p53 Mutation in B-Cell Lymphoid Neoplasms with Reference to Oncogene Rearrangements Associated with Chromosomal Translocations

We investigated mutations of the p53 tumor suppressor gene in B-cell lymphoid neoplasms with reference to oncogene rearrangements associated with specific chromosomal translocations. These included 15 patients with a BCL1/PRAD1 gene rearrangement and/or PRAD1 overexpression, 45 with a BCL2 rearrangement, 2 with a BCL3 rearrangement, 24 with a BCL6 rearrangement, and 6 with both BCL2 and BCL6 rearrangements. Thirty-six patients lacked detectable oncogene rearrangements. Genomic DNA was isolated from involved tissues or leukemic cells obtained at diagnosis and/or at relapse, and established cell lines. Polymerase chain reaction-mediated single-strand conformation polymorphism analysis and direct sequencing were performed to analyze abnormalities of the p53 gene. We detected p53 gene alterations in 18 of 128 patients, representing 21 of the total 151 materials analyzed. In the total of 66 patients with an oncogene rearrangement studied at diagnosis, only one had a mutation; however, 6 of 37 patients studied at relapse showed p53 mutations. Sequential analysis revealed that the p53 mutation was closely associated with transformation from follicular lymphoma to large cell lymphoma, exclusively in BCL2 -positive lymphoma cases. Two of 13 mutations observed in oncogene rearrangement-positive cases and cell lines were transitions at CpG dinucleotides. In contrast, the relationship between p53 mutations and clinical behavior in oncogene rearrangement-negative cases was variable; 5 patients including one with indolent follicular lymphoma were positive for p53 mutation at initial presentation, and 2 of the 5 showed prolonged disease-free survival. Our findings suggest that p53 alteration exhibits diverse functions in the development and progression of B-cell tumors related to the presence or absence of oncogene rearrangement, and that chemotherapy-related influences may be involved in the occurrence of progression-associated p53 mutations.     

Inhalation toxicokinetics of p-dichlorobenzene and daily absorption and internal accumulation in chronic low-level exposure to humans

Inhalation toxicokinetics of p-dichlorobenzene ( p-DCB) in humans was evaluated, and the amounts of daily absorption and internal accumulation were estimated in order to obtain fundamental data for the risk assessment of chronic low-level exposure in the general population. Seven male subjects continuously inhaled about 2.5 ppm of p-DCB vapor for 1 h, and the concentration-time courses of p-DCB in their exhaled air and serum and of urinary 2,5-dichlorophenol (2,5-DCP), a major metabolite of p-DCB, were examined. The toxicokinetics of p-DCB was evaluated on the basis of the time courses using a linear two-compartment model. The amounts of p-DCB absorbed daily and the internal accumulation in chronic low-level exposure were extrapolated using the estimated toxicokinetic parameters. p-DCB was transferred from inhaled air to the body with a constant high absorption rate during exposure. The major route for elimination from the body was urinary excretion followed by metabolism, not exhalation. However, during 9-11 h after the start of exposure, the fraction of p-DCB excreted in urine was only 5-16% of the amount absorbed. Furthermore, most of the absorbed p-DCB seemed to be distributed rapidly to the tissues, such as fat, according to toxicokinetic analysis. Consequently, p-DCB seems to require a long time to be completely eliminated from the body. The amounts of daily absorption and internal accumulation were extrapolated to average 0.27 mg/day and 2.9 mg, respectively, in the subjects exposed chronically to 1 ppb of p-DCB. The amount absorbed daily agreed approximately with that extrapolated from rats which inhaled p-DCB in our previous study.     

Pharmacokinetic and clinical studies on teicoplanin for sepsis by methicillin-cephem resistant Staphylococcus aureus in the pediatric and neonate field

Pharmacokinetics, clinical efficacy and safety of teicoplanin (TEIC) were evaluated in pediatric and neonate patients with MRSA sepsis in the dosages approved in overseas. The administrated dose for pediatrics patients was 10 mg/kg once at hour 0, 12 and 24, followed by every 24 hours intervals. In neonates patients, first dose was 16 mg/kg, then 8 mg/kg every 24 hours intervals. 1. Pharmacokinetic results. All 17 patients (9 neonates and 8 pediatrics) who received TEIC were evaluated for pharmacokinetics. Trough concentrations were analyzed in 16 patients (9 neonates and 7 pediatrics) excluding one patient for lack of measurement of drug concentration at day 7. No patient with a concentration exceeding 60 micrograms/mL in peak or trough concentrations were reported. Mean concentrations in trough at day 3, 4 and 7 in neonates were 15.2, 14.7 and 17.8 micrograms/mL, and in pediatrics were 12.5, 12.2 and 13.1 micrograms/mL, respectively. These results were similar to those reported in foreign pediatrics and neonates patients. 2. Efficacy and safety results. Since no patient was excluded, all patients were evaluated for efficacy and safety. Microbiological efficacy as well as clinical cure were secondarily evaluated in 2 patients for whom MRSA was isolated from blood. Clinical efficacy rate was 76.5% (13/17) and number of cases in judgments of excellent, good, fairly improved and no change were 12, 1, 3 and 1 cases respectively. The patients for whom MRSA was isolated from blood were judged as MRSA eradicated case and cured without any additional anti-MRSA drugs. Adverse events were reported in 2 neonates and 3 pediatric patients. Possibly related adverse events to study drug (adverse drug reactions) were: 1 case of respiratory disorder, thrombocythemia, gamma-GTP increased, GOT increased and GPT increased in 3 pediatrics. These results suggest that an application of overseas dose regimen of TEIC for neonate and pediatrics is appropriate in Japan.     

Thrombus entrapped in a patent foramen ovale of the atrial septum

A 59-year-old women was referred to our hospital due to severe dyspnea and shock status 12 days after intracranial hematoma evacuation for the hypertensive right putaminal hemorrhage. Transthoracic echocardiography revealed right ventricular dilatation and floating structures in the right atrium. Transesophageal echocardiography demonstrated a large, snake-like structure crossing her foramen ovale of the interatrial septum, and impending paradoxical embolism was diagnosed. She did not receive any anticoagulation and surgery due to recent cerebral hemorrhage. Follow-up TEE showed complete disappearance of the thrombus in the atrium two weeks after the onset. Phlebogram of deep vein demonstrated several thrombus in her leg. She underwent placement of inferior vena cava filter and was discharged from our hospital without any symptom of paradoxical embolism.     

Aortobronchial fistula after replacement of descending thoracic aorta with ringed graft; report of a case

A 79-year-old male patient complicated with aortobronchial fistula after replacement of descending thoracic aorta with ringed graft. He underwent replacement of the aortic arch using a four branched vascular graft and open stent grafting to replace the descending thoracic aorta after removing the ringed-graft through median sternotomy. This procedure is useful for patients as the left thoracotomy is risky and the distal anastomotic site of the descending thoracic aorta is too far to anastomose.     

Balloon-occluded retrograde transvenous obliteration (B-RTO) for portal hypertension

We reviewed the current techniques and published results of balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices (GV) and hepatic encephalopathy. The portal hemodynamics of gastric varices were classified into three types according to their feeding vessels, and the development of collateral veins under balloon occlusion of gastro-renal shunt was classified into five grades. The main draining veins of gastric varices were gastro-renal and gastro-inferior phrenic shunts. Preprocedural diagnosis of portal hemodynamics is important in selecting the technique for B-RTO. The rate of disappearance or marked reduction of GV was 98%, and the rate of recurrence of GV was 2%. Hepatic encephalopathy due to gastro-renal shunt improved markedly. In contrast, esophageal varices were aggravated at rates of 10% to 62.5% by the post-procedural elevation of portal pressure. Common adverse effects were hemoglobinuria, abdominal pain, and low-grade fever, but ascites and pleural effusion were also reported. Severe complications such as cardiogenic shock, atrial fibrillation, and pulmonary embolism were reported. We await technical improvements and further indications for this procedure.