Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation

Twenty-six patients with progressive Hodgkin's disease after conventional chemotherapy received intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT); 19 also received additional involved-field radiotherapy. Twenty-one patients [81%, 95% confidence intervals (CI) 61% to 94%] attained complete (n = 18) or partial responses. Ten patients (38%, 95% CI 20% to 59%) are disease- free a median of 4.5 years later (range 3.5 to 7.0 years), including seven patients with continuous complete responses. The likelihood of overall response was not significantly influenced by any clinical or treatment variable examined. However, there was a trend favoring patients with higher Karnofsky scores, and higher scores were associated with attainment of complete responses (P = .06 and P = .02, respectively, Mann-Whitney U test). Both higher Karnofsky scores and shorter durations of disease before transplantation were associated with improved survival in a stepwise Cox multivariate analysis. The chief cause of failure was progression at sites previously involved with Hodgkin's disease. No patient relapsed in the marrow, and two of three patients with a history of marrow involvement with Hodgkin's disease achieved durable complete responses after transplantation. These data suggest that inadequate pretransplant conditioning, and not the reinoculation of occult tumor cells in the autologous marrow, caused most relapses. Fatal treatment-related toxicity occurred in six patients. Three patients died of idiopathic interstitial pneumonitis; each had previously received local mediastinal irradiation before intensive chemoradiotherapy. Intensive chemoradiotherapy and ABMT produces durable responses in some patients with Hodgkin's disease incurable with conventional therapy. Use of such therapies at the first sign of failure with conventional chemotherapy and development of more effective conditioning regimens should further improve results.     

A survey on mortality from non-variceal upper gastrointestinal bleeding: Is the emergency referral system adequate?

Background

Non-variceal upper gastrointestinal bleeding (NVUGIB) is an important cause of mortality and morbidity worldwide. Little information is available on the clinical management of non-variceal upper gastrointestinal bleeding in Italy in relation to the current organization of the Italian Emergency Health Services into Level-I and Level-II Emergency Departments (ED), the latter being more complex structures with greater resources.

Methods

A retrospective survey on clinical, endoscopic, and survival data was conducted by the regional sections of the 3 main Italian gastroenterological societies, AIGO, SIED and SIGE, recording all consecutive episodes of non-variceal upper gastrointestinal bleeding referred to 7 centres (4 of which were Level-II Emergency Departments) in Rome, Italy, during a one-year period. A total of 624 consecutive patients (64% males, mean age 67.6 ± 16.2 years) were included. Thirty-day mortality was 4.6%. Main factors associated with survival at both univariate and multivariate analysis were the presence of full Rockall score <5 and the admission to a Level-II Emergency Departments (p < 0.001). Level-I Emergency Departments admitted patients with a full Rockall score ≥5 (p = 0.02) more frequently than patients with negative endoscopic findings (p < 0.001).

Conclusions

Referral of non-variceal upper gastrointestinal bleeding patients to Emergency Departments with more resources (Level-II) is associated with reduced mortality. Yet, unfortunately, high-risk patients were more often admitted to Level-I Emergency Departments, which suggests the need for a better organization of the emergency referral system.     

Prospective evaluation of transabdominal bowel sonography in the diagnosis of intestinal obstruction in Crohn's disease: comparison with plain abdominal film and small bowel enteroclysis.

Transabdominal ultrasonography is a noninvasive, radiation-free method that is well tolerated by patients with acute abdominal symptoms. The aim of this study was to investigate the validity of transabdominal ultrasonography, compared with plain abdominal film and small bowel enteroclysis in the diagnosis of small bowel obstruction in patients with Crohn's disease (CD). Forty-four patients with CD ileitis or ileocolitis and acute obstructive symptoms who received ultrasonography and plain abdominal film at hospital admission were evaluated by small bowel enema before dismissal or surgery and were considered for statistical analysis. Small bowel obstruction was diagnosed by ultrasonography in 23 of 44 patients (52%), by plain abdominal film in 26 of 44 patients (59%), and by small bowel enema in 28 of 44 patients (64%); the diagnostic accuracy of plain abdominal film and ultrasonography compared with small bowel enema was 73% and 89%, respectively. Ultrasonography proved to be highly specific (100%) with no false positive results. Surgery performed in 25 of 44 patients for symptoms refractory to medical treatment confirmed the high diagnostic value of ultrasonography. The result of this study indicates that transabdominal ultrasonography is accurate and highly specific in the diagnosis of small bowel obstruction and can be considered a valuable first choice examination in CD patients with obstructive symptoms.