Ho-Young Yhim

Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response

The aims were to investigate the feasibility of imatinib mesylate (IM) discontinuation in chronic myeloid leukemia patients who were initially treated with IM and achieved complete molecular response (CMR). Fourteen patients were included. Ten were relapsed within 9.5 months after discontinuation of IM. All 7 patients with high Sokal risk were relapsed. The probability of CMR persistence at 1-year was 28.6%. All relapsed patients were still responsive to IM. A high Sokal risk and delayed acquisition of CMR were associated with relapse. IM discontinuation in patients achieved CMR after treatment with front-line IM might be feasible. Further studies are warranted.

Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study

BackgroundThe breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis.MethodsWe retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009.ResultsMedian age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 ± 7.6%, and overall survival (OS) was 60.3 ± 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 ± 8.9% vs. 27.5 ± 11.4%, p = 0.001; 5-year OS, 74.3 ± 7.6% vs. 24.5 ± 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 ± 5.4% vs. 49.0 ± 15.1%, p = 0.001).ConclusionsOur results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.

The prognostic significance of tumor human papillomavirus status for patients with anal squamous cell carcinoma treated with combined chemoradiotherapy.

The prognostic relevance of tumor human papillomavirus (HPV) status in anal squamous cell carcinoma (SCC) had not been previously investigated, although its relevance to cervical, head and neck SCC is known. We retrospectively evaluated outcomes in 47 patients with anal SCC treated with combined chemoradiotherapy (CCRT) and determined tumor HPV status by HPV DNA chip method and p16 expression by immunohistochemistry (IHC) from paraffin‐embedded tumor tissues. The median age was 65 years (range, 44–90 years). Sixteen (34%) patients were diagnosed with T stage 3 to 4, and 18 (38%) patients had regional nodal disease (N‐positive). Thirty‐five (75%) patients were HPV positive, and 31 (66%) patients were genotype 16 (HPV16‐positive). Thirty‐nine (83.0%) patients were positive for p16. After median follow‐up of 51.7 months (range, 5.1–136.0 months), HPV16‐positive group had significantly better 4‐year progression‐free survival (PFS, 63.1% vs. 15.6%, p < 0.001) and overall survival (84.6% vs. 39.8%, p = 0.008) than HPV genotype 16 negative (HPV16‐negative) group. Patients with p16‐positive tumor also had a better 4‐year PFS (52.5% vs. 25.0%, p = 0.014) than those with p16‐negative tumor. In multivariate analysis for PFS, N‐positive and HPV16‐negative were independent prognostic factors for shorter PFS. Comparing patterns of failure, time to loco‐regional failure was statistically superior in HPV16‐positive over HPV16‐negative groups (p = 0.006), but time to systemic failure was not different (p = 0.098). Tumor HPV genotype 16 status is a prognostic and predictive factor in anal SCC treated with CCRT, and p16 expression determined by IHC might be advocated as a surrogate biomarker of HPV integration in anal SCC. Further studies are warranted.

Clinical outcome of elderly patients with Epstein–Barr virus positive diffuse large B-cell lymphoma treated with a combination of rituximab and CHOP chemotherapy

Several studies have suggested the possibility of a prognostic relationship between Epstein–Barr virus (EBV) and diffuse large B‐cell lymphoma (DLBCL). The clinical outcome of EBV‐associated DLBCL is not clear, especially since the introduction of rituximab. We retrospectively analyzed 222 elderly patients (≥50 years) with DLBCL who received R‐CHOP chemotherapy and evaluated the state of EBV‐encoded RNA‐1 (EBER). Eighteen cases (8.1%) were EBER‐positive (+). After a median of six cycles of R‐CHOP chemotherapy, the response rate (≥partial response) was 72.2% (13/18) in the EBV (+) patients and 90.2% (184/204) in the EBV (−) DLBCL patients (P = 0.021). Four of 18 (22.2%) EBV (+) DLBCL patients received two or fewer cycles of R‐CHOP chemotherapy. R‐CHOP chemotherapy was also interrupted early more frequently compared with the EBV (−) group (2.5%) (P = 0.00). At a median follow‐up of 32.8 months, there was no significant difference in the overall survival between the groups (P = 0.627). The EBV (+) DLBCL patients with early interruption of R‐CHOP chemotherapy showed a trend toward a high EBV‐DNA titer (≥1,000 copies/mL) (P = 0.091). The results suggest that the EBV (+) tumoral status of elderly DLBCL patients who undergo R‐CHOP chemotherapy does not predict their survival but that their EBV status may contribute to the early interruption of R‐CHOP chemotherapy. Am. J. Hematol. 88:774–779, 2013.

Incidence of venous thromboembolism following major surgery in Korea: from the Health Insurance Review and Assessment Service database

Data on the incidence of venous thromboembolism (VTE) following major surgery in Asian populations are limited.

Use of curcumin to decrease nitric oxide production during the induction of antitumor responses by IL-2.

Nitric oxide (NO) synthesis is strongly induced during interleukin (IL)-2 treatment of mice and humans. Although this free radical can act as a cytotoxic effector molecule against cancer cells, immunosuppressive effects have also been suggested. We evaluated the effects of curcumin on IL-2-induced NO synthesis and IL-2-induced antitumor responses in a mouse ascites tumor model. Curcumin inhibited inducible nitric oxide synthase (iNOS) expression and NO production, and thereby enhanced the proliferation and cytotoxic activity of cocultured lymphocytes and macrophages during IL-2 stimulation which we earlier established as an in vitro model of IL-2-induced NO synthesis. Curcumin also decreased apoptosis of cocultured lymphocytes and macrophages during IL-2 stimulation. In contrast, the curcumin-induced changes in proliferation and apoptosis were not observed in cultures of lymphocytes alone, macrophages alone, and cocultured lymphocytes/iNOS-knock out macrophages, all of which produced little nitrite during IL-2 stimulation. In conjunction with IL-2 treatment, oral curcumin administration significantly inhibited IL-2 therapy-induced urinary nitrite/nitrate excretion and iNOS expression of tumor tissues, and further increased the IL-2 therapy-induced prolongation of survival in a murine Meth-A ascites tumor model. Curcumin may be useful as an adjunct to increase the antitumor activity of IL-2 therapy.

Clinical outcome and prognosis of patients with primary sinonasal tract diffuse large B-cell lymphoma treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy: a study by the Consortium for Improving Survival of Lymphoma

Abstract We evaluated the clinical outcomes and relapse patterns of 80 patients with primary sinonasal tract diffuse large B-cell lymphoma (SN-DLBCL) treated with rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy at 22 institutions. A total of 59 (73.8%) patients received R-CHOP chemotherapy alone, whereas 21 (26.3%) were treated with R-CHOP followed by involved field radiotherapy (IFRT). In 73 patients with Ann Arbor stage I–II disease, no significant difference was found in the response rate or overall survival (OS) between R-CHOP alone (n = 52) and R-CHOP followed by IFRT (n = 21). Among 11 relapsed patients in this study, the most common pattern of relapse was local (n = 8, 11.8%), whereas central nervous system (CNS) relapse was observed in only one (1.9%) patient. These results suggest that patients with primary SN-DLBCL treated with R-CHOP have a relatively low CNS relapse rate and better OS compared to previous studies before the introduction of R.

Sunitinib-Induced Hyperammonemic Encephalopathy in Gastrointestinal Stromal Tumors

Objective: To report 2 cases of hyperammonemic encephalopathy induced by sunitinib in patients with metastatic gastrointestinal stromal tumor (GIST). Case Summary: A 58-year-old man with imatinib-resistant metastatic GIST presented to the emergency department with confusion that developed 17 days after the initiation of sunitinib 50 mg/day. His serum ammonia level was markedly elevated (210 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. His neurologic status normalized within 24 hours and his serum ammonia level decreased to 64 μg/dL A 68-year-old woman with imatinib-resistant metastatic GIST was admitted into the emergency department with confusion and irritability that developed 10 days after the start of sunitinib therapy. Her serum ammonia level was markedly elevated (389 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. Within 24 hours, her mental status was improved and her serum ammonia level was decreased to 116 μg/dL. Sunitinib was reintroduced, and the same symptoms occurred after day 7 of administration. Sunitinib was not prescribed afterward and the woman did not experience any further encephalopathy symptoms. Discussion: Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases such as stem cell factor receptor, vascular endothelial growth factor, and platelet-derived growth factor. It is used as second-line therapy for patients with imatinib-resistant GIST. Hyperammonemic encephalopathy is an uncommon fatal complication of chemotherapy. According to the Naranjo probability scale, sunitinib was a probable cause of hyperammonemic encephalopathy in the patients described here. Although the mechanism of hyperammonemia is unclear, hyperammonemic encephalopathy might be caused by a vascular disorder related to the antiangiogenic properties of sunitinib, and it has ethnic differences associated with genetic polymorphisms. Conclusions: Sunitinib may Induce hyperammonemic encephalopathy in some patients. Although further studies are warranted, clinicians should be aware of this severe adverse event when using sunitinib for treatment of GIST.

Korean patients with superwarfarin intoxication and their outcome.

This observational study aimed at evaluating recent superwarfarin intoxication of Korean patients. Ten patients were diagnosed as or highly suspicious for superwarfarin intoxication. Case report forms described by attending hematologists of the patients were collected and analyzed. Bleeding symptoms were varied among the patients. Patients uniformly showed prolonged prothrombin time (PT) and activated thromboplastin time (aPTT) with decreased activity of vitamin K dependent coagulation factors. Positive serum brodifacoum test results in 4 of 5 requested patients contributed to confirmatory diagnosis. Psychiatric interview revealed an attempted ingestion in one patient. High dose vitamin K1 therapy promptly corrected prolonged PT and aPTT, but hasty discontinuation caused repeated bleeding diathesis in 6 patients. Route of intoxication was unknown or not definite among 8 of 10 patients. Three patients had a possibility of environmental exposure considering their occupations: there might be intoxication by transdermal absorption or inhalation. Therefore, high dose and prolonged use of vitamin K1 therapy is necessary for effective detoxification. Further detailed investigation on environmental exposure and efforts to improve availability of the blood level test in clinic are requested.

Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT.

The aims of this study were to investigate the outcomes of second salvage auto-SCT and to identify the impacts of a second auto-SCT compared with systemic chemotherapy alone on disease outcome. Data from 48 patients who underwent second auto-SCT were matched to 144 patients (1:3) who received systemic chemotherapy alone from the Korean Myeloma Registry. Groups were matched for nine potential prognostic factors and compared for treatment outcomes. The median age of matching-pairs at relapse was 55.5 years. A total of 156 patients (81%) received vincristine, doxorubicin and dexamethasone induction therapy before the first auto-SCT. Thirty-five patients (73%) in the second auto-SCT group received novel agent-based therapies before the second auto-SCT, and similar proportion in both groups received novel therapies after relapse of front-line auto-SCT. With a median follow-up of 55.3 months, patients who underwent a second auto-SCT had significantly better median OS (55.5 vs 25.4 months, P=0.035). In multivariate analysis for OS, <18 months time to progression after first auto-SCT, International Staging System III and salvage chemotherapy alone were independent predictors for worse OS. The outcomes of second auto-SCT appear to be superior to those of systemic chemotherapy alone. A randomized trial comparing both treatment strategies is required.