Pazopanib for Non-small Cell Lung Cancer: The First Case Report in Korea.

Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors' knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer.

Radiation recall dermatitis induced by tamoxifen during adjuvant breast cancer treatment.

Tamoxifen and radiotherapy are used in breast cancer treatment worldwide. Radiation recall dermatitis (RRD), induced by tamoxifen, has been rarely reported. Herein, we report a RRD case induced by tamoxifen. A 47-year-old woman had a right quadrantectomy and an axillary lymph node dissection due to breast cancer. The tumor was staged pT2N0; it was hormone receptor positive, and human epidermal growth factor receptor 2 negative. The patient received adjuvant chemotherapy followed by tamoxifen and radiotherapy. After 22 months of tamoxifen, the patient developed a localized heating sensation, tenderness, edema, and redness at the irradiated area of the right breast. The symptoms improved within 1 week without treatment. Three weeks later, however, the patient developed similar symptoms in the same area of the breast. She continued tamoxifen before and during dermatitis, and symptoms resolved within 1 week.

Small cell carcinoma of the liver and biliary tract without jaundice.

An 80-year-old woman presenting with chest pain was found to have a large, lobulated soft tissue mass in the liver and nearby tissues on abdominal computed tomography (CT). The tumor had invaded the common hepatic artery and main portal vein. Jaundice developed 4 wk later, at which point, a pancreas and biliary CT scan revealed a large mass in the right lobe of the liver and a hilar duct obstruction, which was found to be a small cell carcinoma. Despite its rarity, liver and bile duct small cell carcinoma should be considered in the differential diagnosis of atypical chest pain without jaundice.

Randomized trial of postoperative adjuvant therapy in Stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: 10-year follow-up.

PURPOSE: To determine the optimal sequence of postoperative adjuvant chemotherapy and radiotherapy in patients with Stage II or III rectal cancer. METHODS AND MATERIALS: A total of 308 patients were randomized to early (n = 155) or late (n = 153) radiotherapy (RT). Treatment included eight cycles of chemotherapy, consisting of fluorouracil 375 mg/m(2)/day and leucovorin 20 mg/m(2)/day, at 4-week intervals, and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on Day 1 of the first chemotherapy cycle in the early RT arm and on Day 1 of the third chemotherapy cycle in the late RT arm. RESULTS: At a median follow-up of 121 months for surviving patients, disease-free survival (DFS) at 10 years was not statistically significantly different between the early and late RT arms (71% vs. 63%; p = 0.162). A total of 36 patients (26.7%) in the early RT arm and 49 (35.3%) in the late RT arm experienced recurrence (p = 0.151). Overall survival did not differ significantly between the two treatment groups. However, in patients who underwent abdominoperineal resection, the DFS rate at 10 years was significantly greater in the early RT arm than in the late RT arm (63% vs. 40%; p = 0.043). CONCLUSIONS: After the long-term follow-up duration, this study failed to show a statistically significant DFS advantage for early radiotherapy with concurrent chemotherapy after resection of Stage II and III rectal cancer. Our results, however, suggest that if neoadjuvant chemoradiation is not given before surgery, then early postoperative chemoradiation should be considered for patients requiring an abdominoperineal resection.

Continuous infusion intermediate-dose cytarabine, mitoxantrone, plus etoposide for refractory or early relapsed acute myelogenous leukemia.

For refractory and early relapsed AML, this prospective phase II clinical trial evaluated a salvage chemotherapy regimen, which was consisted of continuous infusion intermediate-dose cytarabine (1g/m(2)/day, 24h i.v. infusion x 5), mitoxantrone (12 mg/m(2)/day x 3), and etoposide (150 mg/m(2)/day x 3). We treated 33 patients and 17 (51.5%) achieved CR with a median duration of 117 days. Median overall survival was 219 days. Our results suggest that continuous infusion intermediate-dose cytarabine, together with mitoxantrone and etoposide, may induce CR in a significant proportion of patients with refractory or early relapsed AML, although remission duration was short.

Double autologous stem cell transplantation for multiple myeloma: a Korean single center study.

BACKGROUND: Although high dose chemotherapy coupled with an autologous stem cell transplantation (ASCT) is widely accepted as effective therapy for multiple myeloma (MM), few reports are available in Korea, especially in the area of double ASCT. We present the results of an institutional retrospective study of 12 patients with MM treated by double ASCT. METHODS: Eligible patients received induction therapy using vincristine, adriamycin, dexamethasone (VAD), and mobilization was performed using cyclophosphamide plus lenograstim. High-dose melphalan (total 200 mg/m2) was used to condition the ASCT. RESULTS: The median interval from diagnosis to ASCT was 6 months (range, 1.8-15.3 months). The median interval between the 1st and 2nd ASCT was 4.4 months (range 2.1-48.7 months). The median follow up was 18.3 months (range 8.1-50.5 months) for the nine surviving patients. No therapy-related mortality occurred. Following induction chemotherapy, two patients experienced CR. Following double ASCT, eight patients experienced CR. The 5 year OS was 59%. The median duration of event free survival was 2.13 years (95% CI, 0.84-3.42). CONCLUSION: Although the results of study did not demonstrate the advantage of double ASCT, this is the first report to outline the outcome of double ASCT for Korean MM patients.

Prognostic factors identifiable at the time of onset of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

BACKGROUND AND OBJECTIVES: Current grading systems of acute graft-versus-host disease (GVHD) cannot effectively identify patients with poor prognosis at the onset of acute GVHD after allogeneic hematopoietic cell transplantation. DESIGN AND METHODS: In a retrospective analysis, we evaluated the prognostic value of various clinical parameters at the initiation of treatment in 83 patients who developed systemic treatment-requiring acute GVHD after allogeneic hematopoietic cell transplantation. RESULTS: Forty-three of 83 patients (52%) experienced initial treatment failure (40 required secondary treatment due to lack of response and 3 died) and 43 (52%) experienced treatment success, defined as completion of treatment (initial and, if given, secondary) within 100 days. The GVHD-specific survival rate was 65.5%, with 27 deaths due to GVHD-related complications without relapse of underlying malignancies within 1 year. HLA-mismatched transplantation, visceral initiation, and peripheral blood lymphocytopenia ( pound100/mL) were independent variables predicting higher initial treatment failure (Odd ratios (OR)=12.225, 12.036, and 7.481, respectively). The above variables and initial acute GVHD grade III-IV vs. II were independent variables predicting shorter GVHD-specific survival (OR=0.322, 0.247, 0.340, and 0.385, respectively). High-risk disease status, visceral initiation, and hypoalbuminemia ( pound2.8 g/dL) were independent variables predicting lower treatment success (OR=0.221, 0.162, and 0.270, respectively). The predictive value of visceral initiation and lymphocytopenia for GVHD-specific survival was verified in an independent cohort of 58 patients. INTERPRETATION AND CONCLUSIONS: Lymphocytopenia and hypoalbuminemia may be useful baseline prognostic factors for acute GVHD after allogeneic hematopoietic cell transplantation.

Docetaxel plus epirubicin as first-line chemotherapy in MBC (KCSG 01-10-05): phase II trial and the predictive values of circulating HER2 extracellular domain and vascular endothelial growth factor.

The anthracyclines and taxanes are considered to be the most active drugs in metastatic breast cancer (MBC). We conducted a multicenter phase II study to evaluate the efficacy and tolerability of the docetaxel plus epirubicin combination chemotherapy as first-line treatment in MBC and performed a prospective assessment of the predictive values of circulating HER2 extracellular domain (ECD) and vascular endothelial growth factor (VEGF). Docetaxel 75 mg/m(2) and epirubicin 75 mg/m(2) were given intravenously every 3 weeks. Prophylactic G-CSF was not used. Pretreatment serum HER2 ECD and VEGF levels were measured by enzyme immunoassay. Forty MBC patients were enrolled, and 39 patients were evaluable for toxicities and 38 for response. Complete response was observed in 3 (7.9%) patients, partial response in 20 (52.6%) (overall response rate 60.5%), stable disease in 11 (28.9%) and disease progression in 4 (10.5%). After a median follow-up of 22.5 months, the median duration of response was 28 weeks, median time to disease progression was 32 weeks, and median survival was 15.8 months. Two-hundred and fifteen cycles of treatment were administered (median, 6 cycles per patient). Grade 3 and 4 neutropenia were observed during 24 (11.2%) and 74 (35%) cycles respectively, and grade 3 or 4 febrile neutropenia in 24 (11.2%) cycles. Elevated circulating HER2 ECD levels were found to be associated with a shorter response duration (p<0.005) and shorter time to progression (p<0.005). However, elevated VEGF levels were not found to be correlated with response rate or survival. We concluded that the docetaxel and epirubicin combination is an effective first-line treatment in MBC patients and that elevated serum HER2 ECD levels, but not circulating VEGF levels, predict a poor outcome.

Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation.

We investigated the occurrence of hepatic veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT) in 241 adults conditioned with busulfan + cyclophosphamide at a single institute and retrospectively compared 186 patients who received oral busulfan (O-Bu group) with 55 patients who received intravenous busulfan (I-Bu group). Various hemostatic parameters were determined at baseline and on days 0, 7, 14, and 21. Hepatic VOD occurred in 41.7% of the O-Bu group and in 18.5% of the I-Bu group. Multivariate analysis revealed that the I-Bu group had significantly decreased risk of VOD compared to the O-Bu group [p=0.006, odds ratio: (OR) 0.345]. Eleven patients in the O-Bu group and none of the I-Bu group developed severe VOD. A repeated measures analysis of variance (ANOVA) with a between-subjects factor revealed significant differences in post-transplant levels of antithrombin III, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and D-dimer according to the occurrence of VOD. The level of antithrombin III was significantly lower, whereas the level of D-dimer was significantly higher, in the O-Bu group than in the I-Bu group. These findings show that, in adults conditioned with busulfan + cyclophosphamide, intravenous busulfan was associated with significantly decreased incidence of VOD and fewer hemostatic derangements after allogeneic BMT compared to oral busulfan.

Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.

Forty-one of 792 acute leukemia patients suffered fatal intracranial hemorrhage (FICH). Acute promyelocytic leukemia was the most common subtype. Achievement of complete remission in AML was significantly influenced by FICH. FICH accounts for about half of deaths from hemorrhage and this proportion has not changed despite improvements in leukemia management.

Prognostic significance of Fas (CD95) and TRAIL receptors (DR4/DR5) expression in acute myelogenous leukemia.

We analyzed the clinical significance of the expression of the Fas (CD95) and TNF-related apoptosis-inducing ligand (TRAIL) receptors, the death receptors (DR) 4 and 5, by leukemic blasts in 29 patients with acute myelogenous leukemia (AML). CD95 was positive in 18 patients (62%). The DR4 and DR5 receptors were positive in 20 patients (69%) and 29 (100%), respectively. CD95 positivity was not correlated with cytogenetic abnormalities. Complete remission (CR) rate was not significantly different according to the expression of the CD95 or TRAIL receptors. Relapse-free survival was significantly prolonged in patients with CD95-positive AML cells compared with patients with CD95-negative AML cells (73% versus 38% at 3 years; P = 0.047). TRAIL receptors did not show correlation with other clinical parameters.

Leptomeningeal carcinomatosis in gastric cancer.

We analyzed 19 cases of cytologically confirmed leptomeningeal carcinomatosis (LMC) treated at our institution over the past 11 years. LMC was the initial manifestation of gastric cancer in 2 patients. With the exception of 1 patient, the primary gastric cancer was Borrmann type III or IV, and 88% had poorly differentiated or signet-ring cell histology. The gastric cancer was progressive or a recurrent disease in most of the patients. The distribution of extraneural metastasis suggested that Batson's venous plexus might be the predominant route to the subarachnoid space. Eighty percent of the patients had multiple neuraxis syndrome, and the combination of brain plus cranial nerve syndrome was the most common manifestation. Computed tomography (CT) findings were abnormal in a minor proportion of the patients, while magnetic resonance imaging (MRI) revealed abnormality in 67% of the patients, which could help the diagnosis. LMC complicating gastric cancer was ultimately fatal. Median survival was very short, 4 weeks. By univariate analysis, good performance status, intrathecal chemotherapy, and low CSF LDH concentration favored survival. Multivariate analysis revealed that the administration of CSF chemotherapy was the independent prognostic factor for survival.

The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with Non-Hodgkin's lymphoma who receive cytotoxic chemotherapy.

We investigated the effectiveness of lamivudine to prevent hepatitis flare up due to reactivation of hepatitis-B virus (HBV) in hepatitis-B surface antigen (HBsAg)-positive patients with Non-Hodgkin's lymphoma (NHL) during cytotoxic chemotherapy. HBsAg-positive patients with NHL were identified from the lymphoma database of the Asan Medical Center from January 1995 to August 2002, and their medical records were reviewed. We found that 31 patients were received cytotoxic chemotherapy among 41 NHL patients with HBsAg-positive during same period. We divided them into 2 groups of HBsAg patients with NHL as follows: Group A who received cytotoxic chemotherapy with lamivudine 100 mg daily; Group B without any prophylactic antiviral therapy. There were no significant differences between Group A and B in several clinical variables. Seventeen patients (85%) in group B and one patient (9%) in Group A had hepatitis due to reactivation of HBV (p<0.001), with one hepatic failure related death in Group B and none in group A. The mean dose intensity of adriamycin actually delivered was 13.3 mg/m2/week (80% Relative Dose intensity (RDI)) in Group A and 9.1 mg/m2/week (55% RDI) in Groups B (p<0.001). Our data suggest that the frequency of chemotherapy-related HBV reactivation may be significantly decreased by lamivudine prophylaxis with maintenance of the dosage of adriamycin.

Membranous glomerulopathy as a manifestation of chronic graft-versus-host-disease after non-myeloablative stem cell transplantation in a patient with paroxysmal nocturnal hemoglobinuria.

Allogeneic stem cell transplantation (allo-SCT) using related or unrelated donor could eradicate paroxysmal nocturnal hemoglobinuria (PNH) clones and may cure the disease. Chronic graft-versus host disease (GVHD) is a major complication of patients who have undergone allo-SCT. Nephrotic syndrome has been described as one of the rare manifestations of chronic GVHD following the usual myeloablative allo-SCT. We report a case of nephrotic syndrome that developed 25 months after non-myeloablative allo-SCT for PNH. The patient had grade II acute GVHD and extensive chronic GVHD after non-myeloablative allo-SCT. Typically the patient presented with preserved renal function and full nephrotic syndrome including generalized edema, proteinuria, hypoalbuminemia, and hypercholesterolemia. Renal biopsy revealed findings of membranous glomerulopathy (MG). The patient is alive with a stable engraftment and full donor chimerism under the administration of tacrolimus for control of chronic GVHD and MG without refractory hemolysis and cytopenia.

The efficacy of high-dose melphalan with autologous peripheral blood stem cell transplantation in patients with multiple myeloma.

Although high-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) is widely accepted as an effective and safe consolidation therapy for multiple myeloma (MM), few reports on its efficacy are available in Korea. We present the results of a prospective phase II study, involving 33 patients with MM treated with HDT with ASCT. The treatment consisted of 4 courses of VAD (vincristine, adriamycin, dexamethasone) induction, peripheral blood stem cell collection, and high-dose melphalan with stem cell infusion. The overall response rate was 93%, with 45% of patients having complete responses. The toxicity was predictable and tolerable. With a median follow-up of 27.6 months, the 2-year event free survival rate was 43%. At the time of writing, the median overall survival duration had not been reached with 2-year survival and projected 3-year survival rates of 81% and 74%, respectively. The overall survival was significantly better than that of the historical control patients (N=82) treated with conventional chemotherapy at our institution. The results suggest that HDT with ASCT is a valuable first or second-line treatment for patients with MM.

Allogeneic hematopoietic cell transplantation for paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Although allogeneic hematopoietic cell transplantation (HCT) has a potential to cure patients with paroxysmal nocturnal hemoglobinuria (PNH), appropriate indication and conditioning regimen for HCT have not been established. PATIENTS AND METHODS: Between July 1999 and December 2001, five patients with PNH underwent allogeneic HCT: three for refractory hemolysis and two for aggravating cytopenia. Four patients with hypercellular marrow received Bu-Fludara-ATG (busulfan 4 mg/kg/d for 2 d, fludarabine 30 mg/m2/d for 6 d, and ATG 20 mg/kg/d for 4 d) for conditioning therapy and one patient with hypocellular marrow was conditioned with Cy-ATG (cyclophosphamide 50 mg/kg/d for 4 d and ATG 30 mg/kg/d for 3 d). Three patients received stem cell graft from matched sibling donor and two patients from 1-antigen mismatched unrelated donor. RESULTS: One patient who was conditioned with Bu-Fludara-ATG failed to engraft and died at post-transplant day 62. The other four patients showed three lineage engraftment and normal expression of CD55 and CD59 antigens by flow cytometric analysis. They are alive with stable engraftment and full donor chimerism between post-transplant day 510 and 1116. Acute graft vs. host disease (GVHD) of grade II or more occurred in two patients and extensive chronic GVHD in four. CONCLUSION: HCT using related or unrelated donor could eradicate PNH clones and may cure patients with the disease. Further studies are needed to establish the role of allogeneic HCT, especially with reduced intensity conditioning therapy, in the treatment of PNH.

Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation.

We investigated graft-versus-host disease (GVHD)-specific survival (GSS) and the duration of systemic immunosuppressive treatment (IST) in 82 patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation (HCT). These two major study endpoints were calculated using the Kaplan-Meier method. Deaths solely due to the relapse of underlying disease or accidental deaths were censored at the time of occurrence for the analysis of GSS. The probability of GSS at 5 years was 74.2%. The median duration of systemic IST for chronic GVHD was 272 d (range: 7-1450), and the probability of withdrawal of systemic IST at 1, 2 and 3 years was 67.3%, 82.4% and 89.0% respectively. Analysis based on a multivariate model showed that a diagnosis other than leukaemia or myelodysplastic syndrome (P = 0.049), prior occurrence of grade III-IV acute GVHD (P = 0.021), onset of chronic GVHD before d 120 (P = 0.013), serum alkaline phosphatase over 120 IU/l (P = 0.034), and serum bilirubin over 34.2 micromol/l (P = 0.015) were independent adverse prognostic factors for GSS. Prior occurrence of grade III-IV acute GVHD significantly influenced the duration of systemic IST (P = 0.048). In conclusion, analyses of GSS and the duration of systemic IST will allow patients with different outcomes to be stratified for appropriate treatment application and will provide important parameters in prospective trials for the treatment of chronic GVHD.

Collection of peripheral blood progenitor cells: analysis of factors predicting the yields.

We retrospectively analyzed data on 628 leukapheresis from 160 consecutive patients with hematologic or solid malignancies to identify predictive factors affecting the achievement of optimal peripheral blood progenitor cell (PBPC) collection, which was defined as > or = 5x10(6) CD34+ cells/kg. In univariate analysis, a diagnosis of multiple myeloma, no prior axial skeletal radiotherapy, absence of exposure to alkylating agents and cisplatin, fewer cycles of chemotherapy, and fewer number of previous chemotherapy regimens favored the achievement of target number of PBPC. In multivariate analysis, the absence of prior exposure to alkylating agents, especially cyclophosphamide, (P=0.003, RR=2.08) and cisplatin (P=0.015, RR=2.50) were independent predicting factors affecting the probability of achieving the target PBPC and the time to reach the target PBPC collection. In addition, the total dose of cyclophosphamide the patient received significantly alters the mobilization.

Efficacy of neoadjuvant chemoradiotherapy in resectable esophageal squamous cell carcinoma--a single institutional study.

A prospective phase II study of neoadjuvant chemoradiotherapy (CRT) for resectable esophageal squamous cell carcinoma was conducted from May 1993 to March 1996. A total of 88 patients fitted the eligibility criteria and were treated with two courses of induction chemotherapy (cisplatin 60 mg/m2/day on day 1 and 5-fluorouracil (5-FU) 1000 mg/m2/day on days 2-6) with concurrent hyperfractionated radiotherapy (48 Gy/40 fractions/4 weeks) followed by esophagectomy or definitive CRT comprising 4 cycles of cisplatin/5-FU and hyperfractionated radiotherapy (additional 12 Gy) with intracavitary brachytherapy (9 Gy). Clinical response and downstaging were achieved in 83% and 42% of the patients, respectively. With a median follow-up of 77 months, median survival time was 18 months with a 5-year survival rate of 23%. The clinical responses to CRT and surgery were independent prognostic factors for overall survival. Among the intended surgery group (n = 52), 41 (79%) patients underwent surgery and 36 had a resection with a pathologic complete response rate of 43%. When compared with a matched historical control (n = 40), there was a significant survival benefit in the multimodality arm (p = 0.04). This multimodality therapy was feasible and its efficacy was promising, especially when surgical resection was performed. The therapeutic benefit of neoadjuvant CRT remains to be assessed in large well-designed randomized trials, one of which is ongoing at our institution.

Hemorrhagic cystitis following allogeneic hematopoietic cell transplantation.

We conducted a retrospective study to investigate the incidence, risk factors, and clinical features of hemorrhagic cystitis (HC) following allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients who developed HC after allo-HCT were identified from the HCT database of the Asan Medical Center and their medical records were reviewed. From December 1993 to August 2001, a total of 210 adult patients underwent allo-HCT. Fifty-one patients developed HC with a cumulative incidence of 25.7%. The median onset of HC was post-transplant day 24 (range, -2 to 474), and the median duration was 31 days (range, 8 to 369). Significant risk factors for HC by univariate analysis included diagnosis of chronic myelogenous leukemia (p=0.028), unrelated HCT (p=0.029), grade III-IV acute graft-versus-host disease (GVHD) (p<0.001), extensive chronic GVHD (p=0.001), and positive cytomegalovirus antigenemia between post transplant days 31 and 60 (p=0.031). Multivariate analysis showed that grade III-IV acute GVHD was the most important risk factor for the occurrence of HC after allo-HCT (odds ratio, 3.38; 95% CI, 1.36-8.39). Late-onset HC, which occurred beyond 3 weeks after allo-HCT, was more frequently associated with GVHD than early-onset HC (p=0.007). Our data suggest that a portion of late-onset HC might be a manifestation of GVHD.