Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy.

OBJECTIVE: We compared positive surgical margin (PSM) rates for patients with high risk prostate cancer (HRCaP) who underwent open radical retropubic (RRP), robotic (RALP), and laparoscopic (LRP) prostatectomy at a single institution. MATERIALS AND METHODS: We performed a retrospective review of our prospectively maintained IRB approved database identifying prostate cancer patients who underwent RRP, RALP, or LRP between January 2000 and March 2010. Patients were considered to have HRCaP if they had biopsy or final pathologic Gleason score ≥ 8, or preoperative PSA ≥ 20, or pathologic stage ≥ T3a. A positive surgical margin (PSM) was defined by the presence of tumor at the inked surface of the specimen. Patients who received neoadjuvant hormonal therapy and those who underwent a perineal prostatectomy were excluded from the study. RESULTS: Of the 445 patients in this study, surgical technique for prostatectomy included RRP (n = 153), RALP (n = 152), and LRP (n = 140). PSM rate for the three groups were not different: 52.9% RRP, 50% RALP, and 41.4% LRP, (p = 0.13). The PSM rate did not differ when comparing RRP to a combined group of RALP and LRP (p = 0.16). Among patients with a PSM, there was no statistical difference between the three groups in terms of the number of patients with a pathologic stage of T3 or higher (p = 0.83). On univariate analysis, a higher preoperative PSA value was associated with a positive margin (p = 0.04). CONCLUSION: In this HRCaP series, the PSM rate did not differ based on the surgical approach. On univariate analysis, patients with a higher preoperative PSA value were more likely to have a PSM.

Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy

Objective We compared positive surgical margin (PSM) rates for patients with high risk prostate cancer (HRCaP) who underwent open radical retropubic (RRP), robotic (RALP), and laparoscopic (LRP) prostatectomy at a single institution. Materials and Methods We performed a retrospective review of our prospectively maintained IRB approved database identifying prostate cancer patients who underwent RRP, RALP, or LRP between January 2000 and March 2010. Patients were considered to have HRCaP if they had biopsy or final pathologic Gleason score ≥ 8, or preoperative PSA ≥ 20, or pathologic stage ≥ T3a. A positive surgical margin (PSM) was defined by the presence of tumor at the inked surface of the specimen. Patients who received neoadjuvant hormonal therapy and those who underwent a perineal prostatectomy were excluded from the study. Results Of the 445 patients in this study, surgical technique for prostatectomy included RRP (n = 153), RALP (n = 152), and LRP (n = 140). PSM rate for the three groups were not different: 52.9% RRP, 50% RALP, and 41.4% LRP, (p = 0.13). The PSM rate did not differ when comparing RRP to a combined group of RALP and LRP (p = 0.16). Among patients with a PSM, there was no statistical difference between the three groups in terms of the number of patients with a pathologic stage of T3 or higher (p = 0.83). On univariate analysis, a higher preoperative PSA value was associated with a positive margin (p = 0.04). Conclusion In this HRCaP series, the PSM rate did not differ based on the surgical approach. On univariate analysis, patients with a higher preoperative PSA value were more likely to have a PSM. .

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines.

MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in development, differentiation, cell proliferation, and death as well as the complex process of acquired drug resistance. The goal of this study was to identify specific miRNAs and their potential protein targets that confer acquired resistance to gemcitabine in urothelial carcinoma of the bladder (UCB) cell lines. Gemcitabine-resistant cells were established from 6 cell lines following exposure to escalating concentrations of the drug and by passaging cells in the presence of the drug over a 2- to 3-month period. Differential miRNA expression was identified in a microarray format comparing untreated controls with resistant cell lines, representing the maximum tolerated concentration, and results were validated via qRT-PCR. The involvement of specific miRNAs in chemoresistance was confirmed with transfection experiments, followed by clonogenic assays and Western blot analysis. Gemcitabine resistance was generated in 6 UCB cell lines. Microarray analysis comparing miRNA expression between gemcitabine-resistant and parental cells identified the differential expression of 66 miRNAs. Confirmation of differential expression was recorded via qRT-PCR in a subset of these miRNAs. Within this group, let-7b and let-7i exhibited decreased expression, while miR-1290 and miR-138 displayed increased expression levels in gemcitabine-resistant cells. Transfection of pre-miR-138 and pre-miR-1290 into parental cells attenuated cell death after exposure to gemcitabine, while transfection of pre-miR-let-7b and pre-miR-let-7i into the resistant cells augmented cell death. Mucin-4 was up-regulated in gemcitabine-resistant cells. Ectopic expression of let-7i and let-7b in the resistant cells resulted in the down-regulation of mucin-4. These results suggest a role for miRNAs 1290, 138, let-7i, and let-7b in imparting resistance to gemcitabine in UCB cell lines in part through the modulation of mucin-4. Alterations in these miRNAs and/or mucin-4 may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine in UCB.

Management of complex anterior urethral strictures with multistage buccal mucosa graft reconstruction.

OBJECTIVE: To describe the indications and outcomes of salvage urethral reconstruction using the combination of urethrectomy and buccal graft replacement. MATERIALS AND METHODS: We retrospectively identified 91 consecutive patients who had undergone multistage urethral reconstruction from 2003 to 2009. The demographic and surgical outcomes data, including the need for first stage revision, pre- and postoperative urine flow rates, and reconstruction failure was collected for all patients. RESULTS: Of the 91 patients, 51 (56%) subsequently underwent urethral tubularization, 17 (19%) were pending closure, and 23 (25%) had undergone the first stage only, with no plan for completion. The stricture etiology included hypospadias in 41 (45.1%), lichen sclerosus in 29 (31.9%), and a combination of the 2 in 10 (11%). Of the 91 patients, 54.9% had panurethral disease, with the remaining involving varying lengths of the anterior urethra. The mean follow-up was 15 months (range 12-69). A total of 17 patients (18.7%) required revision of their first stage, with 4 requiring ≥2 repairs. Seven patients (7.7%) required revision of their second stage, with 2 undergoing multiple revisions. The urine flow rates increased on average from 6.7 mL/s preoperatively to 21.5 mL/s postoperatively (P <.00001). In 9 patients (9.9%) reconstruction failed, and they required scheduled balloon dilation or a chronic indwelling catheter to maintain urethral patency. CONCLUSION: Urethrectomy with salvage reconstruction using buccal mucosal grafts in a staged fashion is the optimal option for complex anterior urethral stricture resolution in these challenging patients. Surgical revision of the first or second stage could be required in up to 25% of challenging patients. Despite the high complexity and severity of the urethral stricture burden, a 90% success rate was achieved.

The impact of electrocautery method on post-operative bleeding complications after non-newborn circumcision and revision circumcision.

PURPOSE: We evaluated post-operative bleeding complications in non-newborns following use of monopolar versus bipolar electrocautery for circumcision or revision circumcision. MATERIALS AND METHODS: We retrospectively reviewed sequentially performed cases of circumcision and revision circumcision performed by nine pediatric urologists at our institution from 2005 to 2010. In order to incorporate both the monopolar and bipolar electrocautery experience for a single surgeon employing bipolar technique, sequential cases from 2002 to 2010 were reviewed. Variables assessed included age, procedure, method of electrocautery, skin approximation and dressing, and bleeding complications. RESULTS: 1810 patients that underwent either circumcision or revision circumcision were reviewed. Complete data was available for 1617 patients. Age at operation was a mean 3.7 ± 4.9 yrs and median 1.5 yrs. Return for bleeding complication for all surgeons, was 2/336 (0.6%) for bipolar and 28/1281 (2.2%) for monopolar (p = 0.0545). For the single surgeon using bipolar technique, returns were 2/336 (0.6%) for bipolar and 5/309 (1.6%) for monopolar (p = 0.2133). Returns per procedure type were 1/200 (0.5%) bipolar and 24/844 (2.8%) monopolar for primary circumcision (p = 0.0513), and 1/136 (0.7%) bipolar and 4/437 (0.9%) monopolar (p = 0.84) for revision. Four of 1617 (0.2%) patients returned to the operating room [4/1281 (0.3%) monopolar (p = 0.31)]. There was no difference in return to the operating room for circumcision versus revision. CONCLUSION: Return for bleeding complications after circumcision and revision circumcision occurred more frequently after monopolar electrocautery compared to bipolar. However, there was no significant difference between the two electrocautery methods. Either form of electrocautery appears to be effective for this common pediatric urologic procedure.

Temporary targeted renal blood flow interruption using a reverse thermosensitive polymer to facilitate bloodless partial nephrectomy: a swine survival study.

UNLABELLED: What's known on the subject? and What does the study add? Lumagel™ is a reverse thermosensitive polymer (RTP) that has previously been described in the literature as providing temporary vascular occlusion to allow for bloodless partial nephrectomy (PN) while maintaining blood flow to the untargeted portion of the kidney. At body temperature, Lumagel™ has the consistency of a viscous gel but upon cooling rapidly converts to a liquid state and does not reconstitute thereafter. This property has allowed for it to be used in situations requiring temporary vascular occlusion. Previous experience with similar RTPs in coronary arteries proved successful, with no detectable adverse events. We have previously described our technique for temporary vascular occlusion of the main renal artery, as well as segmental and sub-segmental renal branches, to allow for bloodless PN in either an open or minimally invasive approach. These experiments were performed in the acute setting. This study is a two-armed survival trial to assess whether this RTP is as safe as hilar clamping for bloodless PN. Surviving animals showed normal growth after using the RTP, absence of toxicity, no organ dysfunction, and no pathological changes attributable to the RTP. We conclude that Lumagel™ is as safe as conventional PN with hilar clamping, while adding the advantage of uninterrupted perfusion during renal resection. OBJECTIVE: To examine whether randomly selected regions of the kidney could undergo temporary flow interruption with a reverse thermosensitive polymer (RTP), Lumagel™ (Pluromed, Inc., Woburn, MA, USA), followed by partial nephrectomy (PN), without adding risks beyond those encountered in the same procedure with the use of hilar clamping. MATERIALS AND METHODS: A two-armed (RTP vs hilar clamp), 6-week swine survival study was performed. Four swine underwent PN using hilar clamps, while six underwent PN with flow interruption using the RTP. The RTP, administered angiographically, was used for intraluminal occlusion of segmental or subsegmental arteries and was compared with main renal artery clamping with hilar clamps. The resection site was randomized for each swine. Laboratory studies were performed preoperatively, and at weeks 1, 3 and 6. Before killing the swine, repeat angiography was performed with emphasis on the site of previous flow interruption. Gross and microscopic examination of kidney, liver, lung, heart, skeletal muscle was later performed, and the vessel that had supported the previous plug was examined. RESULTS: All animals survived. No abnormal chemistry or haematology results were encountered over the 6 weeks. There were no surgical complications in either group. Using angiography we found 100% patency of vessels that had been occluded with the polymer 6 weeks previously for PN. The only gross or microscopic abnormalities were related to the renal resection and scar formation, and were similar in the two groups. CONCLUSION: Targeted flow interruption with the RTP added no additional risk to PN while allowing bloodless resection and uninterrupted flow to untargeted renal tissue.

Targeted endovascular temporary vessel occlusion with a reverse thermosensitive polymer for near-bloodless partial nephrectomy: comparison to standard surgical clamping techniques.

PURPOSE: To determine whether reversible blood flow interruption to a randomly chosen target region of the kidney may be achieved with the injection of a reverse thermoplastic polymer through an angiographic catheter, thereby facilitating partial nephrectomy without compromising blood flow to the remaining kidney or adding risks beyond those encountered by the use of hilar clamping. METHODS: Fifteen pigs underwent partial nephrectomy after blood flow interruption by vascular cross-clamping or injection of polymer (Lumagel™) into a segmental artery. Five animals were euthanized after surgery (three open and two laparoscopic resection, cross-clamping n = 2), and 10 (open resection, cross-clamping n = 4) were euthanized after 6 weeks' survival. Blood specimens were obtained periodically, and angiogram and necropsy were performed at 6 weeks. RESULTS: Selective renal ischemia was achieved in all cases. Surgical resection time averaged 9 and 24.5 min in the open and laparoscopic groups, respectively. Estimated blood loss was negligible with the exception of one case where an accessory renal artery was originally overlooked. Reversal of the polymer to a liquid state was consistent angiographically and visually in all cases. Time to complete flow return averaged 7.4 and 2 min for polymer and clamping, respectively. Angiography at 6 weeks revealed no evidence of vascular injury. Laboratory data and necropsies revealed no differences between animals undergoing vascular clamping or polymer injection. CONCLUSION: Lumagel was as effective as vascular clamping in producing a near bloodless operative field for partial nephrectomy while maintaining flow to the uninvolved portion of the affected kidney.

Temporary targeted hemostasis to facilitate bloodless partial nephrectomy.

OBJECTIVE: To extend previous robotic-assisted techniques developed in the swine model to studies of laparoscopic and open partial nephrectomy conducted in pigs and calves, designed to encompass vessel diameters similar to those encountered in humans. Lumagel (Pluromed, Woburn, MA), a nontoxic polymer, can be administered intra-arterially under fluoroscopic guidance to obtain a bloodless operative field during partial nephrectomy while maintaining normal circulation to uninvolved renal tissue. METHODS: A total of 10 animals (7 pigs and 3 calves) underwent flow interruption to the kidney, 2 with cross-clamping of the main renal artery, the remaining with Lumagel. Other than the first pig and calf, all the animals then underwent partial nephrectomy. RESULTS: Using Lumagel, targeted blood flow interruption was achieved and circulation to the uninvolved renal tissue was maintained. Hemostasis lasted for ≥30 minutes. The surgical resection time averaged 11 minutes (range 10-13) and 23.3 minutes (range 9-40) in the open and laparoscopic groups, respectively. The estimated blood loss was negligible, with the exception of 2 cases, 1 in which an error in angiographic assessment led to an unoccluded vessel near the resection site and a second case in which a guidewire was inadvertently passed through a vessel. The interval to complete flow return, as determined by direct visualization of the kidney and its corresponding angiogram, averaged 7 and 2.5 minutes for Lumagel and arterial clamping, respectively. CONCLUSION: Lumagel provides reliable and reproducible intraluminal blood flow interruption and flow restoration in both main and segmental renal arteries. By providing blood-free resection, the techniques described could facilitate partial nephrectomy without global renal ischemia.

Novel ZEB1 expression in bladder tumorigenesis.

UNLABELLED: What's known on the subject? and What does the study add? Epithelial-mesenchymal transition (EMT) is involved in tumor progression where the underlying cellular changes associated with EMT have been identified in in vitro models and confirmed in a limited number of in vivo studies. ZEB1, which targets E-cadherin repression, is a transcriptional regulator that has been implicated in EMT, and is associated with uterine and colorectal cancers. Regulation of ZEB1 expression has been shown to involve different microRNAs (miRNAs), identifying a potential role for miRNA in EMT. In the present study we have identified novel expression of ZEB1 in bladder tumours and shown a role for ZEB1 in enhanced migration and invasion potential in in vitro assays. Confirmation of ZEB1 expression in bladder tumours was shown in tissue microarrays (TMAs). OBJECTIVE: To evaluate ZEB1 expression in bladder tumorigenesis and define a possible role for this transcription factor in urothelial carcinomas of the bladder (UCBs). MATERIALS AND METHODS: Five hundred and fifty-eight samples were assembled in 10 tissue microarrays (TMAs; 263 non-muscle-invasive Ta/T1/Tis, 295 muscle-invasive T2-T4). All tumours were transitional cell carcinomas (TCCs) and processed for immunohistochemistry to assess nuclear ZEB1 expression. Expression levels of ZEB1 were modulated in bladder carcinoma cell lines CUBIII or UM-UC-3 after forced expression or shRNA knockdown, respectively. Protein expression levels were determined using western blot analysis and transfectants were assessed for migration and invasion potential in standard in vitro assays. RESULTS: Nuclear ZEB1 expression was recorded in 22.8% of non-muscle-invasive UCBs and 21.7% of muscle-invasive UCBs, including 24.1% grade I/II and 21.1% grade III tumours, and absent in normal bladder mucosa. No significant correlation was observed for tumour stage and grade, nodal involvement, vascular invasion, metastasis and overall or cancer-specific survival. The introduction or knockdown of ZEB1 expression in bladder carcinoma cell lines showed enhanced or reduced migration and invasive potential, respectively. Changes in ZEB1 expression were accompanied by altered microRNA (miRNA) expression underlying events linked to epithelial-mesenchymal transition (EMT). CONCLUSION: The results in the present study showed novel expression of ZEB1 in bladder cancer in the absence of a link to clinical variables of change, including metastasis and survival. However, in vitro assays showed enhanced or reduced migration and invasion after the introduction or reduction of ZEB1, respectively, in transfected bladder cell lines. Modulation in expression of ZEB1 was closely linked to changes in the miR-200 family along with alternative known prognostic indicators of bladder tumour progression.

Enterocutaneous fistula: are treatments improving?

BACKGROUND: We studied the etiology, treatment, and outcome of enterocutaneous fistulas in 106 patients to evaluate our current practice and the impact of newer therapies-octreotide, wound vacuum-assisted closure (VAC), and fibrin glue-on clinical outcomes. Review of the literature and our own 1990 study indicate a mortality rate of 5% to 20% for enterocutaneous fistula, and a healing rate of 75% to 85% after definitive surgery. METHODS: We reviewed all cases of gastrointestinal-cutaneous fistula from 1997 to 2005 at 2 large teaching hospitals. We identified 106 patients with enterocutaneous fistula; patients with irritable bowel disease and anorectal fistulas were excluded. RESULTS: The origin of the fistula was the small bowel in 67 patients, colon in 26, stomach in 8, and duodenum in 5. The etiology of the fistula was previous operation in 81 patients, trauma in 15, hernia mesh erosion in 6, diverticulitis in 2, and radiation in 2. Of the 106 patients in the study, 31 had a high output fistula (greater than 200 mL/day), 44 had a low output fistula, and, in 31 patients, the fistula output was low but there was no record of volume. Initial treatment was nonoperative except for patients with an abscess who needed urgent drainage. In 24 patients, the effect of octreotide was monitored: in 8 patients, fistula output declined; in 16 patients, octreotide was of no benefit. Fibrin glue was used in 8 patients and was of benefit to 1. The wound VAC was used in 13 patients: 12 patients still required operative repair of the fistula, whereas the fistula was healed in 1 patient. The main benefit of the VAC system was improved wound care in all patients before definitive surgery. Total parenteral nutrition was used in most patients to provide nutritional support. Operative repair was performed in 77 patients and was successful in 69 (89%), failing in 6 patients with persistent cancer or infection. Nonoperative treatment was used in 29 patients and resulted in healing in 60%. Of 106 patients, 7 (7%) died of fistula complications. The cause of death was persistence or recurrence of cancer in 4 patients and persistent sepsis in 3. CONCLUSION: Enterocutaneous fistula continues to be a serious surgical problem. The wound VAC and fibrin glue had anecdotal successes (n = 2), and one-third of patients responded to octreotide. We believe that octreotide should be tried in most patients and that the wound VAC has a role in selected patients. Although 7% overall mortality is lower than in previous studies, the number managed without operation (27%) remains the same. In addition to early control of sepsis, nutritional support, and wound care, a well-timed operation was the most effective treatment.