Sung Hwa Bae

Therapeutic Synergy of Human Papillomavirus E7 Subunit Vaccines plus Cisplatin in an Animal Tumor Model: Causal Involvement of Increased Sensitivity of Cisplatin-Treated Tumors to CTL-Mediated Killing in Therapeutic Synergy

Purpose: The goal of this study was to investigate the therapeutic potentials of combining chemotherapy with human papillomavirus (HPV) E7 subunit vaccines in an animal tumor model and to determine the underlying therapeutic mechanisms. Experimental Design: Animals bearing HPV E6/E7–expressing tumors were treated intratumorally with a selected cytotoxic drug, cisplatin, twice at 1-week interval and s.c. with E7 subunit vaccines thrice at 1-week interval. Tumor chemoimmunoresponse was measured by tumor size. Ag-specific CTL activities and tumor histology were checked in mice under treatments. Apoptosis, in vivo T-cell subset depletion, adoptive CTL transfer, and tumor regression were used to determine the mechanisms for antitumor therapeutic effects. Results: Combined therapy using cisplatin plus E7 subunit vaccines improved cure and recurrence rates of tumors and long-term antitumor immunity dramatically more than single therapy alone. In particular, both components of E7 subunit vaccines were required for induction of Ag-specific CTL as well as therapeutic synergy when combined with cisplatin. This therapeutic synergy was abrogated by depletion of CD8+ T cells in vivo and was concomitant with histologic changes (such as heavy infiltration of lymphocytes and reduced tumor cell density). Finally, the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing was found to be responsible for therapeutic synergy. Conclusions: E7 subunit vaccines plus cisplatin mediate antitumor therapeutic synergy through the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing. Moreover, E7-based therapeutic vaccines have the potential to improve chemotherapy in patients with cervical cancer.

Thalidomide for POEMS syndrome.

Dear editor, The POEMS syndrome is a multisystem disorder characterized by the combination of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes [1]. Additional important features are not represented in the acronym, such as sclerotic bone lesions, Castleman’s disease, pappiledema, thrombocytosis, peripheral edema, ascites, effusion, polycythemia, fatigue, and clubbing [2]. Increased levels of cytokines, TNF-α, IL-1β, IL-6, and VEGF appear to play a pathogenic role in the disorder [3, 4]. In this paper, we report a case of chemotherapy refractory POEMS syndrome with high IL-6 levels that rapidly decreased after thalidomide and dexamethasone treatment and which was followed by significant clinical improvement. A 43-year-old Korean female patient was admitted in our hospital because of dyspnea and general weakness. From 1 year ago, skin hyperpigmentation and dyspnea on exertion had been developed, and she complained of extremity weakness and numbness, being unable to walk without help. On physical examination, she had multiple lymph node enlargements in neck and axilla. The spleen and liver were enlarged. Her fingernails were clubbing. She had a pitting edema and did not have enough strength to walk. On blood test, white blood cell and platelet counts were normal, but hemoglobin was 8.8 g/dl. Serum creatinine level was elevated (2.7 mg/dl). Thyroid function test showed hypothyroidism (TSH 13.02 IU/ml, T3 0.637 ng/ml, and T4 0.602 ng/ml). One small serum monoclonal protein was identified, and immunofixation electrophoresis revealed it to be IgA-λ. There were 18.3% plasma cells in bone marrow aspiration. A cervical lymph node biopsy demonstrated reactive follicular lymphoid hyperplasia with burnt-out germinal center and hyalinized vessels; it suggested of the Castleman’s disease, hyaline vascular type. The electroneurographic findings and neurologic examination were consistent with the diagnosis of peripheral sensorimotor axonal polyneuropathy. A chest computed tomography demonstrated multiple lymph node enlargements, osteosclerotic lesions on T1, T9 spine, and sternum. An abdominal computed tomography revealed multiple lymphadenopathy and hepatosplenomegaly. A transthoracic echocardiography revealed pericardial effusion and pulmonary hypertension. The pulmonary-arterial systolic pressure was 44.1 mmHg on transthoracic echocardiography. The patient was given a diagnosis of POEMS syndrome and Castleman’s disease. We scheduled to perform autogolous hematopoietic stem cell transplantation after cyclophosphamide, adriamycin, and dexamethasone chemotherapy. But the patient’s clinical condition worsened during the induction chemotherapy. She suffered from dyspnea, generalized edema, and refractory ascites that needed drainage of fluid every 3 or 4 days. A chest radiography showed progression of pleural effusion. Anemia and azotemia were aggravated and platelet counts were decreased. Therefore, stem cell transplantation was impossible. At that time, her serum IL-6 level was 41.7 pg/ml (normal range 0.22–4.61 pg/ml) and TNF-α was within normal range. Then, administration of thalidomide (200 mg/day) with dexamethasone (20 mg/m p.o. on day 1–4 monthly for 8 months) was initiated in May 2004. After 2 months of treatment, the patient’s clinical condition improved. No drainage of ascitic fluid was needed; she also recovered from dyspnea. The numbness on her lower extremity became tolerable and she was able to walk again without any help. After 8 months of thalidomide administration, her renal function became normal, while anemia and thrombocytopenia were treated. Her serum IL-6 level was also normalized (5.59 pg/ml) (see Table 1). There were S. Y. Kim . S. A. Lee . H. M. Ryoo . S. H. Bae (*) Department of Internal Medicine, Daegu Catholic University College of Medicine, Daemyung-dong, Namgu, Daegu, 705-718, South Korea e-mail: sunghwa@cu.ac.kr Tel.: +82-53-6504388 Fax: +82-53-6226062

Meningeal Relapse in a Patient with Acute Promyelocytic Leukemia : A Case Report and Review of the Literature

The involvement of central nervous system is rare in acute promyelocytic leukemia (APL). We report a APL patient of a 41 yr-old Korean male who presented with fever and petechia. Complete molecular remission was achieved with all-trans retinoic acid (ATRA), idarubicin, and cytarabine. Ten months later, he complained of a mild headache. The results of the physical examination and the complete blood counts were normal. The examination of cerebrospinal fluid showed the presence of promyelocyte. Bone marrow studies showed cytogenetic remission but with molecular relapse. He was treated with intrathecal and systemic chemotherapy.

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.

Adenocarcinoma has an excellent outcome with pemetrexed treatment in Korean patients: a prospective, multicenter trial.

OBJECTIVEnThis prospective multicenter study conducted by the Korean Cancer Study Group evaluated the efficacy and safety of pemetrexed in Korean patients with advanced non-small cell lung cancer (NSCLC) who had prior chemotherapy.nnnPATIENTS AND METHODSnPatients with stage IIIB or IV NSCLC in whom prior chemotherapy failed received pemetrexed 500 mg/m(2) every 3 weeks with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity. Eighty-one patients were enrolled.nnnRESULTSnThe overall response rate for 78 evaluable patients was 5.1% [95% confidence interval (CI) 1.4-12.6; partial response 4/78, no complete response]. The disease control rate including complete, partial response and stable disease was 46.2% (36/78, 95% CI 34.8-57.8). With a median 8.7 months follow-up, the median time to progression was 3.1 months (95% CI 1.17-5.03) and the median overall survival (OS) was 7.8 months (95% CI 5.19-10.35). The median OS for patients with adenocarcinoma histology was 18.7 months compared to 6.1 months for non-adenocarcinoma. In a multivariate analysis, Eastern Cooperative Oncology Group performance status 0-1 [hazards ratio (HR)=0.331, 95% CI 0.135-0.814] and adenocarcinoma (HR=0.504, 95% CI 0.283-0.899) were independent factors for prolongation of overall survival.nnnCONCLUSIONSnPemetrexed monotherapy has promising efficacy in patients with advanced NSCLC as a second-line therapy with less hematologic and non-hematologic toxicity, especially in those with adenocarcinoma histology.

Biological Characterization of Nodal versus Extranodal Presentation of Diffuse Large B-Cell Lymphoma using Immunohistochemistry

INTRODUCTIONnDiffuse large B cell lymphoma (DLBCL) of primary nodal (PN) or primary extranodal (PEN) origin may differ immunophenotypically, in that PEN lymphoma cells may originate from activated rather than germinal center B (GCB) cells. We evaluated the relationship between DLBCL clinicopathological features, including expression of B-cell differentiation markers, and primary tumor site.nnnPATIENTS AND METHODSnExpression of CD10, Bcl-6, Bcl-2, and MUM1 was determined in paraffin-embedded tissues from 123 patients with DLBCL.nnnRESULTSnOf the 123 patients with DLBCL, 40 (32.5%) had the GCB and 83 (67.5%) had the non-GCB phenotype. Fifty-one patients (42%) showed disease involvement at PEN sites, including 29 with disease in the gastrointestinal (GI) tract (14 in the stomach, 15 in the intestine). Of these 51 patients, 16 (31.4%) were classified with the GCB and 35 (68.5%) with the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes among primary sites. Of the 72 patients with PN DLBCL, 22 (31%) had the GCB and 50 (69%) had the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes between patients with PN and PEN DLBCL. Although lactate dehydrogenase (LDH) concentration > normal, stage >II, and rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) treatment were independent predictors of overall survival (OS), GCB subtype, and presence of PEN disease failed to predict survival upon multivariate analysis.nnnCONCLUSIONnThere was no difference in GCB and non-GCB phenotypes between patients with PN and PEN DLBCLs. Additional studies are needed to further assess molecular differences between the two groups.

The Hematologic Response to Anti-apoptotic Cytokine Therapy: Results of Pentoxifylline, Ciprofloxacin, and Dexamethasone Treatment for Patients with Myelodysplastic Syndrome

TNF-α mediated apoptosis of the hematopoietic cells has been thought to contribute to the ineffective hematopoiesis observed in myelodysplastic syndrome (MDS). The combination of pentoxifylline (P) and ciprofloxacin (C) has been shown to reduce the serum levels of TNF-α, and an earlier trial of P and C with dexamethasone (D) provided good palliation for patients with MDS. The purpose of this study is to assess the hematologic response to PCD therapy for patients suffering with MDS. 21 of 25 patients who completed at least of 12 weeks of treatment were evaluable for the treatment efficacy. At baseline, the patients median age was 60 yr (range: 18-75 yr). The diagnoses according to WHO classification included: RA (n=5), RCMD (n=10), RARS (n=1), RCMD/RS (n=1), RAEB (3), and CMML (n=1). 11 patients (52%) had at least single lineage response. 3 patients (11%) showed improvement of triple lineage cytopenia. There were no differences in the response rates between the FAB subtypes. The median time to response was 4 weeks (range: 2-12 weeks), and it is interesting that 9 of 11 patients who had a response remained without relapse for a median of 177 days (range: 78-634 days). These preliminary results indicate that anti-cytokine therapy with PCD is an effective and well tolerated palliative treatment for patients with MDS.

Abstract 2238: Clinical characteristics and outcome of patients with Rituximab-CHOP resistant/refractory DLBCL: Presence of B symptom and high LDH at diagnosis predict survival

Introduction: The addition of the anti-CD20 monoclonal antibody rituximab to conventional chemotherapy has dramatically improved overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL), with more than 50% of these patients achieving long-term disease-free survival. However, approximately one-third of patients eventually die due to disease progression, treatment-related toxicities, another cancer, or other causes, and some patients show progression during or immediately after treatment. We sought to determine the characteristics of patients with DLBCL who were refractory or resistant to R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) chemotherapy and the factors influencing patient outcomes. Patients and Methods: Of all patients newly diagnosed with DLBCL at nine institutions in Korea and treated with R-CHOP with curative intent, 94 failed to achieve complete (CR) or partial response (PR) during or after R-CHOP chemotherapy or showed disease progression within 12 months of diagnosis. Results: Median patient age was 53 years (range 18∼85 years), and median time to progression was 5.7 months (range 1.1∼11.2 months). According to the International Prognostic Index (IPI), 44 patients (46.8%) were of low risk (0 to 2) and 50 (53.2%) were of high risk (3 to 5). Of the 94 patients, 59 (62.8%) had progression of primary lesions, 19 (20.2%) had progression at other sites, and 16 (17%) had progression at both primary and other sites. Sixty-three patients (67%) had progression during R-CHOP treatment, including 22 (23.4%) with progression after no response and 41 (43.6%) with progression after CR or PR. The remaining 31 patients (33.0%) showed disease progression after 6∼8 cycles of R-CHOP chemotherapy. Of the 74 patients (78.7%) who received second-line chemotherapy, 8 (10.8%) achieved CR or unconfirmed CR (CRu), 14 (18.9%) achieved PR, 3 (4.1%) achieved stable disease and 36 (48.6%) showed progressive disease. The overall response rate was 29.7% and the median duration of response was 4.2 months. Median OS was 4.7 months and median progression-free survival (PFS) was 3.0 months. Median OS after diagnosis of lymphoma was 10.7 months. Multivariate analysis showed that normal (vs. elevated) LDH concentration and absence (vs. presence) of B symptoms were significant predictors of longer OS. However, other IPI variables, such as age, performance status, and extranodal disease, did not predict survival of R-CHOP resistant/refractory patients. Conclusion: The prognosis of patients with R-CHOP refractory/resistant DLBCL was dismal, with conventional salvage chemotherapy having little effect on survival. Novel biomarkers and new treatment strategies are needed to further improve survival in R-CHOP refractory/resistant DLBCL patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2238. doi:10.1158/1538-7445.AM2011-2238