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Background: The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted., Methods: We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort., Findings: We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group., Interpretation: PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy., Funding: Samsung Biomedical Research Institute., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24-hr CI without idarubicin (C-FLAG), which was compared with the results of C-FLAG with idarubicin (CI-FLAG2) in younger patients' trial. A total of 33 and 68 patients were enrolled in C-FLAG and CI-FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C-FLAG and CI-FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C-FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C-FLAG (P < 0.001) and was a favorable predictor of longer survival by multivariate analysis (P = 0.009). Median overall survival was 3.19 (95% CI, 2.05-4.33) months and similar with that of CI-FLAG2 (P = 0.841). Attenuated salvage regimen C-FLGA in elderly patients was as effective as more intensive younger patients' regimen CI-FLAG2 in terms of response and survival although elderly patients had more unfavorable clinical characteristics., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Myeloproliferative neoplasms are associated with lymphoproliferative diseases following the administration of cytotoxic drugs or exposure to radiation, but are rare prior to therapy. The present study reports the case of a 61-year-old female with a history of transient ischemic attack. The patient, who presented with a palpable mass in the epitrochlear area of the left arm, was simultaneously diagnosed with follicular lymphoma and an unclassifiable myeloproliferative neoplasm. Excisional lymph node biopsy revealed stage I follicular lymphoma (grade 1). Laboratory findings demonstrated leukocytosis, erythrocytosis, thrombocytosis and decreased erythropoietin. Biopsy of the bone marrow revealed hypercellularity, with predominance of erythroid cells, and large polylobated megakaryocytes with increased mitotic figures, but no evidence of lymphomatous infiltration. The janus kinase 2 V617F mutation was also detected in the cells derived from the bone marrow specimen. Following local excision of the lymph node in the left epitrochlear area, radiation was delivered to the involved field, at a dose of 24 Gy in 12 fractions. The patient was started on hydroxyurea (1 g twice per day, orally) 2 weeks subsequent to radiotherapy, and was administered 500 mg twice per day as maintenance therapy. At the six-month follow-up, the white blood cell count, hemoglobin levels and platelet count had reduced, and the patient was in a healthy condition. A computed tomography scan of the neck, chest and abdomen indicated no abnormalities. To the best of our knowledge, the present study is the first case report of follicular lymphoma coexisting with an unclassifiable myeloproliferative neoplasm in a previously healthy patient. Molecular and genetic studies are required to further evaluate this infrequent disease association.

We compared the outcomes of patients with higher-risk diffuse large B-cell lymphoma (DLBCL) who were treated with either up-front autologous stem cell transplantation (ASCT) or salvage chemotherapy followed by delayed ASCT after relapse. Data for 122 DLBCL patients who underwent ASCT as up-front or salvage treatment were analyzed. The 3-year overall survival (OS) rate in DLBCL patients who underwent up-front ASCT was 76.6%, and the rate for those who underwent delayed ASCT was 60.9% (p = 0.017). In a subgroup analysis of patients with a high-intermediate/high-risk age-adjusted International Prognostic Index, achievement of complete remission translated into improved OS in the up-front ASCT group, whereas patients who achieved partial remission had similar OS rates in both groups. The up-front ASCT group had improved OS in patients aged <50 years or with good performance status, whereas the OS rates of both groups were similar in patients aged ≥ 60 years or with poor performance status. When the OS outcome is analyzed by the number of factors (no complete remission during R-CHOP induction chemotherapy, age ≥ 50 years, and performance status ≥ 2), the 3-year OS rates of patients with zero or one, two, and three clinical factors were 80.2%, 51.6%, and 0%, respectively (p < 0.001). In conclusion, in higher-risk DLBCL patients, induction chemotherapy followed by up-front ASCT may have a survival benefit compared with induction chemotherapy alone in highly selected patients who have achieved a complete remission, who are aged <50 years, and who have a good performance status at diagnosis., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA., (© 2016 S. Karger AG, Basel.)

Aims: Adjuvant chemotherapy is recommended for gastric cancer after a gastrectomy with D2 dissection. However, its survival benefit in elderly patients is unclear. Here we investigated the use of adjuvant chemotherapy in patients ≥70 years old with stage II or III gastric cancer., Methods: Patients ≥70 years old diagnosed with stage II or III gastric cancer at Ulsan University Hospital were identified. A retrospective analysis of electronic and paper patient records was performed., Results: From 2008 to 2012, 277 patients ≥70 years old underwent gastrectomy with D2 dissection. Of these patients, 94 were pathologically diagnosed with stage II or III; 55 of these patients (58.5%) received adjuvant chemotherapy and 39 received regular checkups without chemotherapy. Fluoropyrimidine-alone regimens, including TS-1 composed of tegafur, gimestat and otastat potassium (n = 26) and doxifluridine (n = 22), were more commonly used than fluoropyrimidine-platinum combination regimens (n = 7). With a median follow-up of 30.9 (range 0.8-65.5) months, the median relapse-free survival of patients with adjuvant chemotherapy or regular follow-up only was 35.5 and 20.4 months, respectively (P = 0.030). Multivariate analysis revealed that adjuvant chemotherapy is associated with longer relapse-free survival (hazard ratio 0.50; 95% confidence interval 0.27-0.96). There was a trend toward an improved overall survival in the adjuvant chemotherapy group compared with the follow-up only group (P = 0.242)., Conclusions: Although well-designed prospective studies are required, adjuvant chemotherapy may confer a potential survival benefit in elderly patients (aged 70 or older) with stage II or III gastric cancer after a gastrectomy with D2 dissection., (© 2015 Wiley Publishing Asia Pty Ltd.)

The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET., (©2015 American Association for Cancer Research.)

Background/aims: The purpose of this study was to determine the correlations between inflammatory factors-including absolute lymphocyte count, lactate dehydrogenase, β2-microglobulin, albumin, C-reactive protein, and ferritin-and the prognosis for survival in patients with multiple myeloma (MM) treated with induction chemotherapy containing thalidomide and who underwent autologous stem cell transplantation (ASCT)., Methods: Data from patients at 13 university hospitals in South Korea were collected retrospectively between December 2005 and May 2013., Results: The median age of the 232 patients was 57 years (range, 33 to 77) and the male to female ratio was 1.09:1. In the multivariate analysis, fewer than two combined abnormal inflammatory factors was the only independent prognostic factor for superior progression-free survival (relative risk [RR], 0.618; 95% confidence interval [CI], 0.409 to 0.933; p = 0.022), and platelet count > 100 × 10(9)/L and fewer than two combined abnormal inflammatory factors were independent prognostic factors for superior overall survival (RR, 4.739; 95% CI, 1.897 to 11.839; p = 0.001 and RR, 0.263; 95% CI, 0.113 to 0.612; p = 0.002, respectively)., Conclusions: Patients with two or more than two combined inflammatory factors who were treated with thalidomide induction chemotherapy and who underwent ASCT showed significantly shorter survival compared to those with fewer than two combined inflammatory factors. These results could be helpful for predicting prognosis in patients with MM.

Limited data exist on up-front autologous stem cell transplantation (ASCT) in extranodal natural killer/T cell lymphoma (ENKTL). Sixty-two patients (43 men and 19 women) with newly diagnosed ENKTL who underwent up-front ASCT after primary therapy were identified. Poor-risk characteristics included advanced stage (50%), high-intermediate to high-risk International Prognostic Index (25.8%), and group 3 to 4 of NK/T Cell Lymphoma Prognostic Index (NKPI, 67.7%). Pretransplant responses included complete remission in 61.3% and partial remission in 38.7% of patients, and final post-transplantation response included complete remission in 78.3%. Early progression occurred in 12.9%. At a median follow-up of 43.3 months (range, 3.7 to 114.6), 3-year progression-free survival (PFS) was 52.4% and 3-year overall survival (OS) was 60.0%. Patients with limited disease had significantly better 3-year PFS (64.5% versus 40.1%, P = .017) and OS (67.6% versus 52.3%, P = .048) than those with advanced disease. Multivariate analysis showed NKPI and pretransplant response were independent prognostic factors influencing survival, particularly NKPI in limited disease and pretransplant response in advanced disease. Radiotherapy was an independent factor for reduced progression and survival in patients with limited disease, but anthracycline-based chemotherapy was a poor prognostic factor for progression in patients with advanced disease. Up-front ASCT is an active treatment in ENKTL patients responding to primary therapy., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Here we report a case of a 76-year-old man with diffuse large B-cell lymphoma (DLBCL) with simultaneous involvement of the right breast and left testicle. The patient underwent complete resection of the involved testis, followed by immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and prophylactic radiotherapy to the contralateral testis. Following this multimodal therapy, he achieved a complete response. This is a rare case of DLBCL involving both the breast and the testis in a male patient.

Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI), is approved for the second-line treatment of chronic myeloid leukemia (CML) in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML) are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA). We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm) in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.

The practical usefulness of Helicobacter pylori eradication for immune thrombocytopenia (ITP) patients is still controversial. However, some ITP patients respond to H. pylori eradication. We conducted a multi-center, open label, prospective phase II study to define the efficacy and toxicities of H. pylori eradication as the first line treatment for persistent or chronic ITP patients with moderate thrombocytopenia. Patients with persistent or chronic ITP showing moderate thrombocytopenia (30 × 10(9)/L ≤ platelet count ≤ 70 × 10(9)/L) and positive C(13)-urea breath test (UBT) were selected. Medication consisted of lansoprazole 30 mg, amoxicillin 1000 mg, and clarithromycin 500 mg orally twice daily for a week. Complete response (CR) rate at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 50.0, 50.0, 26.9, and 65.4%, respectively. Overall response rate (ORR) at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 57.7, 65.4, 30.8, and 69.2%, respectively. Median maximal platelet count during the first 3 months was 110 × 10(9)/L (range, 40-274). Median time to CR was 8 weeks (95% CI = 5.429-10.571). Median time to ORR was 4 weeks (95% CI = 1.228-6.772). Only per-protocol population was a response predictor for ORR at 3 months (70.0%, p = 0.054) and maximal ORR (80.0%, p = 0.051), but not for CR at 3 months (60.0%, p = 0.160). Therefore, eradication of H. pylori is an effective and durable first line treatment for persistent or chronic ITP with moderate thrombocytopenia with high ORR and rapid onset in this study.

Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

Although serum beta-2 microglobulin (B2M) has been suggested as an independent prognostic factor for several lymphoproliferative diseases, it has rarely been investigated in extranodal natural killer/T cell lymphoma (ENKTL). From a prospectively collected database, 145 patients with ENKTL were identified. Among them, a total of 101 patients were included in the analysis, with exclusion of patients without baseline serum B2M level and those did not receive anticancer therapy. Serum B2M (<3.0 vs. ≥3.0 mg/L) was analyzed for association with overall survival (OS). Seventy-nine (78 %) patients had nasal ENKTL, and 22 (22 %) had extranasal ENKTL. In overall patients, median OS was 26.7 months (95 % confidence interval (CI), not assessable), with a median follow-up of 32.4 months (range, 0.9-155.2 months). While median OS was not reached in patients with nasal ENKTL, extranasal ENKTL group had median OS of 5.1 months (95 % CI, 1.2-8.9 months; p < 0.001). Baseline serum B2M was significantly associated with OS in patients with nasal ENKTL (p < 0.001). This was consistent in limited (stages I and II) nasal ENKTL (p = 0.002) and disseminated (stages III and IV) nasal ENKTL (p = 0.02). However, there was no difference of OS in extranasal ENKTL patients (p = 0.69). In multivariate analysis including other prognostic factors, elevated serum B2M was significantly associated with poor OS (hazard ratio (HR) = 3.8, 95 % CI 1.7-8.2, p = 0.001, in a model including Korean Prognostic Index, and HR = 3.6, 95 % CI 1.6-8.2, p = 0.002, in a model including International Prognostic Index). In patients with nasal ENKTL, baseline serum B2M is a powerful prognostic factor. The prognostic value of B2M was independent of previously established prognostic models. Further investigations are necessary to validate the role of B2M in ENKTL.

Several studies have reported that imatinib may induce tumor responses and prolonged disease stabilization in aggressive fibromatosis (AF). This effect may relate to the PDGFR-β pathway and KIT mutations. Sunitinib not only inhibits PDGFRs, KIT, and FLT3, it also blocks VEGFRs and thus serves as an antiangiogenic agent. The aim of this prospective multicenter uncontrolled study was to evaluate the efficacy and safety of sunitinib in patients with advanced AF. Nineteen patients with pathologically proven AF were recruited between June, 2008, and March, 2012, from three centers. One treatment cycle consisted of 37.5 mg/day sunitinib for 4 weeks without a break. The primary endpoint was tumor response rate according to RECIST 1.0. Ten (53 %) patients were female and the median age was 30 years (range, 22-67). Most of the primary sites were intra-abdominal (12, 63.2 %), and AF associated with familial adenomatous polyposis in ten patients (52.6 %). With a median of six cycles per patients (range, 1-47 cycles), five patients (26.3 %) achieved a partial response and eight (42.1 %) had stable disease. The overall response rate was 26.3 % (95 % confidence interval [CI], 6.3-45.7) in intention-to-treat analysis. With a median follow-up time of 20.3 months (range, 1.8-50.7), the 2-year rates of progression-free and overall survival were 74.7 % and 94.4 %, respectively. Grade 3 or 4 adverse events of sunitinib that occurred in >5 % of patients were neutropenia (33.3 %), diarrhea (5.3 %), and hand-foot syndrome (5.3 %). In 3 of 12 patients with mesenteric AF, mesenteric mass bleeding (n = 1), bowel perforation (n = 1), and bowel fistula (n = 1) with tumor mass necrosis were observed early during sunitinib treatment. Therefore, sunitinib showed potential antitumor activity and may be useful for the management of non-mesenteric AF.

Multiple myeloma (MM) is characterized by clonal expansion of malignant bone marrow cells producing a unique monoclonal immunoglobulin. The appearance of abnormal protein band (APB) in MM has been reported during follow-up. We aimed to evaluate the clinical characteristics and outcomes of patients with APB in a single center cohort. A total of 377 consecutive MM patients were treated at the Asan Medical Center between January 2002 and December 2012. We compared clinical characteristics and survival outcome between those with and without APB. Of the 377 patients, 34 (9 %) experienced APB. They comprised 18.2 % (27/148) of patients treated with autologous stem cell transplantation (ASCT) and 3.1 % (7/229) of those not receiving ASCT. APB occurred after a median of 7.9 months (range, 2.2-95.7 months) from diagnosis. Immunoglobulin isotypes at diagnosis were as follows: IgG (n = 10), IgA (n = 8), IgD (n = 5), free κ (n = 4), and free λ (n = 7). Nine patients experienced a second APB. With a median follow-up of 54.1 months, the median overall survival (OS) has not been reached in patients with APB and was 38.3 months in patients without (P < 0.001). Multivariate analysis indicated that the development of APB was a significant favorable prognostic factor for OS (hazard ratio 0.21; 95 % confidence interval 0.08-0.52). Serum β₂-microglobulin, albumin, creatinine, and ASCT were also independent prognostic factors for OS. Further investigation is required to establish the mechanisms underlying APB in MM.

We previously assessed continuous infusion (CI) of fludarabine and cytarabine plus idarubicin (CI-FLAG1) for patients under 65 years of age with resistant acute myeloid leukemia. Induction chemotherapy consisted of idarubicin (IDA) plus fludarabine and cytarabine (ARAC) as a 24-hour CI. In response to induction, 31.6% of patients achieved complete remission (CR) and in 68.4% the treatment failed. We concluded that CI-FLAG1 carried a high risk of toxicity and reduced CI-FLAG doses were recommended. Therefore, we revised the protocol (CI-FLAG2) by reducing the dose of IDA and ARAC. In total, 38 and 68 patients were enrolled into CI-FLAG1 and CI-FLAG2, respectively. When comparing outcomes between CI-FLAG1 and CI-FLAG2, there were no differences in terms of the CR rate (p = 0.306) and the overall response rate (ORR; p = 0.206). The treatment failure patterns were different between CI-FLAG1 and CI-FLAG2. The median overall survival showed only a trend towards longer survival in CI-FLAG2 (p = 0.074). Among intermediate-risk patients, there were high response rates favoring CI-FLAG2 in terms of the CR rate (p = 0.108), the ORR (p = 0.031), and overall survival (p = 0.033). This represented a relatively improved response rate compared to our previous study. There was decreased aplasia with dose reductions at the expense of increased resistance. A reduced dose of CI-FLAG might be most beneficial for intermediate-risk groups., (© 2014 S. Karger AG, Basel.)

Aim: To evaluate tumor markers as prognostic factors in patients with metastatic or recurrent gastric cancer receiving first-line chemotherapy., Methods: Between January 2000 and December 2008, 1178 patients with metastatic or recurrent gastric cancer were assayed for expression of three serum tumor markers, CA 19-9, CA 72-4 and carcinoembryonic antigen (CEA), prior to the initiation of first-line chemotherapy., Results: Elevated serum concentrations of carbohydrate antigen (CA) 19-9 (>37 U/mL), CA 72-4 (>4 U/mL) and carcinoembryonic antigen (CEA) (>6 ng/mL) were observed in 38, 56 and 33% of patients, respectively. Univariate analysis showed that elevated serum concentration of each of the three markers, CA 19-9 (P = 0.001), CA 72-4 (P = 0.001) and CEA (P = 0.030), was significantly associated with poor patient prognosis. However, multivariate analysis showed that an elevated CA 19-9 concentration only was significantly associated with shorter survival (hazard ratio [HR] 1.22; 95% CI, 1.08-1.37, P = 0.002). In the good risk and moderate risk groups, previously defined by clinical factors alone, survival was significantly lower in patients with elevated CA 19-9 (P < 0.001 and P = 0.021, respectively), but this difference was not observed in the poor-risk group., Conclusion: Elevated serum CA 19-9 concentration in patients with metastatic or recurrent gastric cancer, especially in good or moderate risk groups, is an independent negative predictor of prognosis., (© 2012 Wiley Publishing Asia Pty Ltd.)

Background: Leptomeningeal metastasis (LM) is one of the major problems in the management of metastatic breast cancer; typically, LM has a devastating prognosis and often represents a terminal event. The present study analyzed the clinical features and outcome of LM in patients with breast cancer., Methods: The medical records of patients diagnosed with LM from breast cancer at Asan Medical Center, between 2002 and 2012, were reviewed retrospectively., Results: Of 95 LM patients, 38 (40 %) had an ECOG performance status (PS) ≤ 2, and the median age was 47 years (range 26-72 years). At the time of LM diagnosis, 46 patients (48.4 %) presented with coincidental failure of systemic disease control. Seventy-eight patients (82.1 %) underwent intrathecal (IT) chemotherapy, resulting in cytologic negative conversion in 26 patients, and 46 patients (48.4 %) received systemic chemotherapy. The median overall survival (OS) time was 3.3 months, and 7.8 % of the patients survived for more than 1 year. OS tended to be higher in patients who achieved cytologic negative conversion from IT chemotherapy than in those who did not (4.5 vs. 2.4 months, P = 0.088). Multivariate analysis demonstrated that ECOG PS ≤ 2, controlled extracranial disease at the time of LM diagnosis, and systemic chemotherapy after LM diagnosis were independent factors associated with survival., Conclusions: The prognosis of patients with LM from breast cancer is poor. Systemic chemotherapy, in addition to intrathecal chemotherapy, might confer a survival benefit, even after the detection of LM.

Background: Several studies have described the efficacy of topical vitamin K1 cream in the prevention and treatment of acneiform rash during cetuximab treatment., Objectives: An interventional study with a historical control was conducted to investigate the efficacy of vitamin K1 cream for acneiform rash associated with cetuximab., Methods: For the historical control, data were collected from 40 patients with metastatic colorectal cancer who had participated in a previous clinical trial of cetuximab plus irinotecan. The experimental group consisted of 61 patients who were instructed to prophylactically apply topical vitamin K1 cream beginning on the first day of cetuximab treatment. The incidence, severity, and time to occurrence of acneiform rash were compared between groups., Results: The incidence of grade≥2 acneiform rash after 4 weeks of cetuximab treatment was 42.5% in the historical control group and 55.5% in the experimental group. The median time to grade≥2 rash in the experimental group was 4 weeks compared to 6 weeks in the historical control group (p=0.340). By multivariate analysis, male gender was the only independent risk factor for grade 2 or worse acneiform rash (HR=2.49; 95% CI, 1.27-4.88; p=0.007). Prophylactic application of topical vitamin K1 cream did not decrease the risk of acneiform rash (HR=1.33; 95% CI, 0.57-3.10; p=0.507)., Conclusions: The prophylactic application of topical vitamin K1 cream did not translate into clinically meaningful benefit in terms of reducing acneiform rash in patients with metastatic colorectal cancer treated with cetuximab.

We previously showed that hematopoietic progenitor cell (HPC) count is a useful surrogate for the timing of autologs stem cell collection (ASCC). We investigated the role of HPC count increment in predicting the time for optimal ASCC in patients with multiple myeloma (MM). Between May 2002 and January 2011, 138 patients with MM who underwent ASCC after mobilization with cyclophosphamide (4 g/m(2)) and granulocyte-colony stimulating factor at Asan Medical Center. HPC monitoring was started on the 10th day of cyclophosphamide administration and ASCC was performed when HPC count reached at least 10/mm(3). Velocity of HPC increment (/mm(3) /day) was calculated as HPC count on the first day of ASCC/number of days from cyclophosphamide infusion to the first day of ASCC. A total of 422 leukapheresis were performed in 136 patients (median per patient: 3; range: 2-8). Of these patients, 131 (94.9%) successfully achieved optimal ASCC (≥5 × 106 CD34+ cells/kg). The median velocity of HPC increment was 2.17/mm(3) /day (range: 0.07-144.2/mm(3) /day). The mean ± standard error numbers of apheresis procedures in patients with velocity of HPC increment ≤2.0/mm(3) /day and >2.0/mm(3) /day were 3.43 ± 0.17 and 2.70 ± 0.11, respectively, and their median times to optimal ASCC were 15 and 13 days, respectively, with a hazard ratio of 0.47 (95% confidence interval, 0.32-0.68; P < 0.001) on multivariate analysis. Therefore, a slower increase of HPC of ≤2.0/mm(3) /day is associated with larger number of apheresis procedures for optimal ASCC., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: The clinical features of extranodal natural killer (NK)/T-cell lymphoma (ENKL) that originates in extranasal sites are less well defined than those of ENKL that originates in nasal sites. Therefore, we compared the clinical characteristics and prognoses of patients with nasal ENKL and patients with extranasal ENKL., Methods: We retrospectively analyzed 117 consecutive patients with ENKL that included 89 (76.1%) with nasal and 28 (23.9%) with extranasal disease., Results: Extranasal ENKL was associated with more adverse clinical features than nasal ENKL, which included the presence of B symptoms, stage III/IV disease, ≥2 extranodal sites, and involvement of regional lymph nodes and bone marrow. After a median follow-up of 33.1 months (range, 0.7-152.2 months), the median overall survival (OS) of patients with extranasal and nasal NK/T-cell lymphoma was 8.6 and 86.5 months, respectively. Multivariate analysis revealed that extranasal NK/T-cell lymphoma was a significant factor that affects OS. When patients with extranasal ENKL were classified into low-risk and high-risk categories according to the Korean Prognostic Index (KPI) and International Prognostic Index (IPI), these indices categorized the two groups with significantly different survival outcomes (P = 0.025 and 0.035, respectively)., Conclusions: Patients with extranasal ENKL have worse clinical outcomes than those with nasal ENKL. The KPI and IPI appear useful for the prognosis of patients with extranasal ENKL., (© 2012 John Wiley & Sons A/S.)

The purpose of this study is to validate the recently published Breast-Graded Prognostic Assessment (GPA) and propose a new prognostic model and nomogram for patients with brain parenchymal metastases (BM) from breast cancer (BC). We retrospectively investigated 171 consecutive patients who received a diagnosis of BM from BC during 2000-2008. We appraised the recently proposed Sperduto's BC-specific GPA in training cohort through Kaplan-Meier survival curve using log-rank test and area under the curve for the BC-GPA predicting overall survival at 1 year and developed a new nomogram to predict outcomes using multivariate Cox-regression analysis. By putting the Sperduto's Breast-GPA together with our nomogram, we developed a new prognostic model. We validated our new prognostic model with an independent external patient cohort from 2 institutes for the same period. On the basis of our Cox-regression analysis, therapeutic effect of trastuzumab and status of extracranial systemic disease control were incorporated into our new prognostic model in addition to Karnofsky performance status, age, and hormonal status. Our new prognostic model showed significant discrimination in median survival time, with 3.7 months for class I (n = 15), 7.8 months for class II (n = 82), 10.7 months for class III (n = 42), and 19.2 months for class IV (n = 32; P < .0001). The new prognostic model accurately predicted survival among patients with BC from BM in an external validation cohort (P < .0001). We propose a new prognostic model and a nomogram reflecting the different biological features of BC, including treatment effect and status of extracranial disease control, which was excellently validated in an independent external cohort.

Background: Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen., Methods: We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE., Results: The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×10(9)/L) and neutrophil engraftment (>0.5×10(9)/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted., Conclusion: Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.

Background: High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) after combined chemotherapy with infusional vincristine/doxorubicin plus dexamethasone is effective in multiple myeloma (MM). Outpatient treatment with bolus vincristine/doxorubicin infusion plus dexamethasone is convenient and has acceptable efficacy and toxicity for MM. Thalidomide has recently been shown to have significant antimyeloma activity. We assessed the efficacy and toxicity of the combination of bolus vincristine/doxorubicin and reduced dose dexamethasone with thalidomide (T-bVAd), administered on an outpatient basis, in untreated MM., Patients and Methods: Twenty-six patients prospectively received T-bVAd, consisting of intravenous (i.v.) vincristine 0.4 mg plus doxorubicin 9 mg/m(2), administered as a single bolus on days 1 to 4, dexamethasone 20 mg per os daily for 4 days, and thalidomide 200 mg/day at bedtime. Response assessment was conducted after each 4-week treatment cycle. Patients who achieved response were allowed to proceed to high-dose chemotherapy with ASCT., Results: On an intention-to-treat basis, 23 of the 26 patients (88%) responded to treatment, with 16 (61%) achieving complete response (CR), 2 (8%) very good partial response (VGPR) and 5 (19%) partial response. Only three patients (12%) were rated as non-responders. Grade 3 and 4 hematologic toxicities consisted of neutropenia (13%), febrile neutropenia (6%), and thrombocytopenia (4%), without significant nonhematologic events. Of the 23 patients who showed response, 7 proceeded to single ASCT and 9 to tandem ASCT. With median follow-up time of 15.3 months (range, 9-25 months), median event free survival (EFS) and overall survival (OS) have not been reached yet, and OS and EFS rates for patients who achieved complete response after T-bVAd regimen were significantly higher than patients not., Conclusions: Induction therapy with T-bVAd, administered as an outpatient regimen, was efficient and relatively well tolerated in the treatment of MM.

Small bowel perforation due to hematogenous metastatic tumor emboli is a rare event, especially in a patient with rectal cancer. We report a 75-year-old man with relapsed rectal cancer who developed an acute abdomen, which was found to be due to a perforated terminal ileum. Emergency surgery involved segmental resection and ileostomy. The pathology of the resected small bowel showed multifocal and extensive metastatic tumor emboli in the entire wall, leading to transmural infarction followed by perforation, without a discrete tumor mass. The pathology with immunohistochemistry showed a rectal tumor that was positive for CK-20 but negative for CK-7 and TTF-1. This extremely rare complication of rectal cancer resulted from ischemia and infarct caused by disseminated metastatic tumor emboli without direct invasion or mass formation.

The treatment of choice for relapsed/refractory non-Hodgkin's lymphoma (NHL) consists of high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Little is known, however, regarding the comparative toxicity and efficacy of various HDC regimens applied in NHL. We have retrospectively evaluated the clinical aspects of the BCNU, etoposide, cytarabine, and cyclophosphamide (BEAC) and BCNU, etoposide, cytarabine, and melphalan (BEAM) regimens for ASCT. Between April 1994 and February 2005, 97 NHL patients underwent HDC with BEAC (N = 69) or BEAM (N = 28), followed by ASCT, at the Asan Medical Center. We matched each BEAM patient with two BEAC patients having the same International Prognostic Index. Thus, 84 patients (56 BEAC and 28 BEAM) were analyzed. Median age was 40.5 years, and baseline characteristics were well balanced between the two groups. The median time to neutrophil engraftment (>500/mm(3)) was significantly longer with BEAC than with BEAM (12 vs 11 days, P = 0.001), as was the total amount of red blood cell transfusion (6.5 vs 3.7U, P = 0.037), but the median time to platelet engraftment (>20,000/mm(3)) and the total amount of platelet transfusion did not differ between the two groups. BEAM patients had significantly more frequent World Health Organization grade greater than or equal to 2 diarrhea than BEAC patients (46.4 vs 19.6%, P = 0.010), but the incidence of mucositis, nausea/vomiting, and bleeding and the number of episodes of febrile neutropenia and septicemia did not differ between the two groups. Median follow-up for survivors was 33 months in the BEAM group and 89 months in the BEAC group. Median overall survival and median event-free survival were not reached in the BEAM group and were 7.9 (95% confidence interval [CI], 1-14.8 months, P = 0.003) and 3.7 months (95% CI, 0.1-7.2 months, P = 0.001), respectively, in the BEAC group. BEAM appeared to be superior to BEAC for survival. Regimen-related toxicities were similar, except that BEAM was associated with more frequent but acceptable diarrhea.

Objective: To investigate the efficacy and safety of docetaxel monotherapy as salvage chemotherapy for advanced gastric cancer (AGC) in clinical practice and to determine the prognostic factors in these patients., Methods: We retrospectively reviewed the medical records of patients with AGC for whom fluoropyrimidine and platinum had previously failed and who had received docetaxel salvage monotherapy between December 2000 and March 2006. Docetaxel was administered at a dose of 75 mg/m(2) intravenously every 3 weeks with dexamethasone prophylaxis., Results: A total of 154 patients received 583 cycles of docetaxel with a median of three cycles per patient (range 1-10). The median age was 54 years (range 27-75 years). The objective response rate of 86 patients with measurable lesions was 14%, with 1 complete response and 11 partial responses, with a median response duration of 5.6 months. An additional 25 patients achieved stable disease. The median time to progression (TTP) for all patients was 2.6 months [95% confidence interval (CI), 2.2-2.9] and the median overall survival (OS) from the start of docetaxel chemotherapy was 7.2 months (95% CI, 5.9-8.5). The chemotherapy was generally well tolerated. Multivariate analysis showed that the Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) was an independent prognostic factor for both TTP and OS. Disease status indicative of a relatively small tumor burden (resected metastatic or recurrent tumor) was a predictor for better TTP and good differentiation of the tumor was a predictor for better OS., Conclusion: Docetaxel 75 mg/m(2) is relatively active and tolerable as a second-line salvage treatment after failure of fluoropyrimidine and platinum in general clinical practice for AGC.

We report a case of a 41-year-old man admitted with respiratory distress and found to have masses in both atria of the heart and in the testicle. The patient received palliative radiotherapy to relieving obstruction of blood flow tract caused by the intracardiac masses, followed by radical orchiectomy. After the diagnosis of testicular seminoma, he was treated successfully with 4 cycles of systemic chemotherapy. This is a rare case that presented with metastatic testicular seminoma involving both atria of heart and causing symptomatic obstruction of blood flow tract.