival outcomes, and the role of upfront autologous stem cell transplantation (ASCT) in these patients.Materials and Methods Patients with PTCL receiving chemotherapy with curative intent were registered and prospectively monitored. All patients were pathologically diagnosed with PTCL.Results A total of 191 patients with PTCL were enrolled in this prospective registry study. PTCL, not otherwise specified (PTCL-NOS) was the most common pathologic subtype (n=80, 41.9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (n=60, 31.4%). With a median follow-up duration of 3.9 years, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 39.5% and 60.4%, respectively. The role of upfront ASCT was evaluated in patients who were considered transplant-eligible (n=59). ASCT was performed as an upfront consolidative treatment in 32 (54.2%) of these patients. There were no significant differences in PFS and OS between the ASCT and non-ASCT groups for all patients (n=59) and for patients with PTCL-NOS (n=26). However, in patients with AITL, the ASCT group was associated with significantly better PFS than the non-ASCT group, although there was no significant difference in OS.Conclusion The current study demonstrated that the survival outcomes with the current treatment options remain poor for patients with PTCL-NOS. Upfront ASCT may provide a survival benefit for patients with AITL, but not PTCL-NOS.

PurposeFebrile neutropenia (FN) can cause suboptimal treatment and treatment-related mortality (TRM) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Materials and methodsWe conducted a prospective cohort study to evaluate the effectiveness of pegfilgrastim prophylaxis in DLBCL patients receiving R-CHOP, and we compared them with the PROCESS cohort (n=485). ResultsSince January 2015, 986 patients with DLBCL were enrolled. Pegfilgrastim was administered at least once in 930 patients (94.3%), covering 90.3% of all cycles. FN developed in 137 patients (13.9%) in this cohort (23.7% in the PROCESS cohort, p

Supplementary Table 1. Best response to treatment among response-evaluable patients treated with RPIID (n = 43)

Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib.Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage.Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively.Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.

The Article’s Abstract is not available.

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood-brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.

Background/aim Biliary tract cancer (BTC) has a poor prognosis due to its highly invasive and metastatic potential. Ataxia-telangiectasia mutated (ATM) is a key regulator of DNA damage response and an emerging therapeutic target; however, the association between the expression of ATM and the prognosis in advanced BTC is unknown. We aimed to identify the relationship between ATM expression, clinicopathological characteristics, and survival outcomes in patients with advanced BTC. Patients and methods We analyzed 113 patients with advanced BTC who received first-line gemcitabine and platinum. Results The tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 43 patients, extrahepatic cholangiocarcinoma (EH-CCC) in 49, and gallbladder (GB) cancer in 21 patients. Fifty-four patients (47.8%) exhibited loss of ATM protein expression. The overall response rate (ORR) of ATM loss and intact ATM was 13.3% and 19.6%, respectively. In a subgroup analysis, EH-CCC patients with ATM loss tended to have improved PFS after platinum-based chemotherapy compared to those with intact ATM (7.9 vs. 6.2 months, respectively; p=0.050). Conclusion We demonstrated that ATM loss could be a prognostic marker after platinum-based chemotherapy in patients with advanced EH-CCC.

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.

Objective Crizotinib is a novel targeted anticancer agent for non–small cell lung cancer. In this study, we report our clinical outcomes from Gamma Knife radiosurgery (GKS) for brain metastasis (BM) under crizotinib treatment in non–small cell lung cancer patients. Methods We performed a retrospective review of 29 patients who underwent a total of 51 GKS procedures for BM while continuing on crizotinib. We compared 2 groups on the basis of the number of BMs: oligometastases (≤5) and polymetastases (>5). Results The actuarial 1- and 2-year overall survival rates from initial GKS were 73.5% and 42.6%, respectively. The estimated local progression-free survival (PFS) rates of the oligometastases group were 91.8% at 6 months and 84.2% at 12 months, whereas the local PFS rates of the polymetastases group at 6 and 12 months were 91.6% and 58.2%, respectively ( P = 0.153). The estimated distant PFS rates of the oligometastases group were 50.7% at 6 months and 20.3% at 12 months, whereas the distant PFS rates of the polymetastases group were 32.7% at 6 months and only 6.5% at 12 months ( P = 0.029). Conclusions GKS combined with crizotinib showed effective local tumor control and excellent outcome, especially in oligometastases. However, distant progression of BM during crizotinib after GKS occurred in most of the cases within a year. Thus brain surveillance after GKS is important for adequate and timely salvage treatment even when extracranial disease is well controlled by crizotinib.

Purpose The purpose of this study was to assess the tumor characteristics and long-term clinical outcomes of adjuvant treatments after surgery with a curative aim for patients with breast cancer who are 65 years and older. Materials and Methods Patients with breast cancer who underwent curative surgery from 2000 to 2009 were analyzed (n=4,388). Tumor characteristics and survival outcome were compared by dividing the patients into two age groups (< 65 and ≥ 65 years old). The Kaplan-Meier method was used for comparison of survival rates by log-rank test, and a Cox regression model was used to examine the effect of variables. Results Among 4,388 patients with invasive breast cancer, 317 patients (7.2%) were 65 years or older and the median age of all patients was 47 years (range, 18 to 91 years). Tumor characteristics were similar between the two age groups, but the older patients were treated less often with adjuvant treatments. During a median follow-up period of 122 months, recurrence-free survival (RFS) was equivalent for patients 65 years and older compared to younger patients, but significantly worse in overall survival (OS) and breast cancer–specific survival (BCSS) (5-year OS, 94.3% vs. 90.5%; p < 0.001 and 5-year BCSS, 94.7% vs. 91.8%; p=0.031). In the multivariate model, age ≥ 65 years old was identified as an independent risk factor for OS and RFS. Conclusion Elderly breast cancer appeared to have worse outcomes with very low prevalence in Korea, despite similar tumor characteristics. More active adjuvant therapies would have a role for aggressive subtypes for fit, elderly patients.

Overexpression of PD-L1 has been shown to be associated with better clinical responses to PD-1/PD-L1 blockade in melanoma. However, the utility of PD-L1 immunostaining as a predictive biomarker for anti-PD-1 treatment remains unclear, especially in melanoma of acral/mucosal origin. Materials and methods We collected and reviewed the medical records of 37 patients with metastatic melanoma who were treated with the anti-PD-1 antibodies pembrolizumab or nivolumab between January and December 2015. Patients with histologically diagnosed malignant melanoma and whose pretreatment tumor specimens were available for immunohistochemical staining of PD-L1 expression in tumor or immune cells were included. Results Of 37 patients, 26 patients had either acral or mucosal melanoma. The overall response rate was 10.8 % (95 % CI, 0.8-20.8 %). The response rate to PD-1 inhibitor was 11.5 % (95 % CI, 0-23.8 %) in acral/mucosal melanoma and that for cutaneous melanoma was 9.1 % (95 % CI, 0-26.1 %). Of these 37 patients, 18 had pre-treatment tumor specimens available for PD-L1 staining. Of 18 patients, 10 (55.5 %) were of acral/mucosal origin. In all patients with acral melanoma, the overall response rate (ORR) was 16.7 % (1 of 6 patients) and disease control rate (DCR) was 50 % (3 of 6 patients). In the PDL-1(+) melanoma group (1 % cut-off value), ORR was 20 % (2/10) and DCR was 80 %; for PDL-1 (-) group, ORR was 12.5 % (1/8) and DCR of 37.5 %. In the PDL-1 (+) group by 5 % cut-off value, ORR was 33.3 % (2/6) and DCR was 83.3 %; for patients with PDL-1 (-), ORR was 8.3 % (1/12) and DCR was 50 %. The median PFS was 6.8 months in PDL-1(+) group and 1.9 months in PDL-1(-) group (p = 0.149). Anti-PD-1 treatment was very well tolerated without serious adverse events of grade 3 or 4 in all patients. Conclusions The treatment outcome to PD-1 antibody was not different in acral/mucosal melanoma when compared with cutaneous melanoma. The immunohistochemical PD-L1 expression seemed to be correlated with better clinical outcomes of anti-PD-1 treatment in limited cases.

Background: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. Material and Methods: Between January 2012 and June 2015, 40 BTC patients’ samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors. Results: Extrahepatic cholangiocarcinoma (N = 15, 37.5%), intrahepatic cholangiocarcinoma (N = 10, 25.0%), gallbladder cancer (N = 14, 35.0%), and ampulla of Vater cancer (N = 1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%). Conclusions: PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.

Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis.

// Ji Yun Lee 1, * , Kyunghee Park 2, * , Sung Hee Lim 1 , Hae Su Kim 1 , Kwai Han Yoo 1 , Ki Sun Jung 1 , Haa-Na Song 1 , Mineui Hong 3 , In-Gu Do 3 , TaeJin Ahn 2 , Se Kyung Lee 4 , Soo Youn Bae 4 , Seok Won Kim 4 , Jeong Eon Lee 4 , Seok Jin Nam 4 , Duk-Hwan Kim 5 , Hae Hyun Jung 6 , Ji-Yeon Kim 1 , Jin Seok Ahn 1 , Young-Hyuck Im 1 , Yeon Hee Park 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Samsung Genomic Institute, Samsung Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Center of Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea 6 Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Yeon Hee Park, e-mail: yhparkhmo@skku.edu Keywords: breast cancer, brain metastasis, gene, mutation, mechanism Received: August 27, 2015 Accepted: October 06, 2015 Published: October 20, 2015 ABSTRACT Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0–7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

Megalocytic interstitial nephritis is a rare form of kidney disease caused by chronic inflammation. We report a case of megalocytic interstitial nephritis occurring in a 45-yrold woman who presented with oliguric acute kidney injury and acute pyelonephritis accompanied by Escherichia coli bacteremia. Her renal function was not recovered despite adequate duration of susceptible antibiotic treatment, accompanied by negative conversion of bacteremia and bacteriuria. Kidney biopsy revealed an infiltration of numerous histiocytes without Michaelis-Gutmann bodies. The patient's renal function was markedly improved after short-term treatment with high-dose steroid. Graphical Abstract Keywords: Acute Kidney Injury, Megalocytic Interstitial Nephritis, Interstitial Nephritis INTRODUCTION Megalocytic interstitial nephritis is a rare form of chronic renal inflammatory disease associated with defect in intracellular destruction of invading foreign organisms by macrophages (1). These unusual inflammatory disorders are often associated with chronic urinary tract infection by Gram-negative bacteria (2). Although the pathogeneses of these diseases are unclear, macrophage bactericidal dysfunction has been presumed as a possible pathogenic mechanism (3). We report an extraordinary case of a 45-yr-old woman who had oliguric acute kidney injury (AKI) and acute pyelonephritis with Escherichia coli (E. coli) bacteremia, accompanied by megalocytic interstitial nephritis.

T790M mutation is most common resistant mechanism to epidermal growth factor receptor gene (EGFR) tyrosin kinase inhibitor (TKI). Several third-generation EGFR-mutant selective TKI, such as AZD9291 (AstraZeneca), Rociletinib (Clovis), or HM61713 (Hanmi) have been developed. Acquired resistant C797S mutation was known to be one of the resistance mechanisms of AZD9291, which has not been reported for HM61713 yet. This is the first case report of C797S mutation as resistance mechanism of HM61713.

Sexual dysfunction is a common long-term complication of hematopoietic stem cell transplantation (HSCT). We assessed the extent to which HSCT survivors and their partners agree on the importance of and satisfaction with sexual activity and causes of sexual dysfunction, using a cross-sectional survey. Ratings of the importance of sexual activity were significantly higher in survivors than those of partners (2.57 vs. 2.14, P

Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively. Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.

8521 Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631.

e21007Background: Overexpression of PD-L1 is associated with better clinical responses to PD-1/PD-L1 blockade in melanoma, but the utility of PD-L1 immunostaining as a predictive biomarker for anti...

e15628Background: Hepatocellular carcinoma (HCC) is the third cause of cancer-related deaths and the 16th absolute cause of deaths globally. Mechanistic target of rapamycin (mTOR) is frequently up-...

9043Background: Various therapeutic strategies are available for NSCLC patients who develop disease progression on first-line EGFR-TKI. However, it has not been established which cytotoxic regimens...

Noncardiac chest pain (NCCP) is one of the most common esophageal symptoms and lacks a clearly defined mechanism. The most common cause of NCCP is gastroesophageal reflux disease (GERD). One of the accepted mechanisms of NCCP in a patient without GERD has been altered visceral sensitivity. Mast cells may play a role in visceral hypersensitivity in irritable bowel syndrome. In this case, a patient with NCCP and dysphagia who was unresponsive to proton pump inhibitor treatment had an increased esophageal mast cell infiltration and responded to 14 days of antihistamine and antileukotriene treatment. We suggest that there may be a relationship between esophageal symptoms such as NCCP and esophageal mast cell infiltration.

e638 Background: The aim of this retrospective study was to evaluate clinical outcomes of biweekly 40 mg/m2 docetaxel plus prednisolone, as compared with standard 3-weekly regimen in Korean patients with castration-resistant prostate cancer (CRPC). Methods: We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were consecutively treated with docetaxel plus prednisolone as first-line chemotherapy between Jan 2012 and Dec 2014 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve CRPC patients received 40 mg/m2 biweekly regimen (n = 24). The primary end point was the PSA response, defined as a greater than 50% decline in PSA levels from baseline. Results: The baseline characteristics of the patients were similar in the two treatment groups. The most common cause of treatment discontinuation was disease progression: 17 (71%) in 3-weekly group and 20 (82%) in biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively. Time-to-failure (TTF, 4.5 versus 3.9 months) and time-to-progression (TTP, 5.0 versus 4.2 months) were statistically similar between the 3-weekly and biweekly groups, respectively. In 3-weekly group, the most commonly observed toxic effects were anemia and neutropenia. Whereas, in biweekly group, fatigue and nail changes were the most commonly observed toxic effects. Conclusions: Within the limitation of a retrospective study, biweekly reduced dose docetaxel regimen is active and well-tolerated in Korean patients with metastatic CRPC.

577 Background: Targeted therapy has shown remarkable treatment efficacy on the outcomes of patients with advanced renal cell carcinoma. However, this advance for treatment outcomes with targeted agents has been limited to patents with clear cell histology. The optimal treatment strategy for metastatic non-clear cell renal cell carcinoma (nccRCC) remains uncertained. Recently, several vascular endothelial growth factor inhibitors have shown efficacies for nccRCC. Thus, we designed a single-arm, open label phase II study to determine the efficacy and toxicity of pazopanib in patients with nccRCC. Methods: Patients with metastatic nccRCC except for collecting duct or sarcomatoid type received 800mg/day of pazopanib daily until progression of the disease or intolerable toxicity was observed. The primary objectives were progression free survival (PFS) and second objectives were overall survival (OS), treatment response and safety profiles. Results: A total of 29 eligible patients were enrolled from September 2012 to August 2014. The median age of the patients was 59 years (range, 30-77 years) and 21 patients were male. The median PFS was 8.3 months (95% CI, 4.0-12.6 months) and median OS was not reached (range, 1.5-34.7 months). Among all 29 patients, five patients (17.2%) are ongoing treatment without disease progression. Disease progression was observed in 16 patients (55.2%) during follow up period. Five patients (17.2%) experienced a treatment-related toxicity of grade 3 or more during the study and they stopped treatment in the end. Eight patients (27%) expired during follow up period but, there were no treatment-related deaths. Conclusions: This prospective phase II study showed that pazopanib demonstrated promising activity and tolerable safety in patients with nccRCC (ClinicalTrials.gov NCT01538238). Clinical trial information: NCT01538238.

Purpose The early molecular response (EMR, ≤ 10% BCR-ABL1 at 3 months) of tyrosine kinase inhibitor (TKI) treatment for patients with chronic myeloid leukemia (CML) in chronic phase (CP) has been reported to have strong correlation with long-term outcome. We aim to investigate the prognostic interaction of the EMR and major molecular response (MMR). Methods We retrospectively reviewed data for a total of 165 patients with newly diagnosed CML-CP who received TKIs (imatinib, nilotinib, or dasatinib) as first-line treatment between January 2003 and April 2013. Of the total 128 patients who were regularly monitored by peripheral blood molecular analysis, 85 had a BCR-ABL1 assessment at 3 months and were finally included in the analysis. Results The median age of all patients was 49 years and 87.1% received imatinib as first line treatment. High risk group by Sokal and EUTOS were 29.4% and 14.1%, respectively. Patients with EMR (n = 56, 65.9%) had a tendency to have low risk disease and to be treated with 2nd generation of TKIs. With a median follow-up duration of 53.6 months (range, 5.4-131.3), the 5-year OS, 5-year FFS, and 5-year EFS were 92.5%, 74.8%, and 68.0%, respectively. Median time to achieve MMR was 11.1 months (95%CI, 8.4 - 13.8). The outcomes at 5 year comparing patients whose BCR-ABL1 transcript levels ≤ 10% vs >10% at 3 months were as follows: OS, 92.2% (95% CI 84.9-99.1) vs 92.8% (95% CI 83.7-102.3), p = 0.819; FFS, 84.7% (95% CI, 75.6-94.4) vs 57.4% (95% CI, 39.0-75.0), p < 0.001; and EFS, 73.6% (95% CI 62.5-85.5) vs 57.8% (95% CI 40.0-76.0), p = 0.050. Six (10.7%) of 56 patients with BCR-ABL1 transcript levels ≤ 10% at 3 months failed to achieved an MMR and 18 (62.1%) of 29 patients with > 10% at 3 months achieved an MMR. Based on these heterogeneous clinical outcomes, we further explored subgroup analysis according to the achievement of MMR for refined discrimination of survival outcomes. There was no significant difference of clinical outcomes between ≤ 10% vs > 10% at 3 months among the patients who achieved MMR (OS, p = 0.376; FFS, p = 0.793; and EFS, p = 0.266). In patients who did not achieved MMR, only FFS was significantly difference between ≤ 10% vs > 10% at 3 months (OS, p = 0.489; FFS, p = 0.014; and EFS, p = 0.199). Conclusion Patients who failed to achieve EMR but finally reached MMR have excellent prognosis that whether we have to change TKI for EMR failure is to be addressed by ongoing prospective clinical trials. Disclosures Jang: Alexion Pharmaceuticals: Research Funding.

Introduction: Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) recipients. Although fluconazole has been widely used as an antifungal prophylactic agent in these patients, it is not reliably effective against mold infection including invasive aspergillosis. Micafungin provides antifungal activity against Candida and Aspergillus species, and previous studies have demonstrated its efficacy when used as a prophylactic agent for fungal infection in neutropenic patients. Here, we evaluated and compared the incidence rate of proven or probable invasive fungal infections (IFIs) with antifungal prophylaxis using micafungin or fluconazole. Methods: This is a prospective, single center, phase II study involving adult patients who received allogeneic or autologous HSCT. Patients were randomly assigned to micafungin or fluconazole arms in the ratio of 2:1, and the treatment was initiated within 24 hour of hematopoietic stem cell infusion and maintained for up to 21 days. Primary objective was the incidence of proven or probable invasive fungal infections (IFIs) during the 100 days after HSCT. Secondary objectives involved the incidence of possible, proven or probable IFIs, need for change of anti-fungal agents before engraftment, IFI-related mortality and survival within 100 days after transplantation. Results: Between March 2010 and May 2015, a total of 257 patients were enrolled. Excluding 7 patients who did not receive at least one dose of study treatment, 250 patients (micafungin, n=165; fluconazole, n=85) were examined for clinical efficacy. The median age was 47 years (20-64) and allogeneic and autologous transplantation comprised 56.0% (n=140) and 44.0% (n=110) of the patients. Baseline characteristics were well balanced between the two groups. Overall, the incidence of proven and probable IFIs within 100 days of HSCT was 7.6% (n=19), and there was no significant difference in the proportion of patients who experienced proven or probable IFIs between the micafungin and the fluconazole groups (7.3% in micafungin group versus 8.2% in fluconazole group, p=0.786). Thirteen patients of micafungin arm (7.9%) and 8 patients of fluconazole arm (9.4%) had to have changed antifungals before engraftment (p=0.824). There was no significant difference in the mortality within 100 days after HSCT (9.1% in micafungin arm vs 12.9% in fluconazole arm, p=0.345). Conclusion: Micafungin is comparable to fluconazole in the prevention of IFIs in HSCT recipients. Table 1. Clinical outcomes including invasive fungal infections within 100 days after transplantation Characteristics (total n=250) Total patients(n=250) Fluconazole(n=85) Micafungin(n=165) p-value Proven IFIs AllCandidiasisAspergillosisMucormycosis 5 (2.0%) 2 (0.8%) 1 (0.4%) 2 (0.8%) 3 (3.5%) 1 (1.2%) 0 (0.0%) 2 (2.4%) 2 (1.2%) 1 (0.6%) 1 (0.6%) 0 (0.0%) 0.341 1.000 1.000 0.115 Probable IFIs 16 (6.4%) 5 (5.9%) 11 (6.7%) 0.810 Possible IFIs 7 (2.8%) 1 (1.2%) 6 (3.6%) 0.428 Proven, probable IFIs 19 (7.6%) 7 (8.2%) 12 (7.3%) 0.786 Proven, probable, possible IFIs 26 (10.4%) 8 (9.4%) 18 (10.9%) 0.713 Invasive mold infections Proven, probable Proven, probable, possible 18 (7.2%)25 (10.0%) 6 (7.1%)7 (8.2%) 12 (7.3%)18 (10.9%) 0.9510.504 Need for anti-fungal agents change before engraftment 21 (8.4%) 8 (9.4%) 13 (7.9%) 0.824 Mortality within 100 days after HSCT 26 (10.4%) 11 (12.9%) 15 (9.1%) 0.345 IFI related mortality within 100 daysafter HSCT 5 (2.0%) 3 (3.5%) 2 (1.2%) 0.341 28 invasive fungal infections were observed in 26 patients Abbreviations: IFI=invasive fungal infection, HSCT=Hematopoietic stem cell transplantation Disclosures No relevant conflicts of interest to declare.

Introduction Sexual dysfunction after receiving hematopoietic stem cell transplantation (HSCT) deteriorates quality of life (QoL) of both HSCT survivors and their partners. However, previous studies have mainly focused on the patients' medical and psychological factors contributing to sexual dysfunction, rather than on the perspectives of the relationship between the patients and their partners. We conducted a cross-sectional, HSCT survivor-partner matching study to determine the concordance of perception, attitude, and problems raised in their sexual activity after receiving HSCT. Methods HSCT survivors and their partners were recruited through the post-HSCT registry from Samsung Medical Center and Korea Blood Cancer Association. HSCT survivors and their partners have separately answered to a set of questionnaire which includes items on their sexual activity, QoL, depression, fear of recurrence and body image. We analyzed the data using McNemar test, paired t-test, kappa coefficients to correct for the amount of agreement and multivariable logistic regression models. Results Between September 2013 and March 2015, 175 patients who received HSCT for hematologic malignancies and had no evidence of recurrent disease were recruited. Finally, 91 pairs of HSCT survivors and their partners were analyzed. Sixty (65.9%) patients were male and mean age of patients and their partners were 51.5 and 49.8, respectively. Type of HSCT were autologous in 29 patients (31.9%), allogenic from sibling donor in 27 patients (29.7%), allogenic from unrelated donor in 25 patients (27.5%) and haploidentical HSCT in 9 patients (9.9%). Twenty-six (28.6%) and 51 patients (56.0%) experienced acute graft-versus-host disease (GVHD) and chronic GVHD, respectively. The average period after HSCT was 3.3 years and 23 patients were treated with corticosteroids at the time of study enrollment. The patients and their partners showed discordance in the aspects of importance and satisfaction of sexual activity. The patients scored higher than their partners at the questions of "Adequate sexual activity is important." (2.57 vs. 2.14, difference 0.44±1.12, p Conclusions HSCT survivors considered sexual activity is important, and they desired to engage in sexual activity more than their partners did. Misunderstanding of the patients' demands by their partners can be one of the causes of decreased sexual activity. Adequate educational and interventional programs for HSCT survivors and their partners are needed for improving QoL after receiving HSCT. Disclosures No relevant conflicts of interest to declare.

Correspondence to Jiwon Hwang, M.D. Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3439, Fax: +82-2-3410-3849, E-mail: ninedw.hwang@samsung.com *Conflict of Interest: The authors disclose no potential conflicts of interest. Copyrightc 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 반복하여 재발한 류마티스 결절증(nodulosis) 1예

Correspondence to Eun-Mi Koh, M.D., Ph.D. Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3433, Fax: +82-2-3410-3849, E-mail: emkoh@skku.edu Copyrightc 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 전신경화증과 류마티스 관절염의 중복 증후군 3예

There have been conflicting reports on the continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with newly developed or progressive brain metastasis of non-small cell lung cancer (NSCLC). Patients with newly developed or progressive intracranial lesions, but who maintained well-controlled extracranial disease during erlotinib treatment, were enrolled in this study. The proposed therapy included stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and/or surgical resection for intracranial lesions. Erlotinib treatment was continued simultaneously unless extracranial disease progressed. The evaluation of both extra- and intra-cranial lesions was perform ed every 3 months. From October 2009 to June 2012, 14 patients were enrolled in this pilot study. For intracranial disease, 4 patients received SRS alone, 7 patients received both SRS and WBRT, 2 patients received SRS, WBRT and surgical resection, and 1 patient received no local therapy due to the presence of asymptomatic lesions. Of the patients with extracranial disease who were placed on continued erlotinib therapy, 6 patients (42.9%) showed partial response (PR), while 7 patients (50.0%) remained in stable disease (SD). The progression-free survival (PFS) of extracranial and intracranial disease was 11.1 (range 1.6-34.6) and 10.2 (range 1.5-34.6) months, respectively. In 5 cases, brain lesions relapsed before the progression of extracranial disease. Overall survival (OS) was 22.6 (range 2.1-50.4) months. For NSCLC patients with progression of only intracranial disease during erlotinib treatment, the continuation of erlotinib in combination with local therapy to brain metastases can be an effective treatment option.

Background Mantle cell lymphoma (MCL) is a rare but unique subtype of B-cell non-Hodgkin lymphoma (NHL) that is molecularly characterized by the chromosomal translocation, t(11;14)(q13:q32) leading to cyclin D1 overexpression. MCL is also characterized by heterogeneous clinical features from indolent to aggressive courses. The majority of patients with MCL initially show slowly progressing nature of disease, however, the treatment outcomes of conventional chemotherapy have been poor. As a result, most patients with MCL have shown repeated relapses ultimately resulting in death. Although upfront use of intensified chemotherapy regimens and active application of autologous stem cell transplantation as a consolidation treatment were introduced, MCL has still remained as one of deadly subtype of NHL because its prognosis is still worse than other NHL. Given this heterogeneity and incurability of MCL, the concept of tumor stem cells has been suggested to explain peculiar characteristics of MCL. Thus, previous in vitro studies reported a small fraction of tumor cells, CD45+/CD19- might reflect the presence of tumor stem cells and showed their resistance to chemotherapeutic agents as well as tumor formation ability. However, the clinical relevance of CD45+/CD19- stem-like cell population in bone marrow or other sites has rarely been studied and demonstrated in patients with MCL. Methods Between 2011 and 2013, we analyzed patients who were pathologically diagnosed with MCL. They all received systemic chemotherapy with curative intent including rituximab-containing chemotherapy. The flow cytometry for isolating CD45+/CD19- cell population was done with bone marrow aspirates or malignant effusion from patients at diagnosis and/or at the time of relapse. The follow-up evaluation of CD45+/CD19- cells was also done at the end of primary treatment. The in vitro experiments with B-cell lymphoma cell lines were performed to evaluate the association of CD45+/CD19- cell population with the resistance to chemotherapeutic agents. The percentage of CD45+/CD19- cells from surviving cells after doxorubicin treatment at the dosage of IC90 for 48 hours were compared with control group. Results Twenty-one patients were enrolled, and the median age was 67 years (range, 50–78 years). Eighteen patients had stage IV disease including 15 cases of bone marrow involvement. All patients’ sample was from bone marrow aspirates except one patient from malignant pleural effusion. The examination for CD45+/CD19- cells was done in six patients at diagnosis and the end of treatment whereas only single evaluation was done in the other patients at diagnosis or at the time of relapse. The median percentage of CD45+CD19- cells was 0.019% (range 0-1.8%) in all examined patients. The mean percentage of patients who relapsed or progressed (0.41%±0.69) was higher than that of patients at diagnosis (0.09%±0.11) or patients at the state of complete or partial response after the completion of chemotherapy (0.01%±0.01). The serial monitoring of three patients who relapsed or progressed showed the increased level of CD45+/CD19- cell population while patients who responded to primary treatment showed the decreased level of CD45+/CD19- cells at the end of treatment. The in vitro study with B-cell lymphoma cell lines, Toledo, Daudi, Raji and BJAB showed the increased fraction of CD19- cells among lymphoma cells resistant to doxorubicin compared to control cells. This increase of CD19- cells was correlated with the increase of ATP-binding cassette subfamily G2 (ABCG2) that was another marker reflecting the presence of tumor stem cells. Conclusion The presence of CD45+/CD19- cell population was demonstrated in bone marrow aspirates of patients with MCL, and its level was correlated with clinical outcome including response to treatment and relapse or progression. Considering the association of CD45+/CD19- cells with resistance to treatment, the presence of this extremely small but significant stem-like fraction might be associated with treatment failure in patients with MCL. Disclosures No relevant conflicts of interest to declare.

Percutaneous left atrial appendage (LAA) occlusion using the Watchman device (Atritech, Plymouth, MN) is suggested as an alternative modality to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (AF). However, peridevice leakage resulting from incomplete LAA occlusion remains 1 of the most frequent limitations. We report a case of progressive increase in peridevice leakage after Watchman device implantation on long-term transesophageal echocardiographic follow-up accompanied by stroke.

6023 Background: Concurrent chemoradiation therapy (CCRT) with every 3 week schedule of cisplatin is the standard treatment for locally advanced nasopharyngeal carcinoma (NPC), but concerns have be...