Computer-Generated R.E.N.A.L. Nephrometry Scores Yield Comparable Predictive Results to Those of Human-Expert Scores in Predicting Oncologic and Perioperative Outcomes.

PURPOSE: We sought to automate R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry scoring of preoperative computerized tomography scans and create an artificial intelligence-generated score (AI-score). Subsequently, we aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to expert human-generated nephrometry scores (H-scores). MATERIALS AND METHODS: A total of 300 patients with preoperative computerized tomography were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors, and geometric algorithms were developed to estimate components of R.E.N.A.L. nephrometry score. Tumors were independently scored by medical personnel blinded to AI-scores. AI- and H-score agreement was assessed using Lin's concordance correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using areas under the curve. RESULTS: Median age was 60 years (IQE 51-68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors, including 27%, 37% and 24% with high stage, grade and necrosis, respectively. There was significant agreement between H-scores and AI-scores (Lin's ⍴=0.59). Both AI- and H-scores similarly predicted meaningful oncologic outcomes (p <0.001) including presence of malignancy, necrosis, and high-grade and -stage disease (p <0.003). They also predicted surgical approach (p <0.004) and specific perioperative outcomes (p <0.05). CONCLUSIONS: Fully automated AI-generated R.E.N.A.L. scores are comparable to human-generated R.E.N.A.L. scores and predict a wide variety of meaningful patient-centered outcomes. This unambiguous artificial intelligence-based scoring is intended to facilitate wider adoption of the R.E.N.A.L. score.

Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.

BACKGROUND: The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling. METHODS: We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model. RESULTS: We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model. CONCLUSIONS: Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.

Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis.

The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome- and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP.

Renal cell carcinoma-derived gangliosides suppress nuclear factor-kappaB activation in T cells.

Activation of the transcription factor nuclear factor-kappaB (NFkappaB) is impaired in T cells from patients with renal cell carcinomas (RCCs). In circulating T cells from a subset of patients with RCCs, the suppression of NFkappaB binding activity is downstream from the stimulus-induced degradation of the cytoplasmic factor IkappaBalpha. Tumor-derived soluble products from cultured RCC explants inhibit NFkappaB activity in T cells from healthy volunteers, despite a normal level of stimulus-induced IkappaBalpha degradation in these cells. The inhibitory agent has several features characteristic of a ganglioside, including sensitivity to neuraminidase but not protease treatment; hydrophobicity; and molecular weight less than 3 kDa. Indeed, we detected gangliosides in supernatants from RCC explants and not from adjacent normal kidney tissue. Gangliosides prepared from RCC supernatants, as well as the purified bovine gangliosides G(m1) and G(d1a), suppressed NFkappaB binding activity in T cells and reduced expression of the cytokines IL-2 and IFN-gamma. Taken together, our findings suggest that tumor-derived gangliosides may blunt antitumor immune responses in patients with RCCs.

Dead or dying: necrosis versus apoptosis in caspase-deficient human renal cell carcinoma.

The antitumor effect of immuno- and chemotherapeutic agents is executed through stimulation of apoptotic programs in susceptible cells. Apoptosis induced in tumor cells requires activation of members of the caspase family of proteases. Deficient expression or activation of caspases may account in part for the failure of many current anticancer therapies. However, recent studies suggest that cell death can proceed in the absence of caspases. We investigated the susceptibility of human renal cell carcinoma (RCC) lines to two distinct modes of cell death, apoptosis and necrosis. RCC lines displayed almost complete resistance to apoptosis in response to the intracellular zinc chelator, N,N,N'N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), which instead induced dramatic accumulation of nonapoptotic necrotic cells. Conversely, TPEN was a potent inducer of apoptosis in caspase-competent normal kidney cells (NK-72) and Jurkat T lymphocytes. Resistance to apoptosis in RCC lines correlated with almost complete loss of caspase-3 expression and variable down-regulation of caspase-7, caspase-8, and caspase-10. These data may explain the resistance of RCC to drugs inducing apoptosis and have important consequences for further attempts to manipulate tumor cell death.

The T cell death knell: immune-mediated tumor death in renal cell carcinoma.

The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.

Mechanisms of apoptosis in T cells from patients with renal cell carcinoma.

Tumors may escape immune recognition and destruction through the induction of apoptosis in activated T lymphocytes. Results from several laboratories suggest that FasL (L/CD95L) expression in tumors may be responsible for this process. In this study of patients with renal cell carcinoma (RCC), we provide evidence for two mechanisms of T-cell apoptosis. One mechanism involves the induction of apoptosis via FasL expression in tumor cells. This is supported by several observations, including the fact that tumor cells in situ as well as cultured cell lines expressed FasL mRNA and protein by a variety of techniques. The FasL in RCC is functional because in coculture experiments, FasL+ tumors induced apoptosis in Fas-sensitive Jurkat T cells and in activated peripheral blood T cells but not in resting peripheral blood T cells. Most importantly, antibody to FasL partially blocked apoptosis of the activated T cells. Moreover, Fas was expressed by T cells derived from the peripheral blood (53% median) and tumor (44.3% median) of RCC patients. Finally, in situ staining for DNA breaks demonstrated apoptosis in a subset of T cells infiltrating renal tumors. These studies also identified a second mechanism of apoptosis in RCC patient peripheral T cells. Whereas these cells did not display DNA breaks when freshly isolated or after culture for 24 h in medium, peripheral blood T cells from RCC patients underwent activation-induced cell death after stimulation with either phorbol 12-myristate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by exposure to FasL in tumor cells or through T-cell activation may contribute to the failure of RCC patients to develop an effective T-cell-mediated antitumor response.

Captopril renography in the diagnosis of renal artery stenosis: accuracy and limitations.

PURPOSE: The purpose of this study was to determine the sensitivity, specificity, and clinical usefulness of renography performed in combination with captopril administration ("captopril renography") in diagnosing renal artery stenosis. PATIENTS AND METHODS: Fifty-five patients with suspected renal artery stenosis underwent renography prior to performance of renal angiography. Renography was performed on two consecutive days using technetium-99m-diethylenetiamine pentaacetic acid (DTPA) as an index of glomerular filtration rate and iodine-131-orthoiodohippurate (OIH) as an index of renal blood flow. Captopril (25 mg orally, crushed) was administered 1 hour before the second study. Renal artery stenosis was defined as a stenosis exceeding 70%. Renographic criteria were then established, retrospectively, to differentiate renal artery stenosis from essential hypertension based on (1) asymmetry of function and (2) the presence of captopril-induced changes. RESULTS: Renal artery stenosis was detected in 35 of 55 patients (21 with unilateral and 14 with bilateral stenosis). Three criteria were established for diagnosing renal artery stenosis: (1) a percent uptake of DTPA by the affected kidney of less than 40% of the combined bilateral uptake, (2) a delayed time to peak uptake of DTPA, which was more than 5 minutes longer in the affected kidney than in the contralateral kidney, (3) a delayed excretion of DTPA, with retention at 15 minutes, as a fraction of peak activity, more than 20% greater than in the contralateral kidney. The presence of one or more of these criteria was diagnostic of renal artery stenosis, with a sensitivity and specificity of 71% and 75%, respectively before captopril administration, and 94% and 95% after captopril administration. Lesser degrees of asymmetry (i.e., uptake of 40% to 50%) had very poor diagnostic specificity. Among patients with bilateral stenoses, asymmetry identified the more severely affected kidney, but the presence or absence of stenosis in the contralateral kidney could not be reliably determined. When pre- and post-captopril studies were compared, the presence of captopril-induced scintigraphic changes was a highly specific finding for renal artery stenosis, but occurred in only 51% of the cases. OIH scintigraphy provided similar results, with slightly lower sensitivity and specificity. CONCLUSION: Asymmetry of DTPA uptake, time to peak uptake, or retention seen on a single post-captopril renogram is a highly sensitive and specific finding in detecting renal artery stenosis but does not distinguish unilateral from bilateral disease. If renograms are obtained both before and after captopril administration, the presence of captopril-induced change is a highly specific finding for the detection of renal artery stenosis, but the sensitivity of this finding is low.

Laparoscopic surgery in children with ventriculoperitoneal shunts: effect of pneumoperitoneum on intracranial pressure--preliminary experience.

OBJECTIVES: We monitored changes in intracranial pressure (ICP) in 2 children with myelodysplasia undergoing laparoscopic bladder autoaugmentation. Both children had ventriculoperitoneal shunts (VPS) secondary to Arnold-Chiari malformations (type II). METHODS: ICP was monitored through a 23-gauge needle placed into the shunt reservoir and connected to a pressure transducer and drainage system. Intraoperative mean arterial pressure, end-tidal CO2 (ETCO2), ICP, abdominal pressure, and cerebral perfusion pressures were all monitored. RESULTS: Both children demonstrated rapid onset and sustained increases in ICP of greater than 12 mm Hg above baseline to a maximum pressure of 25 mm Hg. The average cerebrospinal fluid removed from each patient was 30 cc, thereby lowering ICP with no adverse neurologic sequela. The pCO2 remained constant throughout the procedures, as measured by ETCO2. CONCLUSIONS: We believe that intracranial hypertension (IH) results from a "Valsalva-like" phenomenon, which causes cerebral vascular engorgement. In addition, the pneumoperitoneum may increase the resistance to outflow through the distal peritoneal catheter, causing a partial or complete shunt obstruction. Untreated IH may result in adverse neurologic sequelae from brain herniation in these children with hindbrain anomalies and potentially altered brain compliance. We believe it is prudent to perform intraoperative ICP monitoring in this subgroup of patients undergoing laparoscopic surgery and that IH should be treated by ventricular drainage.

Use of a catheter limiter during intermittent catheterization.

We report on the use of a new device, the catheter limiter, to facilitate clean intermittent catheterization. The device limits the length of catheter entering the urethra. This provides a means to reduce the risk of mechanical injury and perforation, minimizes incomplete emptying, and improves safety and patient acceptance of intermittent catheterization.

Use of a free bladder mucosal graft for simple repair of vesicovaginal fistulae.

The aim of this paper is to describe a simple, fast, and effective method for repair of difficult vesicovaginal fistulae by means of a free bladder mucosal graft. Six patients with high, large, multiple, or recurrent vesicovaginal fistulae were treated using a free bladder mucosal graft. Three patients underwent "early" repair (less than 3 months from time of injury) and 3 "late" repair (more than 6 months from time of injury). Via a suprapubic cystotomy, the mucosa of the fistulous tract was debrided without any attempt to excise the tract or close the bladder or vaginal defects. A free bladder mucosal graft was harvested from an unaffected portion of the bladder and placed over the fistulous tract, and mucosal approximation was made using interrupted 5-0 chromic stay sutures. The donor urothelial defect was allowed to re-epithelialize. A Foley catheter, suprapubic tube, and vaginal packing were left in place. Five patients noted an immediate result, with no evidence of leakage, and the suprapubic tube was removed by week 3. One patient required prolonged catheter drainage, and the tube was successfully removed by week 6. This patient had undergone irradiation. All patients remain dry at follow-up, which ranges from 2 to 6 years. We describe a simple and effective method for transabdominal vesicovaginal fistula repair, involving minimal mobilization, decreased dissection, and no need for rotational or interposition flaps, obviating the need to open the peritoneum. A free bladder mucosal graft can be used regardless of the individual anatomy or proximity to the ureteral orifices, because it can easily be tailored. This technique represents an important repair of difficult, recurrent, or multiple vesicovaginal fistulae.

Laser tissue welding in genitourinary reconstructive surgery: assessment of optimal suture materials.

OBJECTIVES: Laser tissue welding in genitourinary reconstructive surgery has been shown in animal models to decrease operative time, improve healing, and decrease postoperative fistula formation when compared with conventional suture controls. Although the absence of suture material is the ultimate goal, this has not been shown to be practical with current technology for larger repairs. Therefore, suture-assisted laser tissue welding will likely be performed. This study sought to determine the optimal suture to be used during laser welding. METHODS: The integrity of various organic and synthetic sutures exposed to laser irradiation were analyzed. Sutures studied included gut, clear Vicryl, clear polydioxanone suture (PDS), and violet PDS. Sutures were irradiated with a potassium titanyl phosphate (KTP)-532 laser or an 808-nm diode laser with and without the addition of a light-absorbing chromophore (fluorescein or indocyanine green, respectively). A remote temperature-sensing device obtained real-time surface temperatures during lasing. The average temperature, time, and total energy at break point were recorded. RESULTS: Overall, gut suture achieved significantly higher temperatures and withstood higher average energy delivery at break point with both the KTP-532 and the 808-nm diode lasers compared with all other groups (P < 0.05). Both chromophore-treated groups had higher average temperatures at break point combined with lower average energy. The break-point temperature for all groups other than gut occurred at 91 degrees C or less. The optimal temperature range for tissue welding appears to be between 60 degrees and 80 degrees C. CONCLUSIONS: Gut suture offers the greatest margin of error for KTP and 808-nm diode laser welding with or without the use of a chromophore.

An unusual cause of duodenal obstruction: ureteropelvic junction obstruction and the renoalimentary relationship.

Ureteropelvic junction obstruction may present with a variety of urologic and gastrointestinal complaints. The constellation of symptoms is most often attributed to shared visceral pathways. In cases of giant hydronephrosis, mechanical obstruction of the gastric outlet or duodenal sweep may play an additional role in presentation. We present an unusual case of duodenal obstruction caused by ureteropelvic junction stenosis. The anatomic and autonomic renoalimentary relationships are reviewed.

The influence of prostate size on cancer detection.

OBJECTIVES: To determine if cancer detection rates vary with prostate size using a sextant core biopsy pattern. METHODS: We reviewed 1021 transrectal ultrasound (TRUS)-guided sextant pattern prostate biopsies to determine if cancer detection varied based on prostate size. Prostate size was determined using a computer generated elliptical estimation method. Sextant core biopsies were taken, and the patients divided into groups based on estimated size of the prostate and biopsy outcome. Large prostates were those that were estimated by TRUS as 50 cc or more. Prostates were considered small if they were less than 50 cc. Groups were compared based on size and biopsy outcome. RESULTS: Adenocarcinoma was detected in 33% (334 of 1021) of the patients. Large prostates were noted in 34% (346 of 1021), of which 23% (80 of 346) had cancer detected by sextant biopsy. Small prostates were noted in 66% (675 of 1021), of which 38% (254 of 675) had cancer detected. The difference in cancer detection in large and small glands using a sextant pattern was statistically significant (P < 0.01). Patients with positive biopsies had significantly smaller prostate sizes (40 cc +/- 26) when compared with those with negative biopsies (51 cc +/- 33) (P < 0.01). Only 14% (8 of 58) of patients with gland sizes 100 cc or greater had positive sextant biopsies while 49% (118 of 239) with prostates 25 cc or less had cancer detected. Multivariate statistical analysis was used to control for differences in age, prostate-specific antigen (PSA), PSA density, TRUS findings, and digital rectal examination between the large and small prostate groups. The difference in cancer detection persisted (P < 0.05) CONCLUSIONS: Currently no evidence exists to support differing cancer rates based on gland size alone. Our cancer detection rate using a sextant pattern was higher in men with prostates less than 50 cc, and patients diagnosed with cancer had significantly smaller prostates than those with a negative sextant biopsy. Our data suggest that significant sampling error may occur in men with large glands, and more biopsies may be needed under these circumstances. The effects of tumor volume, focality, and specimen size in relation to overall gland size may contribute to these findings.

Biopsy of lesions of the male genitourinary tract.

Biopsy of benign and malignant lesions of the male genitourinary tract using a variety of open and endourologic techniques is possible. A multidisciplinary approach involving close communication between clinicians, radiologists, and pathologists is imperative to a favorable outcome. Urologic practice has pioneered many of these techniques, which continue to evolve as new technologies become available.

23 assessment of T-cell immune dysfunction in patients with renal cell carcinoma.

Functional T cells are the central component of an effective antitumor immune response. However, in patients with renal cell carcinoma (RCC), the growth of antigenic tumors proceeds in the absence of significant T-cell responses, posing a distinct obstacle to the development of effective immunotherapy strategies and cancer vaccines. The minimum required elements of a functional antitumor immune T-cell response have been identified, including T cells that can preferentially recognize tumor-associated antigens (1). However, despite increasing evidence that T-cells recognize discrete tumor antigen, transformed cells continue to evade immune destruction, and tumors thereby progress. There is now little doubt that the immune response to tumor antigens is altered in patients with cancer (2). This rarely manifests clinically as generalized immune suppression, which may reflect the antigen specificity of the immune dysfunction in the initial stages of the disease.

The treatment of non-metastatic prostate cancer with external beam radiation therapy.

Multiple treatment options exist for men with non-metastatic prostate cancer. For nearly 50 years, external beam radiation therapy (EBRT) has been an important means of treating men with this disease. Improvements in technology and better use of pre-treatment variables including prostate specific antigen (PSA), Gleason score and prediction nomograms have steadily improved biochemical and clinical outcomes. This article reviews the current status of EBRT in the treatment of prostate cancer. Differences in technique as well as clinical results using conventional, 3D conformal and intensity modulated radiation therapy are compared and contrasted. The appropriate use of adjuvant hormones as well as the complications of these treatments will also be discussed.

Evaluating prostate cancer mortality and competing risks of death in patients with localized prostate cancer using a comprehensive nomogram.

BACKGROUND: The aim of this study was to determine the optimal treatment for a patient with newly diagnosed prostate cancer weighing the individual's risk of disease progression against his risk of non-cancer death. METHODS: We developed a predictive model incorporating clinicopathological tumor variables, patient age, comorbidity status, and primary treatment modality. We identified 6091 patients with clinically-localized prostate cancer managed with radical prostatectomy (n=4117) or radiation therapy (n=1974) from the Cancer of the Prostate Strategic Urologic Research Endeavor database. Fine and Gray competing-risks proportional hazards regression models were used to calculate the risks of prostate cancer-specific mortality (PCSM) and non-prostate cancer death and to generate a nomogram. RESULTS: The median follow-up after treatment was 53 months (interquartile range 30, 80 months). In total, 983 men died during follow-up, including 167 who died of prostate cancer and 816 who died of non-prostate cancer causes. On multivariate analysis, higher Cancer of the Prostate Risk Assessment score and primary treatment with radiation were associated with an increased risk of PCSM, whereas older age, African-American race, and treatment with radiation predicted non-prostate cancer death. The number of comorbidities and receipt of androgen deprivation therapy correlated with an increased risk of non-prostate cancer death, but not PCSM. The resulting nomogram allows quantification and comparison of the 10-year risk of PCSM and non-prostate cancer death. CONCLUSIONS: Integrating clinicopathological variables with comorbid conditions in a competing-risks model affords quantification and comparison of relative probabilities of PCSM and non-prostate cancer death following treatment. Our model thereby facilitates an individualized approach for counseling patients regarding prostate cancer management.