A paclitaxel-hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity.

PURPOSE: This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts following i.p. administration. EXPERIMENTAL DESIGN: In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal-dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared. RESULTS: ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug. CONCLUSIONS: ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer.     

Chromosomal aberrations in benign and malignant Bilharzia-associated bladder lesions analyzed by comparative genomic hybridization

Background

Bilharzia-associated bladder cancer (BAC) is a major health problem in countries where urinary schistosomiasis is endemic. Characterization of the genetic alterations in this cancer might enhance our understanding of the pathogenic mechanisms of the disease but, in contrast to nonbilharzia bladder cancer, BAC has rarely been the object of such scrutiny. In the present study, we aimed to characterize chromosomal imbalances in benign and malignant post-bilharzial lesions, and to determine whether their unique etiology yields a distinct cytogenetic profile as compared to chemically induced bladder tumors.

Methods

DNAs from 20 archival paraffin-embedded post-bilharzial bladder lesions (6 benign and 14 malignant) obtained from Sudanese patients (12 males and 8 females) with a history of urinary bilharziasis were investigated for chromosomal imbalances using comparative genomic hybridization (CGH). Subsequent FISH analysis with pericentromeric probes was performed on paraffin sections of the same cases to confirm the CGH results.

Results

Seven of the 20 lesions (6 carcinomas and one granuloma) showed chromosomal imbalances varying from 1 to 6 changes. The most common chromosomal imbalances detected were losses of 1p21-31, 8p21-pter, and 9p and gain of 19p material, seen in three cases each, including the benign lesion.

Conclusion

Most of the detected imbalances have been repeatedly reported in non-bilharzial bladder carcinomas, suggesting that the cytogenetic profiles of chemical- and bilharzia-induced carcinomas are largely similar. However, loss of 9p seems to be more ubiquitous in BAC than in bladder cancer in industrialized countries.

     

Effect of trimetazidine on 99Tcm-tetrofosmin uptake in patients with coronary artery disease

Myocardial uptake of 99Tcm-tetrofosmin in vivo is determined by a combination of flow and metabolic status of myocytes. The accumulation of tetrofosmin in the mitochondria is related to their ability to transduce metabolic energy into electronegative membrane potential. Trimetazidine (TMZ), an anti-ischaemic drug, appears to have a metabolic cytoprotective effect related to mitochondrial function, since it does not induce systemic or coronary haemodynamic changes. In this study, we evaluated the effects of TMZ on tetrofosmin uptake in hypoperfused myocardial regions in patients with coronary artery disease (CAD). Twenty-two patients, 14 with previous myocardial infarction (group A) and eight with a history of angina (group B), with angiographically documented CAD were studied. All patients underwent two tetrofosmin SPET studies at rest, before (baseline) and 1 week after TMZ administration (post-TMZ). On quantitative analysis, 131 segments showed less tetrofosmin uptake at baseline. In these segments, tetrofosmin uptake was 51 +/- 13% at baseline and 55 +/- 15% post-TMZ (P < 0.001 vs control). In the 86 hypoperfused segments of group A, tetrofosmin uptake was 48 +/- 14% at baseline and 52 +/- 17% post-TMZ (P < 0.001 vs control). In the 45 hypoperfused segments of group B, tetrofosmin uptake was 56 +/- 9% at baseline and 60 +/- 10% post-TMZ (P < 0.001 vs control). In the remaining 309 segments, no significant difference in tetrofosmin uptake before and after TMZ was observed. In conclusion, our results suggest that TMZ administration may increase myocardial uptake of tetrofosmin in hypoperfused regions at rest in patients with CAD, based on its metabolic effect.     

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial.

This study provides an updated report of the consecutive multicenter Gruppo Italiano Trapianto Midollo Osseo trial employing an intensified, purging-free, total body irradiation-free, high-dose sequential chemotherapy schedule with peripheral blood stem cell autograft (i-HDS) in advanced-stage follicular lymphoma (FL). Special interest has been devoted to late toxicities and outcome in terms of molecular status. Ninety-two untreated FL patients aged 相似文献   

360° laparoscopic fundoplication with tension-free hiatoplasty in the treatment of symptomatic gastroesophageal reflux disease

Background: Since laparoscopic Nissen fundoplication was first described by Cuschieri in 1989 and later by Dallemagne in 1991, this procedure has been widely employed for the treatment of symptomatic gastroesophageal reflux disease (GERD) and/or hiatal hernia. However, a relatively high incidence (7–11%) of intrathoracic Nissen valve migration/paraesophageal hernia following laparoscopic fundoplication has recently been reported. Methods: Between November 1992 and August 1995, 65 consecutive patients with severe GERD and/or hiatal hernia underwent laparoscopic 360° fundoplication. In nine of these 65 (13.8%) patients, an intrathoracic Nissen valve migration had occurred within 4 months. Six of these patients were symptomatic and were again submitted to the laparoscopic intervention. Videotapes of both the first and second operation were reviewed. In all cases, it was apparent that, at the first operation, closure by stitches of the hiatus was under tension, and at the second operation, the muscle fibers of the right crus were disrupted, probably due to the tension between the suture margins during the inspiratory movements of the diaphragm. These findings prompted us to perform an effective tension-free closure of the hiatus. A polypropylene mesh (3 × 4 cm) was placed on the hiatus behind the esophagus and fixed with eight metallic agraphes (2 + 2 on the superior edge and 2 + 2 on the lateral sides of the right and left cruses). Results: Between August 1995 and February 1998, the technique, complete with 360° fundoplication, was used for 67 patients with GERD. At mean follow-up of 22.5 months (range, 1–30), there was no evidence of postoperative paraesophageal hernia or complications related to the use of the mesh. Conclusions: This tension-free hiatoplasty seems to be an effective solution to prevent postoperative paraesophageal hernia in patients undergoing antireflux laparoscopic surgery. However, longer follow-up is still needed. Received: 9 July 1998/Accepted: 19 April 1999