An expedient synthesis of flexible nucleosides via a regiocontrolled enzymatic glycosylation of functionalized imidazoles.

A versatile two-step synthesis of C4- and C5-arylated 2'-deoxyribosylimidazoles was elaborated using enzymatic N-transglycosylation followed by microwave-assisted Pd-catalysed arylation reactions. We report herein the reaction conditions that permit managing regioselectivity (N3 versus N1-isomers) in the enzymatic glycosylation of 4-iodoimidazole using the nucleoside N-deoxyribosyltransferase from L. leichmannii. Regiocontrolled glycosylation was also observed among several other imidazole derivatives studied, providing simple access to isomers not readily accessible by chemical routes. Finally, a series of flexible nucleosides was obtained in one step from 4- or 5-iodo-imidazole nucleosides by the Suzuki-Miyaura cross-coupling reaction with (hetero)aryl-boronic acids in aqueous media. Moreover, this chemoenzymatic approach is compatible with a one-pot two-step process affording a straightforward access to a broad array of potential anticancer and antiviral drugs as well as new DNA building blocks.

Expedient and generic synthesis of imidazole nucleosides by enzymatic transglycosylation.

A straightforward route to original imidazole-based nucleosides that makes use of an enzymatic N-transglycosylation step is reported in both the ribo- and deoxyribo-series. To illustrate the scope of this approach, a diverse set of 4-aryl and 4-heteroaryl-1H-imidazoles featuring variable sizes and hydrogen-bonding patterns was prepared using a microwave-assisted Suzuki-Miyaura cross-coupling reaction. These imidazole derivatives were examined as possible substrates for the nucleoside 2'-deoxyribosyltransferase from L. leichmannii and the purine nucleoside phosphorylase from E. coli. The optimum transglycosylation conditions, including the use of co-adjuvants to address solubility issues, were defined. Enzymatic conversion of 4-(hetero)arylimidazoles to 2'-deoxyribo- or ribo-nucleosides proceeded in good to high conversion yields, except bulky hydrophobic imidazole derivatives. Nucleoside deoxyribosyltransferase of class II was found to convert the widest range of functionalized imidazoles into 2'-deoxyribonucleosides and was even capable of bis-glycosylating certain heterocyclic substrates. Our findings should enable chemoenzymatic access to a large diversity of flexible nucleoside analogues as molecular probes, drug candidates and original building blocks for synthetic biology.

Appendicitis after right colectomy? How can this be possible?

This case report concerns a man with appendicitis following right colectomy.

Appendiceal actinomycosis complicated by multiple hepatic abscesses.

We report the case of a patient with appendicitis due to actinomycosis, complicated by multiple liver abscesses. Definitive diagnosis was based on histopathologic examination of the resected appendix. Accurate identification of the pathogen led to curative antibiotic therapy of the liver abscesses.

Synthesis and recognition by DNA polymerases of a reactive nucleoside for DNA diversification.

The synthesis of 1-(2-deoxy-beta-D-erythro-pentofuranosyl)imidazole-4-hydrazide having the features of an ambigous base is reported. The recognition of the analogue by DNA polymerases as an incoming triphosphate as well as a template base was investigated. The mutagenic properties was evaluated by PCR. The potential of this new monomer for DNA diversification is illustrated by the reactivity of the nucleobase towards various aldehydes.

[Direct and reservoir colonic-anal anastomoses. Short and long term results]. / Anastomoses colo-anales directes et avec réservoir. Résultats à court et à long-terme.

STUDY AIM: This retrospective study was designed to assess the operative, oncologic and functional results of total proctectomy with coloanal anastomosis (CAA). PATIENTS AND METHOD: Between 1990 and 1994, 81 patients (44 males/37 females: mean age: 59 years) were operated for a cancer (n = 67) or a benign lesion (n = 14) of the rectum. Sixty-four patients had a straight CAA and 17 patients had a colonic J-pouch. RESULTS: There was no operative mortality. Two patients were reoperated for colonic necrosis and underwent abdominoperineal resection. An anastomotic leak was observed in 11 patients and its severity was decreased by a diverting stoma. An anastomotic stricture was observed in 10 patients. Of the 67 patients with cancer, 19 (28%) developed metastases and 11 (16%) developed local recurrence. The 5-year survival rate was 69%. Twelve months after the operation, continence was similar with the two types of CAA, but the mean daily stool frequency was lower in patients with a reservoir. With a long follow-up (mean = 9 years), functional results were good with regard to continence and stool frequency, almost similar with the two types of CAA; functional disorders (noctumal stools, fragmentation, urgency) were reported by 25 to 40% of patients. CONCLUSION: Total proctectomy with coloanal anastomosis yields good oncologic results. With regard to functional results, the superiority of the colonic J-pouch, which is observed in the first postoperative year, was lost beyond this period; long-term results are good for continence and stool frequency, but some disorders persist in a significant proportion of patients.

[Treatment of adenocarcinoma of the lower esophagus and cardia: resection with or without thoracotomy?]. / Traitement de l'adénocarcinome du bas oesophage et du cardia: résection avec ou sans thoracotomie?

STUDY AIM: In the treatment of adenocarcinoma of the cardia and lower oesophagus, the choice of the approach (with or without thoracotomy) to perform a proximal oesogastrectomy (POG) is still debated. The aim of this retrospective study was to compare mortality, morbidity and long-term survival in a series of patients operated on with or without thoracotomy. PATIENTS AND METHOD: From January 1991 to June 1997, 59 patients (mean ages: 65 +/- 10 years, range: 30-83) underwent POG through a transthoracic (n = 31) or a transhiatal approach (n = 28). All patients underwent both coeliac and left gastric lymphadenectomy. A mediastinal subaortic lymphadenectomy was only performed in patients who had a transthoracic approach. Both groups were comparable concerning age, weight and height, and tumoral staging according to preoperative imaging and pathologic examination. The transhiatal group included more high-risk patients (respiratory insufficiency, ASA score = 3) (NS). RESULTS: Resection was palliative in four patients in the transthoracic group and two patients in the transhiatal group. Operative mortality was 9% in the transthoracic group and 0% in the transhiatal group (NS). Pulmonary complications were as frequent with and without thoracotomy (35% versus 32% respectively). Global (curative and palliative resections) 3-year actuarial survival was similar in both groups (transthoracic: 39% versus transhiatal: 46%, NS), as well as survival after curative resection (44% versus 49% respectively, NS). The operative approach did not influence survival in patients N+ (22% versus 17% respectively, NS) and in patients N- (86% versus 77% respectively, NS). CONCLUSION: These results suggest that, for adenocarcinoma of the cardia and lower oesophagus, the theoretical carcinologic benefit of mediastinal lymphadenectomy can be balanced with an higher operative risk related to the transthoracic approach.

Preoperative systemic 5-fluorouracil does not increase the risk of liver resection.

BACKGROUND/AIMS: The majority of patients who underwent surgery for colorectal liver metastases have been previously treated with 5-FU either as adjuvant chemotherapy or as a primary treatment. We have performed a retrospective study to assess whether this chemotherapy increases the risk of liver resection. METHODOLOGY: Mortality, morbidity and histology of the resected liver of two groups of patients having colorectal liver metastases who underwent major resection were studied. The first group included 17 patients who had received at least 2 courses of 5-FU chemotherapy within 3 months prior to liver resection. The second group included 18 patients who had received no chemotherapy and who were used as controls. RESULTS: Perioperative mortality was nil. Intraoperative blood loss during liver resection (1 +/- 2.5 vs. 1.2 +/- 2 units) was similar in the two groups. Changes of liver function tests on days 2 and 5 were similar in the two groups. Morbidity rate was similar in the two groups (29 vs. 22%) with a mean duration of postoperative hospital stay of 19 +/- 9 days in the 5-FU group and 16 +/- 6 days in the control group. Although 7 (41%) patients in the 5-FU group had an abnormal parenchyma consistency as compared to only 3 (17%) in the control group, the pathological findings within the resected specimen were not different. CONCLUSIONS: 5-FU based systemic chemotherapy does not increase the risk of liver resections.

Long-term functional results of colonic J pouch versus straight coloanal anastomosis.

BACKGROUND: There are very few studies evaluating the long-term functional outcome of coloanal anastomoses. This retrospective study aimed to compare long-term functional results of straight and colonic J pouch anastomoses. METHODS: Thirty-seven patients, 25 with a straight anastomosis and 12 with a J pouch anastomosis, responded to a standardized telephone questionnaire. The mean time since surgery was 10 (range 4-18) years. RESULTS: The mean daily stool frequency was similar in both groups of patients (1.1 in patients with a reservoir, 1.5 in patients with a straight anastomosis). In both groups, two-thirds of patients had perfect continence or limited gas incontinence. Faecal incontinence was reported by two patients with a straight anastomosis and one patient with a pouch. Nocturnal stools and fragmentation were slightly more frequent in patients with a straight anastomosis. Half of the patients regularly used medication. Thirty-five of the 37 patients reported satisfaction with functional results. CONCLUSION: Long-term functional results of coloanal anastomoses are satisfactory and, unlike early results, similar for both types of anastomosis. The functional benefit of a reservoir, seen in the first year after operation, is less evident with increasing time.

Is there a role of preservation of the spleen in distal pancreatectomy?

BACKGROUND: The spleen may be preserved during distal pancreatectomy (DP) for benign disease. The aim of this retrospective study was to compare the postoperative course of DP with or without splenectomy. STUDY DESIGN: From June 1992 to June 1997, 40 adult patients without chronic pancreatitis underwent elective DP for benign lesions. Fifteen underwent spleen-preserving DP (Conservative Group) and 25 DP with splenectomy (Splenectomy Group). In spleen-preserving DP, we attempted to preserve the splenic artery and vein. RESULTS: Spleen-preserving DP was successfully performed in all 15 cases. Patient groups were comparable for clinical features, indication for DP, and surgical procedure. There were no postoperative deaths. The overall incidence of pancreatic fistula was 23%, but was significantly higher in the Conservative Group (40%) than in the Splenectomy Group (12%; p < 0.05). Subphrenic abscesses were more frequently observed in the Conservative Group than in the Splenectomy Group (p < 0.05). The mean duration of postoperative hospital stay was 19 days (range 6 to 46 days) in the Conservative Group and 12.5 days (range 7 to 45 days) in the Splenectomy Group (p < 0.05). At the end of mean followup of 30 months (range 8 to 40 months), no severe postsplenectomy sepsis was observed in the Splenectomy Group. CONCLUSIONS: In our experience, DP with splenectomy has a lower morbidity rate and we consider it to be the best procedure for benign pancreatic disease.

[Palliative treatment of adenocarcinoma of the cardia: is there a role for surgery?]. / Traitement palliatif de l'adénocarcinome du cardia: y a-t-il une place pour la chirurgie?

OBJECTIVES: The value of palliative surgery for adenocarcinoma of the cardia (AC) is controversial, and specific studies are lacking. The aim of this study was to report the results of a palliative resection for AC in 69 patients. METHODS: From 1980 to 1993, 69 patients (mean age 59 +/- 10 years) underwent a palliative resection for AC. Palliative resection was defined by macroscopically incomplete resection, tumoral involvement of resection margins, visceral or serosal metastasis, or N3 metastatic nodes. Patients were classified according to the diagnosis of palliation established preoperatively (group A, n = 26), peroperatively (group B, n = 35), or postoperatively (group C, n = 8) respectively. RESULTS: Six patients (8.7%) died postoperatively. Mortality rates were 3.8%, 8.6% and 25% in groups A, B and C, respectively. Twenty one patients (30%) had postoperative non-fatal complications. Median global survival was 9 months (mean 11 +/- 7 months) without significant difference between groups A, B and C. Forty-four out of 51 patients (86%) followed until death did not have dysphagia. The other patients were free of dysphagia during an average of 70% of the follow-up duration. Among the 14 patients surviving postoperatively with a tumoral esophageal margin, none experienced dysphagia from anastomotic recurrence during follow-up. CONCLUSIONS: In selected patients with AC, a palliative resection can be achieved with an acceptable mortality and a very good functional result. This result can justify a prospective comparison between palliative surgery and alternative treatments.

Output of chyle as an indicator of treatment for chylothorax complicating oesophagectomy.

BACKGROUND: The management of chylothorax complicating oesophagectomy remains controversial. Even if medical management alone can be successful, some authors advocate early reoperation. The aim of this retrospective study was to identify the clinical variables associated with a high probability of full recovery with medical treatment. METHODS: Among 850 Lewis procedures performed for oesophageal carcinoma, 23 patients (2.7 per cent) developed postoperative chylothorax despite systematic preventive ligation of the main thoracic duct. Patients who responded to conservative management were compared with those requiring reoperation for preoperative radiotherapy, unilateral versus bilateral pleural effusion, delay of occurrence of the chylothorax, and ratio of mean chylous output to body-weight 1 and 5 days after its onset. RESULTS: Conservative management was successful in 14 patients with a mean(s.d.) delay of 12(5) (range 7-21) days and there were no hospital deaths. Reoperation was necessary in nine patients; there were two postoperative deaths and no recurrence of the chylothorax. The only significant difference between reoperated and medically treated patients was the mean(s.d.) chylous output at day 5: 23.5(16.6) versus 6.7(5.5) ml per kg body-weight (P< 0.001). At this time, the output was less than 10 ml/kg in 12 of 14 patients in whom medical treatment was successful (sensitivity 86 per cent), and equal to or greater than this cut-off value in all the patients who underwent reoperation (specificity 100 per cent). CONCLUSION: The ratio of chylous output to body-weight on the fifth day after the onset of a chylothorax complicating oesophagectomy seems to reliably predict the success of continuing medical treatment.