Frameshift Mutations at Coding Mononucleotide Repeats of the hRAD50 Gene in Gastrointestinal Carcinomas with Microsatellite Instability

Microsatellite instability (MSI) and frameshift mutations in genes containing nucleotide repeats have been reported in a subset of colorectal and gastric carcinomas. This study describes the analysis of MSI-positive colorectal (39 cases) and gastric carcinomas (36 cases) for the presence of frameshift mutations of the six genes known to be involved in DNA repair and containing mononucleotide repeats in their coding region. Our mutational study of the 75 MSI-positive tumors revealed frequent mutations in hRAD50 (23 cases, 31%), BLM (16 cases, 21%), and hMSH6 (16 cases, 21%); rare mutations in BRCA1 (1 case, 1%) and ATM (3 cases, 4%); and no mutation in NBS1. In contrast, no frameshift mutation was found in 60 MSI-negative colorectal and gastric carcinomas. The mutation of hRAD50, a gene that is involved in the response to cellular DNA damage and forms a complex with hMRE11 and NBS1, has not been reported previously. Our results suggest that frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a role in the tumorigenesis of colorectal and gastric carcinomas with MSI. The MSI targeting of the hRAD50 and BLM genes represents an additional link between MSI and DNA repair because alteration of these genes could accelerate defective DNA repair.ope

Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.ope

Preoperative Chemoradiation Followed by Total Mesorectal Excision for Locally Advanced Rectal Cancer: Oncologic Outcomes According to Pathologic T and N Stage

Purpose: Tumor response of patients with locally advanced rectal cancer after chemoradiation showed 60∼70% of tumor volume reduction and T and N downstaging. Curative resection with total mesorectal excision should be followed for good oncologic outcomes. This study was designed to analyze the oncologic outcomes in patients who received preoperative chemoradiation followed by total mesorectal excision for locally advanced rectal cancer according to pathologic T and N stage. Methods: Total 108 patients with locally advanced rectal cancer treated between 1989 and 2000. All patients were analyzed retrospectively and staged as T3, 4 N (⁢) by transrectal ultrasonography and pelvic MRI. All patients received a 5,040 cGy of radiation over 5 weeks and systemic intravenous bolus chemotherapy 5 FU 450 mg/m2 and leucovorin 20 mg/m2 for 5 days was given during first and fifth weeks of radiation treatment, followed four to six weeks later by radical surgery. Results: Among 108 patients there were 74 males and 34 females. Mean age was 54.4 years in male and 52.3 years in female. Mean follow up periods was 41.3 months. Complete follow up was in 96.4% of patients. Curative resection was done in 90 patients (83.3%). The most common type of surgery was low anterior resection in 40 (44.4%) and unresectable patients in 10 (9.3%). Postoperative morbidities were wound infection (n=10, 9.2%), anastomostic leakage (n=2, 1.9%), and anastomotic stricture (n=1, 0.9%). After chemoradiation, tumor stage were as follows: pathologic complete remission was in 7 (6.5%), pT1, T2 N0 (stage I) was in 21 (19.4%), T3N0 (stage II) was in 28 (25.9%) and T3 N (⁢) (stage III) was in 34 (31.5%). The rate of local recurrence was 10.7% in stage II and 20.6% in stage III. Systemic recurrence was 21.4% in stage II and 47.1% in stage III. 5 year survival rate according to T stage was T0 (100%), T1 (100%), T2 (79.5%), T3 (43.7%), T4 (33.3%) (p=0.0088). According to N stage, N (⁣)(72.0%) and N (⁢) (35.7%)(p=0.002). Among T3 patients, 5 year survival rate was N (⁣)(58.2%) vs. N (⁢)(32.0%)(P=0.0228). Conclusion: Preoperative chemoradiation followed by total mesorectal excision downstaged locally advanced rectal cancer and showed high resectability. Clinical outcomes correlated with pathologic T and N downstaging. Patients who did not show pathologic T and N downstaging showed high local and systemic failure and poor prognosis.ope

Efficacy of Pre - and Postoperative Chemotherapy in Patients with Osteosarcoma of the Extremities

PURPOSE: We evaluated the treatment efficacy including survival and recurrence, and factors associated with recurrence in osteosarcoma patients treated with preoperative chemotherapy, surgery, and adjuvant chemotherapy.0aMATERIALS AND METHODS: Forty nine patients with osteosarcoma were treated with preoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion for 3 cycles, followed by surgery. According to the pathologic response, if tumor was necrotized more than 90%, the same adjuvant chemotherapy was reintroduced for 3 cycles, and if the response was not enough, then the salvage regimen was introduced. Plain chest film and chest CT scan were taken monthly and every 3 months, respectively. When tumor recurred, the metastasectomy was performed whenever possible. 0aRESULTS: Forty three patients were evaluable with amedian follow up of 53 months. Five-year disease-free and overallsurvival rate was 47.0% and 66.9%, respectively. The recurrence was observed in 22 patients (51.2%) with median time of 12.5 months. Baseline alkaline phosphatase (ALP) was the only significant factor for recurrence (pomths vs 5~12 months).0aCONCLUSION: These results indicates that pre- and postoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion showed comparable treatment efficacy and acceptable toxicities.ope

(The) hepatic abscess in Korea

의학과/석사[한글] [영문] Since Hippocrates described about the hepatic abscess there were numerous reports on the hepatic abscess in the world. the abscess of liver is a considerable interest, important and relatively common in Korea. Following the advent of antibiotics and advanced development of chemotheraphy the incidence of hepatic abscess has decreased along with its mortality but the diagnosis and management of liver abscess remain one of the persistent problems, and there is a few reports of a systemic study of th hepatic abscess presenting this problems in Korea since Ludlow 1923. The purpose of this study is to provide a statistical analysis of this problem and a knowledge of the clinical behaviour of the hepatic abscess in Korea. This study is based on analysis of 178 patients with hepatic abscess adminiteed to the Severance Hospital, Yonsei University Medical Center from July, 1955 to June, 1970 and a review of the literature. 1. Among 178 cases of the hepatic abscess, 76(42.7%) were pyogenic abscess and 102(57.3%) were amebic abscess. 2. In both groups of abscesses male outnumbered female in a 5:1 ratio. 3. The peak age incidence for both groups came in the 4th and 3rd decade. 4. The most common clinical manifestations were pain and tenderness over R.U.Q., hepatomegaly, fever and chills in both groups. 5. Positive roentgenologic findings on admission were present in 75% of both groups. 6. Liver scanning showed cold area suggestive of liver abscess in 44 cases of 45 hepatic abscess(97.8%). 7. The right lobe of liver was involved in 88.2% of the pyogenic and 94.1% of the amebic abscess. 8. In direct smear and culture studies the pus was found to be sterile in 27.6% of the pyogenic abscess and the most frequently found organisms were E. coli and staphylococcus. 9. In the amebic abscess ameba was found in the pus in 15.7% and only 11.8% had cysts in their stools. 10. The incidence of complications was 11.8% in the pyogenic and 18.6% in the amebic abscess. 11. The mortally rate was 7.3% in boty groups. 9.2% in the pyogenic and 5.8% in the amebic abscess.restrictio

(The) mode of action of amphotericin B in cardiac muscle

의학과/박사[한글] Amphotericin B (Am B)는 sreptomyces nodosus에 의하여 산출되는 polyene fungicide의 일종으로 1956널에 임상에 소개된 이래 진균감염(mycotic infection)의 치료에 쓰여지고 있다. Am B가 세포막 특히 Cholesterol을 포함하고 있는 어떤 세포막에도 영향을 미쳐 그 투과도를 증가시켜 K**+ 이 세포밖으로 유출되고 Na**+ 이 세포내로 유입된다는 보고는 많이 있으며, 또한 인간을 포함한 포유동물의 적혈구 및 거북이와 두꺼비의 방광같은 세포 막을 사용한 실험보고도 많이 있으나 심장에 미치는 영향에 대하여는 Arora(1965)가 개구리와 쥐의 심장을 사용한 실험에서 Am B가 "Positive cardiotonic action"이 있다고 보고한 외에는 거의 없다. 따라서 Am B의 심장근육에 미치는 작용중 특히 Positive inotropy의 기전을 규명하고저 본 실험에 착수하였다. 실헐재료 및 방법 가토의 심근을 분리하여 건기자극기로 자극을 가하고 그 등장성 수축변화를 polygraph에 기록하였으며, 또한 자극간격을 달리할 때 나타나는 Bowditch 및 Woodworth staircase 현상을 관찰하였다. 심장절된에서 (45)**Ca를 이용하여 Ca**++ 분포량을 측정하였으며 골격근의 aarcoplasmic reticulum (SR)의 Ca**++ -uptake를 "filtration technique"을 이용하여 측정하였다. Glycerine으로 처치된 근육섬유에서 adenosine triphosphate (ATP) 첨가시의 장력변화를 측정하였으며, 또한 심근 세포막에서 는 Na**+ -K**+ adenosine triphosphatases (ATPase)를, SR에서는 Ca**++ ATPase를, glucerine으로 처치된 근육섬유에서는 Mg**++ -Ca**++ - activated ATPase를 측정하였다. 이상의 실험과정에서 실험군에는 Am B를, 대조군에는 Am B제제에 포함되어있는 양만큼의 sodium deoxycholate를 투여하여 비교하였다. 설험성적 및 결론 이상의 실험을 통하여 다음과 같을 결과를 얻었다. 1. Am B는 심장근의 수축력을 현저히 증가시켰고 Woadworth staircase현상은 증가시켰으나 Bowditch staircase 현상은 오히려 억제하였다. 2. Am B는 SR의 Ca**++ -uptake를 억제하였다. 그러나 SR의 Ca**++ -activated ATPase에는 영향을 주지 않았다. 3. Am B는 심근세포내로의 (45)**Ca(Ca**++)의 분포량을 의의있게 증가시켰다. 4. Am B는 glycerine으로 처치된 근육섬유의 장력변화 및 Mg**++ -Ca**++ -activated ATPase에 영창을 주지 않았다. 이상의 성적으로 미fn어 보아 Am B는 심장근육내로 Ca**++ 의 이동을 증가시키고 또 심근세포내외 Ca**++ pool로부터 Ca**++의 유리를 촉진하여 activator Ca**++의 농도를 증가시킴으로서 가토의 심근수축을 증가시키는 것으로 사료된다. [영문] Amphotericin B (AmB), an amphoteric polyene fungicide, bas been employed in the treatment of systemic mycotic infection. Numerous reports have been appeared in the literatures which indicate that AmB alters the functional or structural integrity of a variety of Systems including fungi, erythrocytes, the urinary bladder of the toad and turtle, and the mammalian kidney. The mechanism of these action of AmB is believed to include polyene interaction with sterols in the cell membrane which results in increased membrane permeability. The recent report by Arora (1965) indicates that AmB increases contractility of the cardiac muscle isolated from frog and rat. However the mechanism for this effect was not understood. I therefore undertook the present study to investigate the cardiotonic action of AmB and its mechanism. Experimental methods; The effect of AmB was investigated unsing isolated muscle preparations of rabbit cardiac muscle. The development of tension was measured with varying stimulus interval to observe Bowditch and Woodworth staircase phenomena. The distribution of Ca**++ in the cardiac muscle was measured using (45)**Ca as a tracer. The effect of AmB on the Na**+ -K**+ ATPase activity of the cardiac muscle membrane was studied. In other series of experiments, the effects of AmB on the Ca**++ -uptake and Ca**++ ATPase activity were measured in sarcoplasmic reticulum (SR) of rabbit psoas muscle. In the additional series of experiments, the effects of AmB on the contractile tension and Mg**++ -Ca**++ ATPase activity of the glycerinated psoas muscle were studied. Results and Conclusions; 1. Am8 increased contractile tension of the cardiac muscle of the rabbit and the antibiotic appeared to enhance Woodworth phenomenon, while it inhibited Bowditch phenomenon. 2. AmB reduced the rate of Ca**++ -uptake by SR without affecting activity of Ca**++ ATPase of SR. It had no distinct effect on the contractility and Mg**++ -Ca**++ ATPase activity in the glycerinated rabbit psoas muscle. 3. Similarly, the activity of Na**+ -K**+ ATPase of the cardiac muscle cell membrane was not significantly altered by AmB. 4. The distribution of Ca**++ in the cardiac muscle was increased by AmB. These results suggest that increased contractility of the cardiac muscle by AmB is due to increased activator Ca**++ concentration in the cell by 1) enhanced Ca**++ influx across the cell membrane at rest and low frequency stimulation and 2) Ca**++ release from the intracellular Ca**++ pool after AmB treatment.restrictio