Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

An unusual presentation of a retroperitoneal cyst.

A 34-year-old woman presented to the surgical assessment unit with severe right loin to groin pain. An ultrasound scan of the abdomen revealed a complex cyst in the right iliac fossa and a subsequent CT scan revealed a 7.5 cm retroperitoneal cystic lesion below the lower pole of the right kidney. The patient also had MRI of the kidneys, which confirmed the finding. The image showed the cyst was not attached to the kidneys and was clearly separate. She underwent a laparoscopic excision of the cyst. Histopathology revealed a cyst lined by a single layer of mucinous epithelium of endocervical type with foci of calcification and hyalinisation on the wall. The cyst was thought to be a benign cyst of Mullerian origin.

Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data.

BACKGROUND: Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies. METHODS: On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data. RESULTS: Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with 'low cancer-risk' characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring 'high cancer-risk" characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest 'high cancer- risk' cluster were different than those contributing to the classifiers for the 'low cancer-risk' clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different. CONCLUSIONS: The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on the basis of the heterogeneity within their biomarker data, into five distinct risk subpopulations. Our findings highlight an approach with the promise to unlock the potential of biomarkers. This will be especially valuable in the field of diagnostic bladder cancer where biomarkers are urgently required. Clinicians could interpret risk classification scores in the context of clinical parameters at the time of triage. This could reduce cystoscopies and enable priority diagnosis of aggressive diseases, leading to improved patient outcomes at reduced costs.

The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria.

BACKGROUND: We appraised 23 biomarkers previously associated with urothelial cancer in a case-control study. Our aim was to determine whether single biomarkers and/or multivariate algorithms significantly improved on the predictive power of an algorithm based on demographics for prediction of urothelial cancer in patients presenting with hematuria. METHODS: Twenty-two biomarkers in urine and carcinoembryonic antigen (CEA) in serum were evaluated using enzyme-linked immunosorbent assays (ELISAs) and biochip array technology in 2 patient cohorts: 80 patients with urothelial cancer, and 77 controls with confounding pathologies. We used Forward Wald binary logistic regression analyses to create algorithms based on demographic variables designated prior predicted probability (PPP) and multivariate algorithms, which included PPP as a single variable. Areas under the curve (AUC) were determined after receiver-operator characteristic (ROC) analysis for single biomarkers and algorithms. RESULTS: After univariate analysis, 9 biomarkers were differentially expressed (t test; P < .05). CEA AUC 0.74; bladder tumor antigen (BTA) AUC 0.74; and nuclear matrix protein (NMP22) 0.79. PPP included age and smoking years; AUC 0.76. An algorithm including PPP, NMP22, and epidermal growth factor (EGF) significantly improved AUC to 0.90 when compared with PPP. The algorithm including PPP, BTA, CEA, and thrombomodulin (TM) increased AUC to 0.86. Sensitivities = 91%, 91%; and specificities = 80%, 71%, respectively, for the algorithms. CONCLUSIONS: Addition of biomarkers representing diverse carcinogenic pathways can significantly impact on the ROC statistic based on demographics. Benign prostate hyperplasia was a significant confounding pathology and identification of nonmuscle invasive urothelial cancer remains a challenge.

Subclavian vein thrombosis: an unusual presentation of renal cell carcinoma.

Subclavian vein thrombosis is an uncommon clinical condition which is often associated with venous catheterization or secondary to excessive effort. We present a 54-year-old female with subclavian vein thrombosis as a first presentation of renal cell carcinoma. Although this is an unusual presentation, malignancy should be considered in the differential diagnosis. Hypercoagulability as part of a paraneoplastic syndrome was considered a possible etiology. In patients with otherwise unexplained subclavian vein thrombosis, full systemic examination and radiological evaluation of the abdomen, retroperitoneum and pelvis should be pursued. A review of the literature relevant to this unusual case is provided.

Laparoscopic bladder diverticulectomy.

Acquired bladder diverticulae are herniations of the bladder mucosa through detrusor muscle. Due to the ineffective emptying of the bladder diverticulum, urine accumulation may lead to urinary tract infection, stone disease, and lower urinary tract malignancy in the diverticulum. We report a case of laparoscopic bladder diverticulectomy for transitional cell carcinoma in an acquired bladder diverticulum. To our knowledge, this is the third case of laparoscopic diverticulectomy for a tumor. We report our experience with this case and the technical challenges encountered during the operation, together with literature review.

The utility of prostate-specific antigen velocity thresholds in clinical practice: a population-based analysis.

OBJECTIVE: To investigate the ability of prostate-specific antigen velocity (PSAV) to predict prostate cancer, and assess the test characteristics of several PSAV thresholds for identifying prostate cancer and high-grade cancers. PATIENTS AND METHODS: From a population-based database of PSA results, men with an initial PSA level of <10.0 ng/mL, taken between I January 1994 and 31 December 2003, were identified. Those with three or more PSA tests before diagnosis, taken over > or =18 months, were included. Men were followed for a diagnosis of prostate cancer or histologically confirmed benign disease until 31 December 2003. RESULTS: In all, 24 709 men were included, with 716 (2.9%) diagnosed with prostate cancer and 1488 (6.0%) with benign histology. The mean (10.38 vs 0.43 ng/mL/year) and median (1.47 vs 0.03 ng/mL/year) PSAV were considerably higher in men with prostate cancer than in those with no cancer (P < 0.001). There was no PSAV threshold that could reliably identify prostate cancer or high-grade cancers without requiring many men to proceed to prostate biopsy. CONCLUSION: In this population, PSAV had additional value over one PSA value in identifying men with prostate cancer. Many men with prostate cancer might have a 'normal' (<0.75 ng/mL/year) PSAV. As with total PSA level, there was no PSAV threshold that could reliably predict prostate cancer, but rather a continuum of risk of cancer associated with PSAV level.

Long-term functional outcome of renal units after laparoscopic nephron-sparing surgery under cold ischemia.

BACKGROUND AND PURPOSE: Renal-artery occlusion is used to control bleeding during laparoscopic nephronsparing surgery, but there are worries about ischemic damage. We compared the functional outcomes of kidneys treated under warm and cold ischemia. PATIENTS AND METHODS: Twelve patients treated with warm ischemia and 14 treated with cold ischemia had renal function investigation 3 to 6 months postoperatively. Four and ten patients, respectively, also had preoperative studies. RESULTS: In patients treated with warm ischemia, two kidneys had evidence of possible damage, but the kidney with the longest ischemia (56 minutes) was normal. Among patients treated with cold ischemia, function was lost in one case. Parenchymal transit time was prolonged in five patients, but in four cases, this probably was attributable to performance of a contrast-enhanced CT scan the same day. In the fifth patient, an ischemic injury is possible. CONCLUSION: The parenchymal transit time is a good indicator of ischemic damage. Nephron-sparing surgery can lead to damage even if the ischemia time is short and cold ischemia is used. More data are needed on the factors determining such injury.

Detection of early lymph node metastases in prostate cancer by laparoscopic radioisotope guided sentinel lymph node dissection.

PURPOSE: Radioisotope guided sentinel lymph node (SLN) dissection (SLND) for prostate cancer has been shown to increase the sensitivity of detecting early metastases in open pelvic lymph node dissection. We developed a technique that allows SLND to be performed by laparoscopy in conjunction with laparoscopic radical prostatectomy. MATERIALS AND METHODS: In 71 consecutive patients SLND was performed by 1 surgeon preceding laparoscopic radical prostatectomy. Mean preoperative prostate specific antigen was 8.88 ng/ml (range 2.1 to 25.4). At 24 hours prior to surgery 3 ml (200 MBq) Tc labeled human albumin colloid were injected into the prostate gland under transrectal ultrasound guidance. An especially designed laparoscopic gamma probe was used to measure radioactivity during surgery. SLNs were identified and removed. If frozen section analysis showed metastases, extended pelvic lymph node dissection was performed. RESULTS: Radioactivity was detected on 2, 1 and no sides in 50 (70.4%), 19 (26.7%) and 2 patients (2.8%), respectively. In 81 of the 142 pelvic side walls (54.7%) SLNs were exclusively outside of the obturator fossa. Histopathological examination showed metastases to SLNs in 9 patients (12.9%). Eight of the 11 detected metastases (72.7%) were outside of the obturator fossa. Lymph node metastases were exclusively found in Tc marked lymph nodes. Mean tumor size was 1.7 mm (range 0.2 to 3.9). CONCLUSIONS: SLND is feasible by laparoscopy. It detects micrometastases outside of the obturator fossa in a significant number of patients. We noted that the transperitoneal approach allowing wide exposure and a gamma probe with a 90-degree lateral energy window is the most important factor to enable successful laparoscopic SLND.

Role of laparoscopy in management of renal stones: single-center experience and review of literature.

BACKGROUND AND PURPOSE: Laparoscopy can be an alternative modality in the management of renal stones. We present our experience with laparoscopic renal stone surgery. PATIENTS AND METHODS: Eighteen patients (4 males, 14 females) with mean age of 51 years (range 18-86 years) underwent 19 laparoscopic procedures. The mean stone number and size, excluding five patients who had nephrectomy/heminephrectomy, were 1.9 (range 1-5) and 1.3 cm (range 0.5-4.5 cm), respectively. Three patients with ureteropelvic junction obstruction underwent pyeloplasty and concomitant pyelolithotomy. Three patients with upper-pole caliceal-diverticular stones had nephrolithotomy and fulguration of the diverticular mucosa. Three patients with stones and hydrocalix with scarred cortex had partial nephrectomy, two under cold and one under warm ischemia. Five patients, including one with a horseshoe kidney (who had one procedure on each kidney), had pyelolithotomy as an alternative to percutaneous nephrolithotomy. Patients with stones in a nonfunctioning kidney underwent nephrectomy (three patients) or heminephrectomy (one patient). RESULTS: All procedures were completed laparoscopically. The operative time was variable depending on the complexity of the procedures, from 115 minutes for Fengerplasty to 315 minutes for partial nephrectomy under cold ischemia (mean 178 minutes). The estimated blood loss was 53.2 mL (range 20-120 ml), and none of the patients received a blood transfusion. Complete stone clearance was achieved in 93% of the procedures. The mean hospital stay was 10.5 days (range 5-35 days). Three patients needed temporary pigtail-catheter drainage for obstruction after pyelolithotomy. One patient with a solitary kidney and infected staghorn calculus had prolonged urinary leak, which stopped with conservative management. One nephrectomy for nephrocutaneous fistula was complicated by a late colonic perforation necessitating colostomy. CONCLUSION: Laparoscopic surgery is effective for complex renal stones and allows for adjunctive procedures. It can also be an alternative to percutaneous nephrolithotomy. It complements other minimally invasive procedures, and a need for open stone surgery should be rare in the future.

Laparoscopic adrenal surgery for recurrent tumours in patients with hereditary phaeochromocytoma.

OBJECTIVE: To report our experience with Laparoscopic Partial Adrenalectomy (LPA) for recurrent tumours in patients with hereditary phaeochromocytoma. PATIENTS AND METHODS: Five patients with hereditary phaeochromocytoma (4 with von Hippel-Lindau disease and 1 with Multiple Endocrine Neoplasia 2B), who had undergone adrenal surgery previously, presented with recurrent adrenal tumours. One patient was pregnant at 20 weeks of gestation. All patients underwent hormonal evaluation, genetic screening and imaging with CT or MRI, metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Of the 7 attempted LPA in five patients, five procedures (71%) were successfully completed and total adrenalectomy was needed on two occasions. The adrenal vein could be spared in all patients except one. There were no intra-operative complications. The adrenal function was adequate in all patients without need for steroid supplementation except one patient who lost both adrenals eventually. There was no correlation between the preservation of adrenal vein and adrenocortical function. CONCLUSION: Laparoscopic partial adrenalectomy is feasible, safe and effective in recurrent phaeochromocytoma, despite previous adrenal surgery and is technically easier if the previous approach had been laparoscopic as well. Patients with hereditary phaeochromocytoma are prone for recurrent tumours and may need repeated surgical procedures. Hence, minimally invasive approach is ideal for these patients.

Laparoscopic nephron sparing surgery: evolution in a decade.

OBJECTIVE: To present our experience with laparoscopic nephron sparing surgery (NSS) over a decade. METHODS: Seventy-eight patients underwent NSS since 1994. Two techniques were used-partial nephrectomy without ischemia (group 1) in 29 patients, and with ischemia (group 2) which was in cold or warm ischemia in 24 and 25 patients respectively. The mean tumour size was 1.97 and 2.2 cm in groups 1 and 2 respectively. Renal reconstruction evolved in our hands during this period. We changed many technical details and now we depend more on clips for securing the sutures rather than free hand knotting. RESULTS: The mean operative time was 162 and 216 minutes in groups 1 and 2 respectively. Mean ischemia time for patients with cold and warm ischemia was 44.9 and 33.8 minutes respectively. 3 patients in group 2 were converted to open surgery. Mean blood loss was 254 and 212 ml for group 1 and 2 respectively with two major bleedings in group 2. Minor intra-operative complication occurred in 3 patients, and major and minor postoperative complication in 15 patients. At a mean follow-up of 23.9 and 12.2 months for groups 1 and 2 respectively there was no recurrence. CONCLUSION: Warm and cold ischemia have widened the indications for laparoscopic NSS to more complex tumours and allow renal reconstruction with acceptable complication rate.

Prospective, randomized controlled study: transperitoneal laparoscopic versus retroperitoneoscopic radical nephrectomy.

OBJECTIVES: To evaluate the transperitoneal and retroperitoneal approaches for endoscopic radical nephrectomy in a prospective randomized manner to assess the possible differences in the outcome related to patients' morbidity and technical difficulty for the surgeon. METHODS: A total of 40 patients with Stage cT1-T2 were randomized into two equal groups: laparoscopic radical nephrectomy (LRN) and retroperitoneoscopic radical nephrectomy (RRN). The patient demographics and tumor characteristics were comparable. Two surgeons with differing experience performed an equal number of procedures in both treatment arms. The outcome was compared, and the technical difficulty for the surgeon and assistant was assessed with the European scoring system. RESULTS: All procedures were completed without a need for conversion. No statistically significant differences were found between the two approaches in terms of the number and size of the trocars used, length of incision, specimen weight, pathologic stage, operative time, need for additional procedures such as adrenalectomy and/or lymph node sampling, estimated blood loss, need for blood transfusions, analgesic requirement, length of hospital stay, or the incidence of minor or major complications. All patients in the LRN group resumed oral intake on postoperative day 1, but only 75% did so in the RRN group. The technical difficulty score for either the surgeon or the assistant did not differ significantly between the two groups. Both approaches allowed complete tumor excision. The robotic assistance system (AESOP) was more difficult with RRN compared with LRN. CONCLUSIONS: This first prospective randomized study comparing LRN and RRN did not find any real difference between the two approaches in relation to patient morbidity or the technical difficulty for the surgeon.

Virtual cystoscopy from computed tomography: a pilot study.

OBJECTIVE: To assess the feasibility of virtual cystoscopy reconstructed from helical computed tomography (CT) obtained using an intravenous contrast agent, and to correlate the findings with flexible (FC) and rigid cystoscopy (RC) in patients with bladder tumours. PATIENTS AND METHODS: Eighteen patients (16 men and two women, mean age 72 years, range 59-80) with haematuria and found to have a bladder tumour on FC were included in a pilot study. Contrast-enhanced helical CT scans were taken and based on these datasets, virtual cystoscopy (VC) images were reconstructed by a radiologist unaware of the findings at cystoscopy. All patients had RC and a biopsy taken. The VC images were compared with the findings from FC and RC. RESULTS: At FC, VC and RC, 32, 34 and 36 lesions were identified, respectively; 33 (92%) of the abnormal lesions at RC were correctly identified at VC. At VC, all lesions of >4 mm were identified but only one of three <4 mm was seen. There were two false-positive finding at VC; VC correctly identified 17 (94%) of 18 abnormal bladders. Only 25% of the ureteric orifices were seen. Carcinoma in situ and urethral tumours were not visualized. CONCLUSION: CT-based VC has a high sensitivity for detecting bladder lesions and is comparable with FC; it may have a potential role as a single imaging tool for haematuria. Further larger studies are required to assess its clinical role.

Laparoscopic partial adrenalectomy for recurrent pheochromocytoma in a boy with Von Hippel-Lindau disease.

We describe a case of a boy with Von Hippel-Lindau disease who presented with recurrent right adrenal pheochromocytoma 4.5 years after laparoscopic bilateral partial adrenalectomy. The boy had a second laparoscopic adrenal-sparing removal of the tumor. By this technique, not only the recurrent tumor was successfully removed but also the unaffected adrenal cortex could be preserved for the second time. To our knowledge, this is the first published case of its type.

Intra-testicular varicocele presenting as acute scrotum.

The term varicocele describes a dilated, tortuous and elongated pampiniform plexus of veins, which is well known in relation to the spermatic cord. Recently varicocele has also been observed inside the testis, and this new entity is known as intra-testicular varicocele. We present a case of intra-testicular varicocele presenting as acute scrotum and discuss the management issues.

Squamous cell carcinoma and transitional cell carcinoma arising in bladder augmentations.

Tumours arising in bowel-augmented bladders are rare. Usually these tumours are adenocarcinomas that occur along the anastomotic line. We present two unusual tumours, squamous cell carcinoma and transitional cell carcinoma, that occurred in bladder augmentations. We also emphasize the need for regular cystoscopic surveillance.