Sang Hee Kim

Randomized Trial of Postoperative Adjuvant Therapy in Stage II and III Rectal Cancer to Define the Optimal Sequence of Chemotherapy and Radiotherapy: A Preliminary Report

PURPOSE We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m(2)/d and leucovorin 20 mg/m(2)/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v. 70% at 4 years; P =.043). Twenty-three recurrences occurred in arm I and 38 in arm II (P =.047). Overall survival was not significantly different between arms I and II (84% v. 82% at 4 years; P =.387). CONCLUSION Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.

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 Batsons 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.

Combination chemotherapy of intermediate-dose cytarabine, idarubicin, plus etoposide and subsequent mobilized donor leukocyte infusion for relapsed acute leukemia after allogeneic bone marrow transplantation

The efficacy and side effects of intermediate-dose cytarabine, idarubicin plus etoposide and subsequent donor leukocyte infusion (DLI) were investigated in patients with acute leukemia who relapsed after allogeneic bone marrow transplantation (BMT). Patients were given cytarabine continuous i.v. (1 g/m2 per day x 5), idarubicin i.v. (12 mg/m2 per day x 3), and etoposide i.v. infusion (150 mg/m2 per day x 3). Two days later, G-CSF mobilized donor leukocytes were infused for 2 days. No graft-versus-host disease (GVHD) prophylaxis was given. Between August 1997 and February 2000, 13 patients enrolled (eight acute myeloid leukemia (AML) and five acute lymphoblastic leukemia (ALL)). All patients finished chemotherapy and DLI. Eleven patients (85%) achieved complete remission (CR) at median 27 days after DLI. After median follow up of 10.9 months (2.5-33.3), five of 11 patients who achieved CR relapsed. Overall, six of 13 patients were surviving (6/8 AML and 0/5 ALL, P=0.059). Marrow recovery after chemotherapy and DLI was rapid (12 days for absolute neutrophil count (ANC) >500/microl). Side effects included fever with neutropenia (100%), pneumonia (46%), grade II-IV mucositis (69%), grade III-IV acute GVHD (45%), and extensive chronic GVHD (64%). One patient died from chronic GVHD. Chemotherapy containing intermediate-dose cytarabine and DLI produced a high CR rate in acute leukemia in relapse after allogeneic BMT. A fraction of patients are surviving long term. Side effects were substantial but manageable.

Low‐dose lenograstim to enhance engraftment after autologous stem cell transplantation: a prospective randomized evaluation of two different fixed doses

BACKGROUND: G‐CSF is used to enhance hemato‐ poietic recovery after autologous stem cell transplantation (ASCT), but the optimal dose of G‐CSF during engraft‐ ment has not been established. The medical cost of ASCT is a serious financial burden in developing countries, and G‐CSF is the most costly drug used in this procedure. We evaluated whether a lower, vial‐size fitted dose of lenograstim is clinically equivalent to a higher fixed dose.

Aqueous extract of Orostachys japonicus A. Berger exerts immunostimulatory activity in RAW 264.7 macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE Orostachys japonicus A. Berger (Crassulaceae) (OJ), well-known as Wa-song in Korea is a medicinal plant with immunoregulatory, anti-febrile, antidote, and anti-cancer activities. This study was aimed at evaluating the immunostimulatory effect of O. japonicus A. Berger and its possible mechanisms of action. MATERIALS AND METHODS To evaluate the effect of OJ aqueous extract on macrophage activity, we evaluated the modulation of macrophage activation state by observing structural (phagocytic activities) and the production of nitric oxide increase. The effect of OJ aqueous extract on RAW264.7 cell viability were assessed using Cell Counting Kit (CCK)-8 assay. HPLC analysis was performed to identify potential active compounds of this extract. RESULTS The biological investigations indicated that OJ aqueous extract, among others, possessed the highest macrophage activation as indicated by NO production yield. The results showed that OJ aqueous extract exhibited antioxidant effects, which included scavenging activities against DPPH radicals. OJ aqueous extract increased the phagocytic activity of RAW 264.7 cells against IgG-opsonized red blood cells (RBC). The level of phosphorylated Syk kinase was increased in OJ aqueous extract-treated group as compared to control. Phosphorylation of PLC-γ was increased in the OJ aqueous extract-treated groups. Quercetin-3-O-rhamnose and kaempferol-3-O-rhamnose was detected in OJ aqueous extract by HPLC analysis. CONCLUSIONS OJ aqueous extract might play a pivotal ethnopharmacologic role as an immunostimulatory agent by promoting Fc gamma receptor (FcγR)-mediated phagocytosis of IgG-opsonized RBCs. On the basis of our results, OJ aqueous extract can enhance innate immunity and may serve as an adjuvant for tumor treatment.

Combination chemotherapy utilizing continuous infusion of intermediate-dose cytarabine for refractory or recurrent acute myeloid leukemia

Between October 1991 and December 1998, 19 patients (12 males and 7 females) with refractory (six patients) or recurrent (13 patients) AML were treated with a combination chemotherapy of cytarabine given by continuous infusion over 24-h at a rate of 1 upward arrow g/m2 per day for 5 days along with idarubicin (12 upward arrow mg/m2 per day x 3) and etoposide (150 mg /m(2) per day x 3). Median age of the patients was 28 years (range, 15--61). Seven (37%) of 19 patients achieved complete remission (CR) with median CR duration of 6.7 months (range, 2.5--61.4+). Two patients are surviving for long term (50.1 and 62.6 months). Myelosuppression associated with chemotherapy was severe. Median recovery time to ANC over 500/microl was 28 days (range, 25--59). A significant proportion of patients experienced grade III-VI non-hematologic toxicities including nausea/vomiting (32%), liver function abnormality (32%), and diarrhea (16%). No central nervous system (CNS) toxicity was observed. Our study showed that the administration of cytarabine at a dose of 1 g/m(2) per day by continuous intravenous infusion for 5 days along with idarubicin and etoposide was feasible. Further studies are necessary to elucidate optimum dose and schedule of cytarabine in a setting of refractory or relapsed acute myeloid leukemia (AML).

Combination of 5-fluorouracil and recombinant interferon α-2B in advanced gastric cancer : a phase I study

Based on recent preclinical data suggesting synergism between 5-fluorouracil (5-FU) and Interferon alpha (IFN-a) and clinical activity of the combination therapy in colon cancer, 14 patients with advanced gastric cancer were treated with combination therapy of 5-FU and recombinant interferon alpha 2b (rIFNα-2b) (Intron A, Schering, Kenilworth, NJ, U.S.A.). The maximum tolerated dose was 5-FU 750 mg/m2/day given as a continuous infusion daily for 5 days followed by weekly bolus injection of the same initial daily dose, plus rIFNa-2b 5 χ 106 U given subcutaneously 3 times weekly starting day 1 of 5-FU infusion. The dose-limiting toxicities were fatigue/ weakness, diarrhea, and neurologic toxicities such as somnolence and confusion. The other common side effects were nausea, fever, leukocytopenia, thrombocytopenia, and the darkening of the skin. Of 13 evaluable patients, 4 had a partial response (duration 6, 14, 24, and 28 weeks). These data suggest that combination therapy of 5-FU plus rIFNa-2b is tolerable and has manageable side effects in patients with advanced gastric cancer. Further Phase II study will be needed to define the antitumor activity of this combination.

Phase II trial of a novel platinum analog, SKI 2053R, in patients with previously untreated extensive-stage small-cell lung cancer.

A phase II trial of a novel platinum analog, SKI 2053R, was performed in patients with previously untreated extensive-stage disease (ED) small-cell lung cancer (SCLC). SKI 2053R was administered at the dose of 400 mg/m2 every 3 to 4 weeks as a 1-h infusion. After the first cycle, the dose was escalated to 440 mg/m2 based on toxicity. Thirty-eight patients (31 male) were enrolled between June 1995 and August 1997. The median age was 61 years (range, 36-70 years). Six of 37 evaluable patients achieved a partial response (16.2%; 95% confidence interval [CI], 4.4-28.0%). The durations of response were 1.1, 1.5, 1.7, 1.9, 3.4, and 4.6 months. The estimated median survival time was 7.4 months (95% CI, 5.1-9.7 months). Grade 3 or 4 toxicities were not observed. Grade 1 to 2 leukopenia, anemia, and thrombocytopenia were seen in 5 of 68 cycles, 16 of 68, and 2 of 68, respectively. Nonhematologic toxicities included grade 1 to 2 nausea or vomiting (30 of 68 cycles), nephrotoxicity (27 of 68), and hepatotoxicity (13 of 68). SKI 2053R showed a modest antitumor activity with limited toxicities in patients with ED SCLC. Further clinical trials are warranted in SCLC with a higher dose of SKI 2053R.

Murine bone marrow stromal cells: Implications for their use in gene modified cell therapy

The objectives of this study were to demonstrate that bone marrow stromal cells (BMSC) can be an attractive novel target of genetic modification in gene and cell therapy of hematologic disease. Here, we investigated the therapeutic effects of gene modified BMSC using a murine lymphoma model. BMSC of Balb/c AnN mice were encoded with the human IL-2 gene (hIL-2) using an adenoviral vector. About <formula>1×106</formula> cells of a murine B lymphoma (A20) cell line, were injected into the mice via tail vein. One week after injection of A20 cells, the mice were divided into 4 groups for BMSC therapy: No BMSC (control), unmodified BMSC, BMSC with Ad/ΔE1, and BMSC with Ad/hIL-2. Mice were observed for 8 weeks. The results demonstrated that all mice treated with BMSC (Ad/hIL-2) survived with no evidence of disease during this period of observation. All mice treated with unmodified BMSC or BMSC (Ad/ΔE1) as well as the controls developed disseminated lymphoma, and 80% of mice survived less than 4 weeks. In conclusion, the IL-2 gene-modified stromal cell is a promising therapeutic tool for murine lymphoma.

Analysis of Aroma Patterns in Muskmelon at Different Storage Temperatures Using a Mass Spectrometry-based Electronic Nose

Changes in the flavor of muskmelons stored at different temperatures were examined to judge aroma patterns during storage. A mass-spectrometry based electric nose was used to distinguish the subtle differences in the muskmelons volatile compounds. The data were used for a discriminant function analysis (DFA), and then the partial least square algorithm was used for a quantitative analysis. Volatile components in the muskmelons increased with storage, and the first discriminant function score (DF1: r 2 =99.88%, F=3072.5) moved from a positive position to a negative position as the storage period increased. The proper point of maturity was anticipated as the 28 th day at 0 o C, 21 st day at 4 and 7 o C, and 14 th day at 10 o C. Also, using the DF1 score we could predict the general tendency (vitamin C, stem moisture, acidity) of the muskmelons. The electronic nose revealed that the major volatile compounds that changed during storage of the melons were ethyl ethyl acetate, butyl acetate, nonanol, dodecanoic acid, hexadecanoic acid and tricosane. The amount of volatile compounds detected increased during storage.