Enhancement of the Solubility and Efficacy of Poorly Water-Soluble Drugs by Hydrophobically-Modified Polysaccharide Derivatives

Purpose This work was intended to develop and evaluate a new polymeric system based on amphiphilic carboxymethylpullulans (CMP₄₉C₈ and CMP₁₂C₈) that can spontaneously self-assemble in aqueous solutions and efficiently solubilize hydrophobic drugs. Methods The self-assembling properties of CMP₄₉C₈ and CMP₁₂C₈ were characterized by fluorescence spectroscopy and surface tension measurements. The solubilization of benzophenone and docetaxel was assessed from surface tension measurements, UV spectrometry and HPLC assays. The in vitro cytoxicity of CMP₄₉C₈ solutions and the docetaxel commercial vehicle (Tween 80?/Ethanol–water) were evaluated in the absence and in the presence of docetaxel. Results Compared to CMP₁₂C₈, CMP₄₉C₈ in aqueous solutions appeared to self-organize into monomolecular aggregates containing hydrophobic nanodomains, and to significantly increase the apparent solubility of benzophenone. Docetaxel solubility could also be improved in the presence of CMP₄₉C₈ but to a lower extent due to the surface properties of the drug. Nevertheless, in vitro, the cytotoxicity studies revealed that against cancer cells, the CMP₄₉C₈-docetaxel formulation was equipotent to the commercial docetaxel one. Furthermore, in the absence of the drug, CMP₄₉C₈ appeared less cytotoxic against macrophages than the Tween? 80/Ethanol–water. Conclusions CMP₄₉C₈ is a good candidate for solubilizing hydrophobic drugs and could be applied to docetaxel formulations.     

Morbidity and clinical outcome of nephron-sparing surgery in relation to tumour size and indication

OBJECTIVE: To analyse through a large multicentre series, morbidity of nephron-sparing surgery (NSS) in relation to tumour size and surgical indication. METHODS: The study included patients from eight international academic centres. Age, sex, TNM stage, tumour size, Fuhrman grade, Eastern Cooperative Oncology Group performance status (ECOG-PS), surgical margins, local and distant recurrences, and overall and cancer-specific survival rates were collected and analysed. Indication for elective or mandatory NSS, medical and surgical complication rates, mean blood loss, blood transfusion, and length of hospital stay were specifically recorded for the purpose of this study. Groups were compared for qualitative and quantitative variables by using chi(2) (Fischer exact test) and Student t tests, respectively. RESULTS: A total of 1048 NSS procedures were included in this study. Mean tumour size was 3.4+/-2.1cm. In 730 elective procedures mean operative time (p=0.002), mean blood loss (p=0.01), the need for blood transfusion (p=0.001), and urinary fistula rate (p=0.01) were significantly increased for tumours >4 cm. However, these differences did not result in significantly increased medical (p=0.4), surgical complication rates (p=0.6), or length of hospital stay (p=0.9). Finally, in elective procedures for malignant tumours, positive surgical margins, local or distant recurrence rates, and cancer-specific survival were not significantly different in tumours < or =4 cm and >4 cm. CONCLUSION: Excellent cancer control and outcomes can be achieved with NSS in carefully selected patients with tumours >4 cm. Expanding the size indication of elective NSS results in an increased but acceptable morbidity.     

Introducing a prognostic score for pretherapeutic assessment of seminal vesicle invasion in patients with clinically localized prostate cancer.

PURPOSE: To identify prostate cancer patients who will have the most likely benefit from sparing the seminal vesicles during 3D conformal radiation therapy. METHODS AND MATERIALS: From 1988 to 2001, 532 patients underwent radical prostatectomy for clinically localized prostate cancer. Primary endpoint was the pathological evidence of seminal vesicle invasion. Variables for univariate and multivariate analyses were age, prostate weight, clinical stage, PSA level, Gleason score, number and site of positive prostate sextant biopsies. Multivariate logistic regression with backward stepwise variable selection was used to identify a set of independent predictors of seminal vesicle invasion, and the variable selection procedure was validated by non-parametric bootstrap. RESULTS: Seminal vesicle invasion was reported in 14% of the cases. In univariate analysis, all variables except age and prostate weight were predictors of seminal vesicle invasion. In multivariate analysis, only the number of positive biopsies (P<0.0001), Gleason score (P<0.007) and PSA (P<0.0001) were predictors for seminal vesicles invasion. Based on the multivariate model, we were able to develop a prognostic score for seminal vesicle invasion, which allowed us to discriminate two patient groups: A group with low risk of seminal vesicles invasion (5.7%), and the second with a higher risk of seminal vesicles invasion (32.7%). CONCLUSIONS: Using the number of positive biopsies, Gleason score and PSA, it is possible to identify patients with low risk of seminal vesicles invasion. In this population, seminal vesicles might be excluded as a target volume in radiation therapy of prostate cancer.     

Induction of apoptosis and inhibition of cell proliferation by the lipido-sterolic extract of Serenoa repens (LSESr, Permixon in benign prostatic hyperplasia

BACKGROUND: To determine the mechanism by which prostate volume increases during the development of BPH and to evaluate the effect of LSESr (Permixon), a phytotherapeutic agent, we investigated apoptosis and cell proliferation in the stroma and epithelium of normal prostate and of BPH tissues from patients treated with or without LSESr. METHODS: MIB-1 staining and the in situ end-labeling assay were used to evaluate the proliferative-apoptotic balance in normal prostates and in BPH tissues. Quantitative assessment was performed using an image analysis system. RESULTS: In normal prostates, there was no significant difference between apoptotic and proliferative indices. Cell numbers and proliferative indices were higher in BPH than in normal prostates, while apoptosis values were similar. In the BPH treated group, LSESr significantly inhibited proliferation and induced cell death in both epithelium and stroma. CONCLUSIONS: Induction of apoptosis and inhibition of cell proliferation are likely to be the basis for the clinical efficacy of LSESr.     

Laparoscopic radical prostatectomy: preliminary results

BACKGROUND: Retropubic and perineal radical prostatectomy are used for curative treatment of localized prostate cancer. More complex urological procedures are now being done with laparoscopy. We present our initial results of transperitoneal laparoscopic radical prostatectomy. MATERIALS AND METHODS: Twenty laparoscopic radical prostatectomies were performed between May 1998 and May 1999. The mean age at the time of surgery was 64.2 years. There were 14 stage T1c, 5 stage T2a and 1 stage T2b tumors. The preoperative PSA was 9. 3 ng/ml (normal <4 ng/ml). The Gleason score for positive specimens in 6 random echo-guided endorectal biopsies was 5.7. Four trocars were used. Insufflation pressure was 15 mmHg. The seminal vesicles were first dissected. The prostate was dissected free from the anterior face of the rectum to the prostate apex. Then the peritoneum was incised to find the apex of the prostate. The puboprostatic ligaments were isolated and cut, and the dorsal vein complex was ligated and cut to expose the urethra. The bladder neck was opened and dissected free from the prostate. The lateral pedicles were coagulated before sectioning the urethra. The radical prostatectomy specimen was left along the sigmoid colon, the bladder neck was reconstructed, and a urethrovesical anastomosis was performed with 6 interrupted sutures. The prostatectomy specimen was removed intact in a sack by enlarging the umbilical trocar port. All the prostatectomy specimens were processed according to the Standford protocol. Prostate weight, tumor weight, the Gleason score, and the tumor status of the capsule, seminal vesicles, lymph nodes and surgical margins were studied. RESULTS: The operating time was 385 min. Two patients were transfused. The mean hospital stay was 7. 8 days. The Foley catheter was removed 10.7 days after the operation. Specimen weight was 61 (28-126) g, the Gleason score was 5.9, and tumor volume was 1.4 ml. There were 18 stage pT2, 1 stage pTa (capsular effraction) and 1 stage pT3b (seminal vesicle invasion) tumors. There were four positive surgical margins (2 at the apex and 2 at the bladder neck). All the patients had a postoperative PSA level <0.1 ng/ml at 1 month. The first patient had urethrovesical anastomotic leakage, and required Foley catheterization for 21 days. There was 1 colostomy for rectal injury and 1 urinoma because of urethrovesical anastomotic leakage that required an open surgical procedure. One month after surgery, 15 (75%) patients were fully continent. Six patients had erections, and 5 stated having sexual intercourse. CONCLUSION: These preliminary results show that radical prostatectomy can be performed laparoscopically. Laparoscopy offered excellent vision of all the anatomical structures of the pelvis, permitting precise dissection. Long-term follow-up and further studies are required to confirm and improve these results.     

Is open surgery for partial nephrectomy an obsolete surgical procedure?

During the past few years, the indications for laparoscopic surgery in urology have extended from simple ablative procedures towards more complex reconstructive and organ-preserving interventions. Among them, transperitoneal and extraperitoneal laparoscopic partial nephrectomy have been successfully performed for both benign and malignant lesions. However, this approach raises specific problems because in contrast to other laparoscopic procedures the techniques and tools used during open surgery can not be simply transposed to laparoscopy. The absence of surface hypothermia, the lack of manual palpation, difficulties of vascular control and reconstruction of the collecting system necessitate new solutions readily adaptable to laparoscopic surgery. However, the available series comprise only a few cases, and there are differences in techniques and instrumentation in almost every operation. In these circumstances, it is too early to consider this new approach as reproducible and ready to be used elsewhere than in specialized centres. Although the feasibility and good results of partial nephrectomy for benign conditions and small exophitic tumours is now well documented, the development of new surgical tools and standardization of methodology are required for more complex cases within the scope of well conceived prospective studies.     

The CHEK2(*)1100delC mutation has no major contribution in oesophageal carcinogenesis

In response to DNA damage, the cell cycle checkpoint kinase 2 (CHEK2) may phosphorylate p53, Cdc25A and Cdc25C, and regulate BRCA1 function, leading to cell cycle arrest and DNA repair. The truncating germline mutation CHEK2(*)1100delC abrogates kinase activity and confers low-penetrance susceptibility to breast cancer. We found CHEK2(*)1100delC in 0.5% of 190 oesophageal squamous cell carcinomas and in 1.5% of 196 oesophageal adenocarcinomas. In addition, we observed the mutation in 3.0% of 99 Barrett's metaplasias and 1.5% of 66 dysplastic Barrett's epithelia, both known precursor lesions of oesophageal adenocarcinoma. Since CHEK2(*)1100delC mutation frequencies did not significantly differ among oesophageal squamous cell carcinomas, adenocarcinomas and (dysplastic) Barrett's epithelia, as compared to healthy individuals, we conclude that the CHEK2(*)1100delC mutation has no major contribution in oesophageal carcinogenesis.