Douglas Skarecky

A Multinational, Multi-institutional Study Comparing Positive Surgical Margin Rates Among 22 393 Open, Laparoscopic, and Robot-assisted Radical Prostatectomy Patients

BACKGROUND Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume. OBJECTIVE To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates. DESIGN, SETTING, AND PARTICIPANTS Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort. RESULTS AND LIMITATIONS Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload. CONCLUSIONS This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases. PATIENT SUMMARY In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures.

Phylogeny of Drosophila and related genera inferred from the nucleotide sequence of the Cu,Zn Sod gene.

The phylogeny and taxonomy of the drosophilids have been the subject of extensive investigations. Recently, Grimaldi (1990) has challenged some common conceptions, and several sets of molecular data have provided information not always compatible with other taxonomic knowledge or consistent with each other. We present the coding nucleotide sequence of the Cu,Zn superoxide dismutase gene (Sod) for 15 species, which include the medfly Ceratitis capitata (family Tephritidae), the genera Chymomyza and Zaprionus, and representatives of the subgenera Dorsilopha, Drosophila, Hirtodrosophila, Scaptodrosophila, and Sophophora. Phylogenetic analysis of the Sod sequences indicates that Scaptodrosophila and Chymomyza branched off the main lineage before the major Drosophila radiations. The presence of a second intron in Chymomyza and Scaptodrosophila (as well as in the medfly) confirms the early divergence of these two taxa. This second intron became deleted from the main lineage before the major Drosophila radiations. According to the Sod sequences, Sophophora (including the melanogaster, obscura, saltans, and willistoni species groups) is older than the subgenus Drosophila; a deep branch splits the willistoni and saltans groups from the melanogaster and obscura groups. The genus Zaprionus and the subgenera Dorsilopha and Hirtodrosophila appear as branches of a prolific “bush” that also embraces the numerous species of the subgenus Drosophila. The Sod results corroborate in many, but not all, respects Throckmortons (King, R.C. (ed) Handbook of Genetics. Plenum Press, New York, pp. 421–469, 1975) phylogeny; are inconsistent in some important ways with Grimaldis (Bull. Am. Museum Nat. Hist.197:1–139, 1990) cladistic analysis; and also are inconsistent with some inferences based on mitochondrial DNA data. The Sod results manifest how, in addition to the information derived from nucleotide sequences, structural features (i.e., the deletion of an intron) can help resolve phylogenetic issues.

Continence Definition After Radical Prostatectomy Using Urinary Quality of Life: Evaluation of Patient Reported Validated Questionnaires

PURPOSE After radical prostatectomy continence is commonly defined as no pads except a security pad or 0 to 1 pad. We evaluated the association of pad status and urinary quality of life to determine whether security and 1 pad status differ from pad-free status to better define 0 pads as the post-prostatectomy standard. MATERIALS AND METHODS A total of 500 consecutive men underwent robot assisted radical prostatectomy from October 2003 to July 2007. Data were collected prospectively and entered into an electronic database. Postoperatively men completed self-administered validated questionnaires including questions on 1) daily pad use (0, security, 1, or 2 or more), 2) urine leakage (daily, about once weekly, less than once weekly or not at all), 3) urinary control (none, frequent dribbling, occasional dribbling or total control), 4) American Urological Association symptom score and 5) urinary quality of life. RESULTS Postoperatively men who indicated 0 pad use had a mean +/- SE symptom score of 5.8 +/- 0.3 and pleased quality of life (1.16 +/- 0.08). In contrast, men with a security pad and 1 pad had a symptom score of 7.6 +/- 0.7 and 9.2 +/- 0.6 but mixed quality of life (2.78 +/- 0.18 and 3.41 +/- 0.15, respectively, p <0.0005). CONCLUSIONS Results show a significant decrease in quality of life between no pads (1.16 or pleased), a security pad and 0 or 1 pad (2.78 and 3.41 or mixed, respectively). Findings do not support defining continence with a security pad or 0 to 1 pad. Continence should be strictly defined as 0 pads.

ON THE EVOLUTION OF DOPA DECARBOXYLASE (DDC) AND DROSOPHILA SYSTEMATICS

Abstract. We have sequenced most of the coding region of the gene Dopa decarboxylase (Ddc) in 24 fruitfly species. The Ddc gene is quite informative about Drosophila phylogeny. Several outstanding issues in Drosophila phylogeny are resolved by analysis of the Ddc sequences alone or in combination with three other genes, Sod, Adh, and Gpdh. The three species groups, melanogaster, obscura, and willistoni, are each monophyletic and all three combined form a monophyletic group, which corresponds to the subgenus Sophophora. The Sophophora subgenus is the sister group to all other Drosophila subgenera (including some named genera, previously considered outside the Drosophila genus, namely, Scaptomyza and Zaprionus, which are therefore downgraded to the category of subgenus). The Hawaiian Drosophila and Scaptomyza are a monophyletic group, which is the sister clade to the virilis and repleta groups of the subgenus Drosophila. The subgenus Drosophila appears to be paraphyletic, although this is not definitely resolved. The two genera Scaptodrosophila and Chymomyza are older than the genus Drosophila. The data favor the hypothesis that Chymomyza is older than Scaptodrosophila, although this issue is not definitely resolved. Molecular evolution is erratic. The rates of nucleotide substitution in 3rd codon position relative to positions 1 + 2 vary from one species lineage to another and from gene to gene.

Hypothermic Nerve-sparing Radical Prostatectomy: Rationale, Feasibility, and Effect on Early Continence

OBJECTIVES To report the first application of preemptive local hypothermia during robotic-assisted laparoscopic prostatectomy (hRLP) to attenuate inflammation. Surgical excision of the prostate during radical prostatectomy causes inflammatory damage to the surrounding neuromuscular tissues that could affect urinary continence. METHODS Of 50 consecutive patients undergoing nerve-sparing hRLP (case numbers 668-717; 3 were excluded--2 underwent radiotherapy and 1 was withdrawn because of balloon failure), 47 were prospectively compared with a standard RLP cohort (case numbers 1-667). Pelvic cooling was achieved using cold irrigation and an endorectal cooling balloon cycled with 4 degrees C saline. The intracorporeal temperatures were measured. Continence was defined as 0 urinary pads. The Kaplan-Meier analysis of the time to 0 pads and multivariate Cox proportional hazards regression analysis was used to examine the group differences in continence after adjusting for the baseline characteristics. RESULTS The median temperature was 29.0 degrees C (endorectal cooling balloon only, range 24.4 degrees-35.9 degrees C) and 25.5 degrees C (endorectal cooling balloon plus irrigation, range 19.4 degrees-34.0 degrees C). The time to 0-pad status was determined in 590 of 667 controls (88%). The 3-month hRLP 0-pad rate was 86.8% +/- 5.8% and was 68.6% +/- 2.0% for the controls. The return to continence was faster for hRLP vs controls: median 39 days (range 0-110) vs 59 days (range 1-720), respectively (P = .002, log-rank test). A multivariate analysis adjusting for factors, including age, American Urological Association symptom score, abbreviated International Index of Erectile Function-5, body mass index, prostate weight, stage, nerve-sparing, and learning curve demonstrated a faster return to continence for the hRLP group relative to the control group (hazard ratio 1.66, 95% confidence interval 1.11-2.49, P = .014). CONCLUSIONS This study represents the initial application of local hypothermia to reduce the traumatic inflammatory sequela of RLP. Hypothermia was easily induced and safe and resulted in a statistically significant improvement in early postoperative continence.

Hypothermic robotic radical prostatectomy: impact on continence.

INTRODUCTION Radical prostatectomy undoubtedly causes inflammatory damage to surrounding neuromuscular tissues (i.e., bladder, urethra, and nerves) that may contribute to urinary incontinence. We report the use of local hypothermia during robot-assisted laparoscopic prostatectomy to attenuate this injury. METHODS Regional pelvic cooling was achieved using cold intracorporeal irrigation and an endorectal cooling balloon (ECB). In all, 115 men undergoing hypothermic robot-assisted laparoscopic radical prostatectomy (hRLP) (case #667-782) were prospectively compared with a historical cohort (case #1-666). Intracorporeal rectal and neurovascular bundle temperatures (T) and intrarectal temperatures were measured. Continence was defined as zero urinary pads. Kaplan-Meier analysis of time to zero pads and multivariate Cox proportional hazards regression was used. RESULTS Hypothermia was achieved in 112/115 patients; 6 were excluded (3 ECB malfunction, 2 prior radiation, and 1 completion prostatectomy). Median endorectal T = 18.7 degrees C (range 9.1-29.5 degrees C). Mean intracorporeal T = 25.58 degrees C (ECB + irrigation, range 19.4-34.0 degrees C). Three and 12-month hRLP zero pad rates were 81% to 89% and 100% for initial and extended cooling groups versus 65% and 89% for controls. Return to continence was significantly faster for hRLP versus controls: median time to zero pad use was 39 days for hRLP versus 62 days for controls. Multivariate analysis adjusting for American Urological Association (AUA) symptom score, nerve-sparing surgery, learning curve, international index of erectile function-5, age, and prostate weight demonstrated a significantly faster return to continence (hazard ratio = 1.526; 95% CI 1.11, 2.09). Trends toward improved continence were observed with colder temperatures and older patients. CONCLUSIONS Local hypothermia during prostatectomy resulted in a significant improvement in early postoperative zero pad continence rates. Longer and deeper cooling appears to be associated with improved continence, particularly among older patients.

Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells.

Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high‐grade tumors, but the biologic consequence of this is currently unknown. To elucidate the function of ANXA2 in CaP, we reduced its expression in DU145 cells using shRNA and tested the impact on characteristics of malignancy. Reduction of ANXA2 suppressed anchorage‐dependent and ‐independent cell growth without affecting invasiveness. Interestingly, interleukin‐6 (IL‐6) secretion was reduced concomitantly with the reduction of ANXA2 but independently of S100A10. IL‐6 expression was restored when wild type but not mutant ANXA2 was reexpressed in these cells. In a retrospective study of radical prostatectomy specimens from patients with nonmetastatic CaP, 100% of patients with ANXA2‐positive tumors (n = 4) had a biochemical relapse while only 50% of patients with ANXA2 negative tumors (n = 20) relapsed, suggesting that ANXA2 expression in prostate tumors may be predictive of biochemical relapse. Significant cytoplasmic staining of ANXA2 was detected in 3 of 4 ANXA2‐positive tumors, whereas ANXA2 is localized to the plasma membrane in benign prostatic glands. These finding, taken together, suggests a possible mechanism whereby ANXA2 expression positively contributes to an aggressive phenotype in a subset of CaP and suggest that ANXA2 has markedly different functions depending on its cellular context. Finally, this is the first description of a role for ANXA2 in IL‐6 expression, and ANXA2 represents a new therapeutic target for reducing IL‐6 in high‐grade prostate cancer.

Evaluation of long-term thermal injury using cautery during nerve sparing robotic prostatectomy.

OBJECTIVE In our initial 125 cases, we used cautery during preservation of the neurovascular bundles (NVBs). We previously reported the short-term benefit of a cautery-free versus cautery technique. To assess long-term consequences of cautery, we report 2-year potency outcomes for these robot-assisted laparoscopic radical prostatectomies (RLP). METHODS Between June 2002 and February 2004, 125 consecutive patients underwent RLP by 1 surgeon. All data were entered prospectively into an electronic database. In cases 1 to 15, the vascular pedicle and nerve were dissected with monopolar cautery. In cases 16 to 125, the dissection used bipolar cautery and scissors. Preoperatively, 42 met inclusion criteria: age younger than 66 years, International Index of Erectile Function (IIEF-5) of 22 to 25 and uni (12) or bilateral (35) nerve sparing. Postoperatively all patients were encouraged to use 5-PDE inhibitors. Potency was assessed by self-administered validated questionnaires. RESULTS Four were excluded because of treatment intervention (3) or refusal to follow-up (1). Thirty-eight have follow-up data of 24 or more months. At 3, 9, and 15 months only 3 of 36 (8.3%), 5 of 34 (14.7%), and 16 of 37 (43.2%) were potent. However at 24+ months, 5 of 10 (50%) of unilateral and 19 of 28 bilateral nerve-sparing (68%) were potent with an average IIEF-5 of 18.4 and erectile firmness of 75% to 100% of baseline. CONCLUSION These findings suggest that in addition to other injury, thermal injury to the NVB is dense with very low recovery rates in the first 12 to 18 months. However, with nearly two-thirds ultimately reporting potency return, these injuries are generally not permanent and recovery approaches 75% to 100% of baseline.

Preliminary Study of Virtual Reality and Model Simulation for Learning Laparoscopic Suturing Skills

PURPOSE Repetitive practice of laparoscopic suturing and knot tying can facilitate surgeon proficiency in performing this reconstructive technique. We compared a silicone model and pelvic trainer to a virtual reality simulator in the learning of laparoscopic suturing and knot tying by laparoscopically naïve medical students, and evaluated the subsequent performance of porcine laparoscopic cystorrhaphy. MATERIALS AND METHODS A total of 20 medical students underwent a 1-hour didactic session with video demonstration of laparoscopic suturing and knot tying by an expert laparoscopic surgeon. The students were randomized to a pelvic trainer (10) or virtual reality simulator (10) for a minimum of 2 hours of laparoscopic suturing and knot tying training. Within 1 week of the training session the medical students performed laparoscopic closure of a 2 cm cystotomy in a porcine model. Objective structured assessment of technical skills for laparoscopic cystorrhaphy was performed at the procedure by laparoscopic surgeons blinded to the medical student training format. A video of the procedure was evaluated with an objective structured assessment of technical skills by an expert laparoscopic surgeon blinded to medical student identity and training format. The medical students completed an evaluation questionnaire regarding the training format after the laparoscopic cystorrhaphy. RESULTS All students were able to complete the laparoscopic cystorrhaphy. There was no difference between the pelvic trainer and virtual reality groups in mean +/- SD time to perform the porcine cystorrhaphy at 40 +/- 15 vs 41 +/- 10 minutes (p = 0.87) or the objective structured assessment of technical skills score of 8.8 +/- 2.3 vs 8.2 +/- 2.2 (p = 0.24), respectively. Bladder leak occurred in 3 (30%) of the pelvic trainer trained and 6 (60%) of the virtual reality trained medical student laparoscopic cystorrhaphy procedures (Fisher exact test p = 0.37). The only significant difference between the 2 groups was that 4 virtual reality trained medical students considered the training session too short compared to none of those trained on the pelvic trainer (p = 0.04). CONCLUSIONS There is no significant difference between the pelvic trainer and virtual reality trained medical students in proficiency to perform laparoscopic cystorrhaphy in a pig model, although both groups require considerably more training before performing this procedure clinically. The pelvic trainer training may be more user-friendly for the novice surgeon to begin learning these challenging laparoscopic skills.

The impact of cavernosal nerve preservation on continence after robotic radical prostatectomy

Study Type – Therapy (case series)