Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells

Patients with solid tumors are increasingly being treated by autologous bone marrow transplantation (BMT). Although response rates appear to be increased, disease recurrence is the commonest cause of treatment failure. Whether relapse is entirely due to residual disease in the patient or arises also from infiltrating malignant cells contained in the autologous marrow transplant has not been resolved. If the latter explanation is correct, then purging would be required as part of the transplantation procedure. We used retrovirally mediated transfer of the neomycin-resistance gene to mark BM harvested from eight patients with neuroblastoma in clinical remission. The marked marrow cells were subsequently reinfused as part of an autologous BMT. At relapse, we sought the marker gene in malignant cell populations. Three patients have relapsed, and in each the marker gene was detected by phenotypic and genetic analyses of resurgent malignant cells at medullary and extramedullary sites. Analysis of neuroblast DNA for discrete marker gene integration sites suggested that at least 200 malignant cells, each capable of tumor formation, were introduced with the autologous marrow transplant and contributed to relapse. Thus, autologous BMTs administered to patients with this solid tumor may contain a multiplicity of malignant cells that subsequently contribute to relapse. The marker-gene technique we describe should permit evaluation of the mechanisms of relapse and the efficacy of purging in patients receiving autologous marrow transplantation for other solid tumors that infiltrate the marrow.     

Acute acalculous cholecystitis: sensitivity in detection using technetium-99m iminodiacetic acid cholescintigraphy

Forty-one proved cases of acute acalculous cholecystitis imaged with technetium-99m iminodiacetic acid (IDA) cholescintigraphy were retrospectively analyzed. After the exclusion of one indeterminate scan (showing poor initial hepatic uptake and excretion), the study yielded a 92.5% (37 of 40) sensitivity for the detection of cystic or common bile duct obstruction. Each of the three patients with false-negative scintigrams had other abnormal scintigraphic findings suggestive of biliary tract disease. Of the 20 patients (48.8%) with focal or diffuse gangrenous cholecystitis or perforation, seven (35%) exhibited either free peritoneal spill or increased pericholecystic activity to indicate the presence of advanced disease.     

Incomplete rescue of cystic fibrosis transmembrane conductance regulator deficient mice by the human CFTR cDNA

We have used a mouse model to study the ability of human CFTR to correct the defect in mice deficient of the endogenous protein. In this model, expression of the endogenous Cftr gene was disrupted and replaced with a human CFTR cDNA by a gene targeted 'knock-in' event. Animals homozygous for the gene replacement failed to show neither improved intestinal pathology nor survival when compared to mice completely lacking CFTR. RNA analyses showed that the human CFTR sequence was transcribed from the targeted allele in the respiratory and intestinal epithelial cells. Furthermore, in vivo potential difference measurements showed that basal CFTR chloride channel activity was present in the apical membranes of both nasal and rectal epithelial cells in all homozygous knock-in animals examined. Ussing chamber studies showed, however, that the cAMP-mediated chloride channel function was impaired in the intestinal tract among the majority of homozygous knock-in animals. Hence, failure to correct the intestinal pathology associated with loss of endogenous CFTR was related to inefficient functional expression of the human protein in mice. These results emphasize the need to understand the tissue- specific expression and regulation of CFTR function when animal models are used in gene therapy studies.      

Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67

To assess the prognostic significance of the growth fraction in diffuse large cell lymphoma (DLCL), we studied 105 DLCL patients with the monoclonal antibody Ki-67 applied to frozen tissue sections. Ki-67 detects a nuclear antigen associated with cell proliferation not found in resting cells. Ki-67 findings and other clinical prognostic factors were correlated with outcome using univariate and multivariate analyses in the proportional hazards model. High proliferative activity, defined as nuclear Ki-67 expression in greater than 60% of malignant cells (Ki- 67 greater than 60), was found to be a strong predictor of poor survival among these patients (P = .003, log-rank). The 19 patients with Ki-67 greater than 60% had a median survival of 8 months compared with a median survival of 39 months for the 86 patients with Ki-67 less than or equal to 60%. Examination of pretreatment clinical variables indicated the patient groups were similar with regard to age, sex, stage, B symptoms, tumor bulk, and lactate dehydrogenase (LDH). Both patient groups received comparable curative intent therapy and showed comparable complete response rate precluding treatment differences as modifying outcome. Multivariate analysis indicated Ki-67 is an independent predictor of survival (multivariate P = .006). Further statistical analysis using only B-cell DLCL patients treated with CHOP (63 patients) indicated that Ki-67 greater than 60 retained strong prediction of poor outcome (P = .002, log-rank) among this homogeneous group. We conclude that high proliferative activity (Ki-67 greater than 60) is an independent factor allowing laboratory prediction of probable poor outcome of DLCL.     

Dietary fibre, exercise and serum lipids and lipoprotein cholesterols in 12 to 15 year olds

Serum lipid and lipoprotein cholesterol levels track from childhood and are associated with risk of coronary heart disease. There is some evidence that these are influenced by dietary intake and exercise. Serum lipid and lipoprotein cholesterols were measured in a cohort of 119 British children aged 12–15 y who completed a dietary assessment and exercise questionnaire. The ratio of total- to high-density lipoprotein cholesterol fell with increasing fibre intake, but after adjustment for age, body mass index, sex and other dietary factors, this was not statistically significant. Children exercising at least once a day had significantly lower serum total cholesterol and low density lipoprotein cholesterol levels than those exercising less frequently, even after adjustment for the above factors and dietary fibre intake. No dietary factor was significantly associated with any lipid measure after adjustment for the above factors. The challenge is how to optimize exercise level in adolescent children.     

Colchicine for recurrent pericarditis in children

The incidence of recurrence of acute pericarditis in children varies from 15% to 30% and is accompanied by a high morbidity. Various treatment modalities have been used with variable success rates and side effects. La Serna et al. (Lancet 1987; 26: 1517) were the first to treat adults with recurrent pericarditis with colchicine, and were followed by other authors. To our knowledge no studies in children have been reported. In this paper, we present three children who suffered from viral or idiopathic recurrent pericarditis, despite multiple courses of non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. They responded remarkably well to colchicine, which was administered for 6 months with no adverse reactions. They continue to do well 18, 11 and 12 months after cessation of treatment, respectively.     

Induced drug resistance inhibits selection of initiated cells and cancer development

Compounds exerting a mitoinhibitory effect on normal hepatocytes are potent promoters in the resistant hepatocyte model of chemical carcinogenesis in combination with stimulation of regenerative growth by partial hepatectomy or treatment with carbon tetrachloride. 2- Acetylaminofluorene (2-AAF) almost completely inhibits liver cell regeneration after partial hepatectomy, allowing only resistant cells to participate in regenerative growth. After initiation by diethylnitrosamine and promotion with 2-AAF and partial hepatectomy (PH), focal growth of initiated cells generates liver lesions which occupy 40% of the hepatic volume three weeks after PH. In this work the mechanism for the anti promoting effects of phenobarbital and 3- methylcholantrene were investigated as well as their effects on the development of malignant hepatocellular carcinoma in the resistant hepatocyte model. Treatment with phenobarbital or, especially, 3- methylcholanthrene rendered normal rat hepatocytes resistant to the mitoinhibitory effect of 2-AAF. In combination with 2-AAF/PH, 3- methylcholanthrene shortened the regenerative growth period to less than one week. In the Solt-Farber protocol for experimental hepatocarcinogenesis, treatment with phenobarbital or 3- methylcholanthrene during promotion with 2-AAF/PH permitted hepatocytes surrounding the focal lesions to respond with regenerative growth. The foci and surrounding liver grew until the liver/body mass index reached the control value. With phenobarbital treatment the total focal volume was 20% of the liver volume three weeks after PH, whereas the corresponding value in the case of 3-methylcholanthrene was only 1%. Labelling index data supported the conclusion that growth of the liver lesions in the resistant hepatocyte model was dependent on differential inhibition of normal hepatocyte growth by the promoter and that the size of the foci obtained was related to the length of time after PH required to complete liver regeneration. 3-methylcholanthrene induced 2- AAF resistance prevented the development of large persistent nodules and hepatocellular carcinoma while phenobarbital delayed cancer development with several month. The data thus supports the idea that the degree of clonal expansion during promotion determines the size of the population at risk for malignant transformation, as well as the final frequency of carcinomas.      

铒激光擦皮术后色素沉着的防治对策

０　引言　东方人接受皮肤磨削术治疗后色素沉着的发生率明显高于西方人．尽管采用了目前被认为是最适宜亚洲人的铒激光治疗,色素沉着仍可发生．因此,在实施该手术治疗前应严格掌握适应证,制定严密的预防治疗措施,使得色素沉着的发生率降至最低,从而最大限度的防止医疗纠纷的发生．１　对象和方法１．１　对象　２１例患者,男２例,女１９例,平均年龄２９．２（０８～４８）岁．皱纹祛除８例,浅表疤痕７例,浅咖啡斑、黑子５例,不良纹眉１例．铒激光其它适应证：①老年斑;②细小皱纹;③“白皮肤”雀斑;④痤疮后疤痕⑤色素减退…     

Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial

Introduction

Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF).