Myung Soo Hyun

Randomized Trial of Myeloablative Conditioning Regimens: Busulfan Plus Cyclophosphamide Versus Busulfan Plus Fludarabine

PURPOSE We conducted a phase III randomized clinical trial to compare two myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) in patients with leukemia and myelodysplastic syndrome. PATIENTS AND METHODS After randomization, 64 patients received busulfan (3.2 mg/kg per day × 4 days) plus cyclophosphamide (60 mg/kg per day × 2 days; BuCy), and 62 patients received busulfan (same dose and schedule) plus fludarabine (30 mg/m(2) per day × 5 days; BuFlu). RESULTS The median age was 41 years (range, 17 to 59 years). Five patients in the BuFlu arm experienced graft failure (primary, n = 1; secondary, n = 4). At 4 weeks after HCT, the median percentage of recipient hematopoietic chimerism was significantly greater in the BuFlu arm (0% v 5.5%; P < .001), and complete donor chimerism was greater in the BuCy arm (97.2% v 44.4%; P < .001). Severe (grade 3 or higher) infection and gastrointestinal adverse events were significantly more common in the BuCy arm, but the frequencies of hepatic adverse events were similar in the two arms. Nonrelapse mortality was similar in the two arms, but the BuCy arm had better overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS; OS at 2 years, 67.4% v 41.4%, P = .014; RFS, 74.7% v 54.9%, P = .027; EFS, 60.7% v 36.0%, P = .014). CONCLUSION Our results indicate that the BuFlu regimen is not a suitable replacement for the BuCy regimen in young adults who are eligible for myeloablative conditioning therapy for allogeneic HCT.

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

Clinical Overview of Extrapulmonary Small Cell Carcinoma

The objective of this study was to review the natural history of extrapulmonary small cell carcinoma (EPSCC) with specific emphasis on clinical features, response to treatment and survival. The records of all patients (n=34) with EPSCC treated at Yeungnam University Medical Center and Catholic University of Daegu Medical Center between 1998 and 2005 were retrieved and reviewed. The primary sites of tumor were the esophagus and thymus in 6 patients (17.6%) each, pancreas and stomach in 5 patients each (14.7%); other sites included were the cervix, abdominal lymph nodes, abdominal wall, bladder, colon, maxillary sinus, nasal cavity, ovary, parotid gland and liver. Twenty three patients out of 34 had limited disease. The median survival of all patients was 14 months. Independent prognostic factors included stage and primary tumor location. The prognosis for the patients with extensive disease and in the gastrointestinal group was unfavorable. EPSCC is a non homogeneous disease entity. As a result of its frequent recurrence, multimodal therapy has a better outcome even in cases of limited disease. Combination chemotherapy plays a central role for treatment of extensive disease in EPSCC. Further multicenter studies are now needed to determine more details regarding disease subclass and optimal treatment modality.

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

Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis

Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580) on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway.

Relationship between Urokinase-Type Plasminogen Receptor, Interleukin-8 Gene Expression and Clinicopathological Features in Gastric Cancer

Objective: The serine protease urokinase-type plasminogen (uPA) and its receptor (uPAR) appear to have a major function in tumor invasion and metastasis. Interleukin-8 (IL-8) acts as an angiogenic factor in solid cancer. The purpose of this study was to determine whether the expression of IL-8 and the uPAR gene correlates with clinicopathological parameters in human gastric carcinoma. Methods: We examined the expression of uPAR mRNA and IL-8 mRNA using Northern blot analysis and RT-PCR in 35 gastric carcinomas and the surrounding normal mucosa. Macroscopic and histopathological tumor findings and survival rates were obtained from the patient records. Results: uPAR and IL-8 mRNA expression levels were higher in most neoplasms compared to the corresponding normal mucosal tissue. A correlation between uPAR and IL-8 expression in tumors was observed (r = 0.447, p < 0.01). uPAR mRNA expression in the tumors correlated well with lymph node metastasis (p < 0.02), and its stage (p < 0.01). The IL-8 MRNA expression in the tumors correlated with diffuse-type gastric cancer (p < 0.05). The survival rates of patients with tumors displaying high uPAR expression levels were significantly lower (p < 0.04) than those of patients without uPAR expression, but patients with IL-8 expression only showed a tendency to a lower survival rate. Conclusion: These results suggest that uPAR and IL-8 may be important prognostic factors in human gastric carcinomas.

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia

To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 ± 725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with <1000: 80.6% vs. 19.4%; ≥1000: 94.6% vs. 5.4%; p = 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with <1000: 3.2% vs. 96.8%; ≥1000: 21.4% vs. 78.6%; p = 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of ≥1000 compared with those with a level of <1000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (<1000 ng/mL).

Pain and Its Treatment in Patients with Cancer in Korea

Substantial pain is experienced by a lot of patients with cancer, and undertreated pain significantly undermines their quality of life. Despite international and national guidelines on cancer pain management, the practical effectiveness of management is still problematic. We did a prospective cross-sectional survey on pain prevalence, pain intensity, its impact on daily activity, and adequacy of pain management in 823 patients treated by medical oncologists and radiologic oncologists. At the time of the survey, 29.7% of the patients had pain that was moderate or severe. Performance status and tumor extent were significant predictors of pain presence and its intensity. Pain severity and the proportion of the patients whose function is impaired are highly associated. Among the patients with pain, only 37% rated pain relief as satisfactory. Forty-one percent of the patients with pain received inadequate pain management. Physicians did not adjust the analgesic prescription in about 53% of the patients who reported severe pain. These results demonstrate the alarming degree of undertreatment of pain in patients with cancer in Korea, and indicate the need to improve the management of cancer-related pain. Future research should elucidate the factors that impede adequate pain management in order to overcome obstacles to adequate treatment.

S-1 and Gemcitabine as an Outpatient-based Regimen in Patients with Advanced or Metastatic Pancreatic Cancer

OBJECTIVE The standard beneficial chemotherapy proved for patients with pancreatic cancer is a regimen containing gemcitabine. Novel oral fluoropyrimidine, S-1, can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better convenience for patients. We aimed to evaluate the efficacy and safety of S-1 plus gemcitabine combination chemotherapy as a first-line treatment in patients with locally advanced or metastatic pancreatic cancer. METHODS Patients with histologically confirmed, bidimensionally measurable advanced/metastatic pancreatic cancer were eligible for the study. Chemotherapy consisted of S-1 (30 mg/m(2) p.o. bid from Day 1 to 14) and gemcitabine (1000 mg/m(2) on Days 8 and 15) every 3 weeks based on the results of a previously reported Phase I trial. Treatment was repeated until disease progression or unacceptable toxicity occurred. RESULTS From January 2005 to August 2007, 22 patients were enrolled. Median age was 62 years (range, 50-73). Nineteen patients (86.3%) had metastases and of these, 11 patients (57.9%) had multiple liver metastases. The overall response rate was 27.3% (95% CI, 8.7-45.9), with a partial response in six patients, stable disease in nine (40.9%) and progressive disease in seven (31.8%). With a median follow-up of 25.4 months, the median time to progression and overall survival were 4.6 (95% CI, 2-7.2 months) and 8.5 months (95% CI, 6.8-10.1 months), respectively, and 1-year survival rate was 27.3%. S-1 plus gemcitabine was well tolerated. Grade 3/4 hematological adverse events were neutropenia (9.1/9.1%) and anemia (4.5/0%). Non-hematological adverse events were mainly gastrointestinal events. Twenty patients (91%) received chemotherapy on an outpatient basis. CONCLUSIONS Combination chemotherapy of S-1 plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.

Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia

Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA).