Mixed blast crisis with the cytogenetic evidence of three clonal evolutions

A 46-year-old man was diagnosed as having chronic myelogenous leukemia (CML) in chronic phase in Dec. 1985. In Dec. 1987, anemia and leukocytopenia progressed, and the percentage of blast cells increased in the bone marrow. The blast cells were lymphoblastoid and positive for TdT. It was treated as a lymphoid crisis with vincristine and prednisolone, and complete remission was achieved. However, the blasts (11%) were observed in the bone marrow in Mar. 1988, and the chromosomal analysis revealed 46, XY, t (2q-; 11q+), t (9q+; 22q-) in 13 out of 20 cells. In June, the percentage of the blasts increased again, but chromosomal analysis showed a different karyotype, 46, XY, t(2p-; 11p+), t(9q+; 22q-) which was observed in 9 out of 10 cells. Then, myeloblastoid cells increased rapidly in spite of the chemotherapy in Dec. 1988. The chromosomal analysis showed 46, XY, 2p-, 7q-, 9q+, 11p+, 22q- in all analyzed cells. The rearrangement of the bcr gene could be detected by the Southern blotting. The blasts were positive for CD7, CD11, CD13, CD33, CD36, CD41 and CD42, suggesting that the blasts had the surface phenotypes of both myeloid and megakaryocytoid-lineage. This is a case with the mixed blast crisis that changed from the lymphoid to the myelo-megakaryocytoid in nature, in which three clonal evolutions were observed during the clinical course.     

Effect of a synthetic thrombin-inhibitor MD805 on the reaction between thrombin and plasma antithrombin-III

MD805, a synthetic thrombin-inhibitor, effectively retarded the time-dependent inactivation of thrombin which was generated endogeneously or added exogeneously in human plasma. The kinetical study of the time-dependent inactivation indicated that the type of inhibition was competitive and the obtained Ki of MD805 for thrombin was 3 × 10⁻⁸M. MD805 also inhibited the formation of thrombin-ATIII complex. These results indicated that the active site of thrombin was involved in the reaction between thrombin and ATIII, and that MD805 competed with ATIII for thrombin in exactly the same manner as it competed with fibrinogen or synthetic peptide substrates. As a result, MD805 would serve as a protective agent for ATIII from being consumed, in addition to its potent thrombin-inhibitory activity without the aid of ATIII. By contrast, heparin accelerated the time-dependent inactivation rate of thrombin and the formation of thrombin-ATIII complex, which indicates that heparin accelerates the consumption of ATIII.     

Pneumatosis Cystoides Intestinalis Following Steriod Pulse Therapy in a Patient with Polyarteritis Nodosa

We present a case of a 67‐year‐old female with polyarteritis nodosa, complicated by pneumatosis cystoides intestinalis. The definite diagnosis of polyarteritis nodosa was obtained by histological findings on a biopsy specimen from her sural nerve. Following steroid pulse therapy, she developed gastrointestinal symptoms such as nausea, abdominal fullness and watery diarrhea. Abdominal X‐ray and computed tomography showed an abundance of gas contrast within the large intestinal wall. Colonoscopy revealed submucosal tumor‐like multiple elevated lesions from the sigmoid to transverse colon. These findings indicated pneumatosis cystoides intestinalis and the patient was accordingly treated with a high concentration of oxygen via a nasal catheter. One week later, her symptoms and the gas in the bowel wall completely disappeared. Pneumatosis cystoides intestinalis may be one of the complications of steroid pulse therapy.     

A Case of Purulent Pancreatic Ductitis Successfully Treated by Endoscopic Stenting

A 50‐year‐old male received conservative medical treatment for acute exacerbation of chronic pancreatitis. High fever, abdominal pain, as well as enhancement of inflammatory response and pancreatic enzymes in serum, persisted after treatment for 1 month. Purulent pancreatic fluid was drained by endoscopically placing an 8F plastic stent in the main pancreatic duct, resulting in marked improvement of clinical symptoms. This case appears to provide useful information in considering indications for pancreatic stents.     

Reduction of orthodontic tooth movement by experimentally induced periodontal inflammation in mice

Orthodontic therapy is known to have an aggravating effect on the progression of destructive periodontitis if oral hygiene is not maintained. However, it is largely unknown how active periodontitis affects the velocity of orthodontic tooth movement. In this study, we examined the effect of periodontal inflammation on orthodontic tooth movement using a mouse model. Orthodontic force was applied on the maxillary first molar of mice, with or without ligature wire to induce experimental periodontitis. The distance moved by the first molar was significantly reduced by the ligature-induced experimental periodontitis. Tartrate-resistant acid phosphatase staining revealed that the number of osteoclasts present during orthodontic treatment was lower in the pressure zone of alveolar bone in the presence of periodontal inflammation. Consistently, the expression level of receptor activator of nuclear factor-κB ligand (RANKL) in the pressure zone was decreased in the ligature group. By contrast, experimental periodontitis increased the expression of cyclooxygenase-2 mRNA in the periodontal tissues, while in vitro treatment with prostaglandin E₂ decreased extracellular signal-regulated kinase phosphorylation and RANKL expression induced by mechanical stress in osteoblasts. Taken together, these results suggest that the orthodontic force-induced osteoclastogenesis in alveolar bone was inhibited by the accompanying periodontal inflammation, at least partly through prostaglandin E₂, resulting in reduced orthodontic tooth movement.     

Pharmacokinetics of 1-phthalidyl-5-fluorouracil (PH-FU)

The blood level of PH-FU following oral administration to rabbits and tumor-bearing mice was considerably lower than that of Tegafur, HCFU or 5'DFUR, and decreased more rapidly. The t1/2 beta was 0.48 h (rabbits) and 1.74-1.91 h (mice). The blood level of 5-FU derived from PH-FU was higher at an earlier time after administration than that derived from other 5-FU derivatives, but it disappeared more rapidly. The tissue level of PH-FU in S-180-and Lewis lung carcinoma-bearing mice was detected at a low level in various tissues of mice, except for a higher level in the digestive tract and a lower level in the brain and muscle. The tissue level of 5-FU in both types of mice was high in the digestive tract and kidney. The 5-FU level in the 2 kinds of tumor tissues was relatively high and persisted for several hours. After incubating PH-FU and tissue homogenates from humans and mice at 37 degrees C for 2 h, PH-FU was converted to 5-FU very strongly in the liver and kidney, and considerably strongly in the muscle, heart, tongue and testis. In conclusion, PH-FU seems to be characterized by a low blood and tissue level of unchanged drug, a high production of 5-FU and a short duration of the level.     

Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis

Loss of heterozygosity (LOH) and K-ras mutation were analyzed in 111 colorectal polyps and 26 invasive carcinomas from 40 patients with familial adenomatous polyposis of distinct histopathological types. LOH, being less than 2% in moderate adenomas, was detected on chromosome 5q (20%) in severe adenomas, on 5q (26%) and 17p (38%) in intramucosal carcinomas, and on 5q (52%), 17p (56%), 18 (46%), and 22q (33%) in invasive carcinomas. LOH on chromosome 5q occurred most frequently in the region close to the APC gene both in adenomas and carcinomas, and a loss of the normal allele of the APC gene was demonstrated in 3 cases. K-ras mutation markedly increased in the step of development from moderate (11%) to severe (36%) adenomas. These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.     

Wound healing of canine vocal folds after phonosurgery

To develop phonosurgical techniques, the authors investigated the healing mechanisms of wounds on the vocal folds of canine larynges, and devised a method to cover the raw surfaces of such wounds. To restore the normal physiologic properties of the vocal folds, the normal mucosa should be removed as little as possible in phonosurgery. When the mucosa of the vocal folds is extensively removed by surgical intervention and the raw surface cannot be covered with the local pedicle flap, it should be covered with a free mucosal flap. We found an activated human fibrinogen concentrate, which is a biologic tissue adhesive, to be suitable for adhering a free mucosal flap to the raw surface by a laryngomicrosurgical approach.     

Frequent allelic losses and mutations of the p53 gene in human ovarian cancer.

The p53 gene on chromosome 17p is considered to be a tumor suppressor gene, and frequent mutations of the p53 gene have been found in a wide variety of human cancers. We examined 31 ovarian cancers for allelic losses and mutations of the p53 gene by polymerase chain reaction-single strand conformation polymorphism analysis as well as restriction fragment length polymorphism analysis. Allelic loss of the p53 gene was detected in 16 of 20 cases (80%). Mutations were detected in 9 of 31 cases (29%): 2 cases in exon 4; 5 cases in exons 5-6; and 2 cases in exons 7-8. In 8 of 9 cases, p53 mutations were accompanied by losses of the normal allele. These alterations of the p53 gene were commonly detected from stage I to stage IV. These results suggest that alterations of the p53 gene play an important role in the development of human ovarian cancers.