Evaluation of AMSA in previously treated patients with acute leukemia: results of therapy in 109 adults

AMSA was evaluated in the treatment of 109 adults with previously treated acute leukemia. Of the 102 evaluable patients, 82 had AML, 17 ALL, and 3 CML in blastic phase. A number of different dose schedules of AMSA were explored, and we conclude that the optimum dose of AMSA for remission induction in acute leukemia is 120 mg/sq m/day for 5 days. Complete remissions were observed in 23 (28%) patients with AML and in 1 patient with ALL. Patients who achieved complete remission were maintained on AMSA using a dose of 30-40 mg/sq m/day for 5 days repeated at 4-wk intervals. The median duration of complete remission was 12 wk (3-59 wk), and the responders survived significantly longer than the failures (27 wk versus 8 wk, p = 0.002). The side effects associated with AMSA therapy included mild nausea and vomiting, stomatitis, diarrhea, phlebitis, alopecia, and myelosuppression-related infections. Our results indicate that AMSA is a useful new antileukemic agent for the treatment of relapsed acute leukemia and appears to have activity comparable to that of the currently available drugs, such as cytarabine and the anthracycline antibiotics.     

Practice patterns of ureteral stenting after routine ureteroscopic stone surgery: a survey of practicing urologists

BACKGROUND: Controversy exists regarding the need for ureteral stent insertion after routine ureteroscopic stone surgery. We designed a questionnaire to assess and better understand the practice patterns of urologists for stent applications. MATERIALS AND METHODS: A 26-question survey was distributed to 570 community and academic urologists. The answers were anonymously tabulated to determine the practice patterns for stent placement. RESULTS: Of the 173 respondents, 97.7% performed ureteroscopic surgery, with the majority (77%) performing 1 to 10 procedures per month. Sixty-eight percent of urologists considered more than 70% of their ureteroscopic procedures "routine." Only 21% of urologists dilated the ureteral orifice more than 90% of the time. Those who dilated the ureteral orifice used a balloon (43%), ureteral access sheath (13.5%), or both (21%). The use of an access sheath did not change stenting practices for 75% of urologists. Patterns vary with regard to length of indwelling time, with 85% of urologists maintaining the stent for fewer than 7 days. Most urologists use either cystoscopy (42%) or pull-suture in clinic (37%) to remove stents. Patient tolerance is the most significant problem with stents reported by 97.6% of urologists. The respondents were divided into three experience-based groups: group 1, <2 years of experience; group 2, 2 to 10 years; and group 3, >10 years. Using Fisher's exact test, there were no statistically significant differences between the groups. CONCLUSION: A wide variability exists among urologists in the practice patterns of stent insertion after routine ureteroscopic surgery. Most consider their procedures routine and are more likely to place stents after ureteral dilation despite growing evidence to the contrary. Knowledge of the varied practices may aid less experienced urologists in their decision to insert a stent after ureteroscopy.     

GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo

BACKGROUND AND PURPOSE

Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.

EXPERIMENTAL APPROACH

The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.

KEY RESULTS

GSK1440115 (pK_i= 7.34–8.64 across species) and GSK1562590 (pK_i= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA₂= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pK_b= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pK_b= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.

CONCLUSIONS AND IMPLICATIONS

Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.     

Effect of obesity on prostate-specific antigen recurrence after radiation therapy for localized prostate cancer as measured by the 2006 Radiation Therapy Oncology Group-American Society for Therapeutic Radiation and Oncology (RTOG-ASTRO) Phoenix consensus definition

BACKGROUND: Given the limited data regarding the impact of obesity on treatment outcomes after external beam radiation therapy (EBRT) for the definitive treatment of prostate cancer, the authors sought to evaluate the effect of obesity as measured by body mass index (BMI) on biochemical disease recurrence (BCR) using the most current 2006 Radiation Therapy Oncology Group-American Society for Therapeutic Radiation and Oncology (RTOG-ASTRO) Phoenix consensus definition (prostate-specific antigen [PSA] nadir + 2 ng/mL). METHODS: A retrospective cohort study identified men who underwent primary EBRT for localized prostate cancer between 1989 and 2003 using the Center for Prostate Disease Research (CPDR) Multi-center National Database. BMI was calculated (in kg/m(2)) and the data were analyzed. Univariate and multivariate Cox proportional hazards regression analyses were used to determine whether BMI significantly predicted BCR. RESULTS: Of the 1868 eligible patients, 399 (21%) were obese. The median age of the patients and pretreatment PSA level were 70.2 years and 8.2 ng/mL, respectively. Of 1320 patients for whom data were available with which to calculate PSA recurrence (PSA nadir + 2 ng/mL), a total of 554 men (42.0%) experienced BCR. On univariate analysis, BMI was found to be an independent predictor of PSA recurrence (P = .02), as was race, pretreatment PSA level, EBRT dose, clinical T classification, Gleason score, PSA nadir, and the use of androgen-deprivation therapy (ADT). On multivariate analysis, BMI remained a significant predictor of BCR (P = .008). CONCLUSIONS: To the authors' knowledge, this is the first study to report the association between obesity and BCR after EBRT for localized prostate cancer as measured by the updated 2006 RTOG-ASTRO definition. A higher BMI is associated with greater odds of BCR after undergoing definitive EBRT.     

Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys

BACKGROUND AND PURPOSE: Horseshoe kidneys are a complex anatomic variant of fused kidneys, with a 20% reported incidence of associated calculi. Anatomic causes such as high insertion of the ureter on the renal pelvis and obstruction of the ureteropelvic junction are thought to contribute to stone formation via impaired drainage, with urinary stasis, and an increased incidence of infection. In this multi-institutional study, we evaluated whether metabolic factors contributed to stone development in patients with horseshoe kidneys. PATIENTS AND METHODS: A retrospective review of 37 patients with horseshoe kidneys was performed to determine if these patients had metabolic derangements that might have contributed to calculus formation. Stone compositions as well as 24-hour urine collections were examined. Specific data points of interest were total urine volume; urine pH; urine concentrations of calcium, sodium, uric acid, oxalate, and citrate; and number of abnormalities per patient per 24-hour urine collection. These data were compared with those of a group of 13 patients with stones in caliceal diverticula as well as 24 age-, race-, and sex-matched controls with stones in anatomically normal kidneys. RESULTS: Eleven (9 men and 2 women) of the 37 patients (30%) with renal calculi in horseshoe kidneys had complete metabolic evaluations available for review. All patients were noted to have at least one abnormality, with an average of 2.68 abnormalities per 24-hour urine collection (range 1-4). One patient had primary hyperparathyroidism and underwent a parathyroidectomy. Low urine volumes were noted in eight patients on at least one of the two specimens (range 350-1640 mL/day). Hypercalciuria, hyperoxaluria, hyperuricosuria, and hypocitraturia were noted in seven, three, six, and six patients, respectively. No patients were found to have gouty diathesis or developed cystine stones. Comparative metabolic analyses of patients with renal calculi in caliceal diverticula or normal kidneys revealed a distinct profile in patients with horseshoe kidneys, with a higher incidence of hypocitraturia. CONCLUSIONS: All patients with renal calculi in horseshoe kidneys were noted to have metabolic abnormalities predisposing to stone formation. In this initial series of 11 patients, hypovolemia, hypercalcuria and hypocitraturia were most common metabolic defects. These findings suggest that metabolic derangements play a role in stone formation in patients with a horseshoe kidney. Patients with calculi in anatomically abnormal kidneys should be considered for a metabolic evaluation to identify their stone-forming risk factors in order to initiate preventative selective medical therapy and reduce the risk of recurrent calculus formation.     

Ureteral access sheath provides protection against elevated renal pressures during routine flexible ureteroscopic stone manipulation

BACKGROUND AND PURPOSE: New-generation flexible ureteroscopes allow the management of proximal ureteral and intrarenal pathology with high success rates, including complete removal of ureteral and renal calculi. One problem is that the irrigation pressures generated within the collecting system can be significantly elevated, as evidenced by pyelovenous and pyelolymphatic backflow seen during retrograde pyelography. We sought to determine if the ureteral access sheath (UAS) can offer protection from high intrarenal pressures attained during routine ureteroscopic stone surgery. PATIENTS AND METHODS: Five patients (average age 72.6 years) evaluated in the emergency department for obstructing calculi underwent percutaneous nephrostomy (PCN) tube placement to decompress their collecting systems. The indications for PCN tube placement were obstructive renal failure (N=1), urosepsis (N=2), and obstruction with uncontrolled pain and elevated white blood cell counts (N=2). Flexible ureteroscopy was subsequently performed with and without the aid of the UAS while pressures were measured via the nephrostomy tube connected to a pressure transducer. Pressures were recorded at baseline and in the distal, mid, and proximal ureter and renal pelvis, first without the UAS, and then with the UAS in place. RESULTS: The average baseline pressure within the collecting system was 13.6 mm Hg. The mean intrarenal pressure with the ureteroscope in the distal ureter without the UAS was 60 mm Hg and with the UAS was 15 mm Hg. With the ureteroscope in the midureter, the pressures were 65.6 and 17.5 mm Hg, respectively; with the ureteroscope in the proximal ureter 79.2 and 24 mm Hg, and with the ureteroscope in the renal pelvis 94.4 and 40.6 mm Hg, respectively. All differences at each location were statistically significant (P<0.008). Compared with baseline, all pressures measured without the UAS were significantly greater, but only pressures recorded in the proximal ureter and renal pelvis after UAS insertion were significantly higher (P<0.03). CONCLUSIONS: The irrigation pressures transmitted to the renal pelvis and subsequently to the parenchyma are significantly greater during routine URS without the use of the UAS. The access sheath is potentially protective against pyelovenous and pyelolymphatic backflow, with clinical implications for the ureteroscopic management of upper-tract transitional cell carcinoma, struvite stones, or calculi associated with urinary tract infection.     

Hand-assisted laparoscopic nephrectomy: the transfer of experience to a new academic center

BACKGROUND AND PURPOSE: Hand-assisted laparoscopic nephrectomy (HALN) has become widely used for the management of localized renal masses and for simple nephrectomy [corrected] Centers of excellence have slowly disseminated this surgical approach throughout academic institutions and private practices. The transfer of this technique to inexperienced surgeons and centers has not been well studied. We examined our outcomes for HALN with an experienced surgeon (DMA) [corrected] at a new academic center. We also examined the effectiveness of the transfer of these techniques as trainees go out into practice [corrected] PATIENTS AND METHODS: A total of 85 hand-assisted laparoscopy procedures were performed between September 2001 and August 2003 of which 61 were HALN. Four fellows and eight chief residents, under the guidance of one attending surgeon (DMA), performed all HALN procedures. Parameters measured included patient age, ASA score, body mass index, operative time, estimated blood loss, number of trocars used, time to oral intake, analgesics required, length of stay, complications, and tumor size. The average patient age was 57.4 years (range 26-87 years) and the mean ASA score 2.5 (1-4). The mean BMI was 28.3 (range 20-46) [corrected] There was a slight predominance of right-sided lesions. In addition to evaluating our early results with HALN, a questionnaire was sent to all graduates of our program starting 2 years prior to the arrival of DMA to assess the application of laparoscopy to their practices [corrected] RESULTS: All cases were completed without open conversion. The total operative time averaged 184 [corrected] minutes (range 67-257 [corrected] minutes), with 80% of patients requiring two trocars. The average blood loss was 136 [corrected] ml (range 25-700 mL), but only one patient required transfusion postoperatively [corrected] The mean time to oral intake was 17.1 hours (range 1.5-240 hours), the average length of stay was 4.3 days (range 1-28 days), and total narcotic requirements averaged 111 mg of morphine sulfate equivalents (range 6.7-519 mg). Sixty-six percent of the procedures were performed for malignancy. The average tumor size in these cases was 3.9 cm (range 1-12 cm). There was one death, in an 80-year-old patient who had a bowel injury necessitating re-exploration and bowel resection. This patient had a postoperative myocardial infarction and died. Two patients developed postoperative hernias at their hand-port site. Other significant [corrected] complications included diaphragmatic [corrected] injury (repaired laparoscopically), one [corrected] pulmonary embolus, two cases of pancreatitis, and one case of pneumonia. Three patients experienced postoperative ileus. Of the 20 graduates of this program since 2000, 4 were laparoscopic/endourology fellows, and 2 of the residents pursued fellowship training after graduating. Graduates of the year 2000 and 2001 represent surgeons who graduated prior to the arrival of DMA. Of those resident graduates who did not pursue fellowship, two of the seven surgeons who graduated prior to the arrival of DMA are performing laparoscopy. Both of these surgeons pursued formal postgraduate laparoscopic training. Six of the seven non-fellowship-trained residents who graduated since DMA's arrival are performing laparoscopy; the other is early in practice and intends to do so. None of these surgeons has pursued postgraduate training prior to performing laparoscopy in their practices [corrected] CONCLUSIONS: The HALN techniques can be transferred quickly and efficiently between [corrected]one center and [corrected] another under the guidance of an experienced surgeon. Operative times are acceptable, with complication rates comparable to [corrected] previously reported series. Our data show that exposure during residency markedly increases the likelihood that surgeons will carry the techniques into their practices [corrected]     

Serum protein s-100 predicts clinical outcome in patients with melanoma treated with adjuvant interferon--comparison with tyrosinase rt-PCR

OBJECTIVE: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. PATIENTS AND METHODS: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2-3 months thereafter. RESULTS: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2-76). In the univariate analysis, under treatment S-100 > or =0.15 microg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels > or =0.15 mug/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67-9.15; p = 0.004) and 2.2 (95% CI, 1.05-4.6; p = 0.016) for S-100 > or =0.15 microg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 microg/l. CONCLUSIONS: S-100 > or =0.15 microg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 microg/l.     

In vitro comparison of fragmentation efficiency of flexible pneumatic lithotripsy using 2 flexible ureteroscopes

PURPOSE: Pneumatic lithotripsy has been shown to be an effective and safe intracorporeal lithotripsy modality for renal and ureteral calculi, capable of fragmenting stones of all compositions. We determined the in vitro stone fragmentation abilities of the 0.5 mm flexible pneumatic lithotripsy probe when inserted through the working channel of 2, 7.5Fr flexible ureteroscope designs (straight working channel and offset working channel at approximately 30 degrees from the long axis of the endoscope). The velocity and displacement of the pneumatic probe tip were also evaluated with the probe inserted through each endoscope. MATERIALS AND METHODS: The 0.5 mm (1.5Fr) stainless steel probe was tested at 5 deflection angles, namely 0, 12, 24, 33 and 48 degrees, at a pneumatic pressure of 2.5 bar when inserted through the offset and straight working channel ureteroscopes. A noncontact optical laser system was used to measure or calculate the displacement and velocity of the 0.5 mm probe tip at each angle of deflection with the 2 ureteroscopes. Fragmentation at all deflection angles was assessed using plaster of Paris stone phantoms with the pneumatic device on continuous mode at 2.5 bar pressure for 30 seconds. Stones were weighed after each fragmentation cycle and the percent weight lost was determined. Comparisons were made between the 2 ureteroscopes at each angle. RESULTS: Probe tip displacement was significantly better through the straight channel ureteroscope with 30% improvement at all angles tested compared to the offset channel. Moreover, a substantial decrement in tip displacement was noted as the angle of deflection increased regardless of the endoscope used. Conversely tip velocity was relatively unchanged throughout the study and it was equivalent from straight to offset channel measurements. Phantom stone fragmentation correlated inversely with the severity of the deflection angle. An approximately 80% loss of fragmentation ability was noted as the angle increased from 0 to 48 degrees. Although the pneumatic device performed better through the straight channel scope, a similar percent loss in fragmentation from 0 to 48 degrees was seen when using either endoscope. CONCLUSIONS: The flexible pneumatic 0.5 mm lithotripsy probe appears to be best used through a straight channel flexible ureteroscope, out performing use through the offset channel scope at all angles of deflection. Tip displacement and fragmentation ability were inversely related to the degree of active deflection as the angle increased from 0 to 48 degrees. Use of the flexible pneumatic probe to aid in managing renal or proximal ureteral calculi may be limited until an improved probe can be developed, allowing complete and unencumbered fragmentation throughout all angles of deflection.