Selective vs. Global Renal Denervation: a Case for Less Is More.

PURPOSE OF REVIEW: Review the renal nerve anatomy and physiology basics and explore the concept of global vs. selective renal denervation (RDN) to uncover some of the fundamental limitations of non-targeted renal nerve ablation and the potential superiority of selective RDN. RECENT FINDINGS: Recent trials testing the efficacy of RDN showed mixed results. Initial investigations targeted global RDN as a therapeutic goal. The repeat observation of heterogeneous response to RDN including non-responders with lack of a BP reduction, or even more unsettling, BP elevations after RDN has raised concern for the detrimental effects of unselective global RDN. Subsequent studies have suggested the presence of a heterogeneous fiber population and the potential utility of renal nerve stimulation to identify sympatho-stimulatory fibers or "hot spots." The recognition that RDN can produce heterogeneous afferent sympathetic effects both change therapeutic goals and revitalize the potential of therapeutic RDN to provide significant clinical benefits. Renal nerve stimulation has emerged as potential tool to identify sympatho-stimulatory fibers, avoid sympatho-inhibitory fibers, and thus guide selective RDN.

The role of pathology review of transurethral bladder tumor resection specimens in the modern era.

PURPOSE: The value of pathological reinterpretation of tissue slides has long been questioned. At the Cleveland Clinic subspecialization in genitourinary pathology began in 2003 and has been maintained. We evaluate the role of second review on transurethral bladder tumor resection pathology slides before and after subspecialization and potential impact on treatment. MATERIALS AND METHODS: Transurethral bladder tumor resection specimens from 78 and 116 patients with bladder cancer in 2002 and 2004, respectively, were reviewed. Initial surgical pathology reports from institutions outside the Cleveland Clinic were compared with review report by a pathologist with genitourinary pathology specialization (HSL). Those cases with differences in diagnosis or staging were then evaluated by a urologist (JSJ) considering current standards of care. RESULTS: The reinterpretation differed substantially from the initial report in 26 of 78 cases (33.3%) in 2002 and in 31 of 116 (26.7%) in 2004 (p = 0.3), resulting in a possible impact on management in 28.2% (22 of 78) in 2002 and 23.3% (27 of 116) in 2004 (p = 0.54). In each year 4 cases diagnosed with bladder cancer elsewhere were determined to have no malignancy. The majority of discrepancies related to the presence of carcinoma in situ in 2002 and to the presence or absence of muscularis propria and/or muscle involvement by carcinoma in 2004. CONCLUSIONS: Second review of transurethral bladder tumor resection specimens shows differences of interpretation in 26.7% to 33.3% of cases, which is sufficient to alter management. There was no significant difference in the rate of discrepancies before and after genitourinary pathology subspecialization. Referral centers must assume responsibility for establishing the diagnosis before consultation and/or therapy.

Microscopic bladder neck involvement by prostate carcinoma in radical prostatectomy specimens is not a significant independent prognostic factor.

The independent prognostic importance of microscopic bladder neck involvement by prostate cancer in radical prostatectomy is questionable. We studied a cohort of 1845 patients to determine the significance of microscopic bladder neck involvement. Bladder neck involvement was defined as prostate cancer present within the coned bladder neck. We further categorized the cases as 'true bladder neck involvement' and 'false bladder neck involvement.' True bladder neck involvement required prostate cancer within thick smooth muscle bundles without intermixed benign prostatic glands. False bladder neck involvement was characterized by prostate cancer intermixed with benign prostatic glands. Bladder neck involvement was analyzed in relation to preoperative serum prostate-specific antigen (PSA) level, extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, radical prostatectomy Gleason score, and tumor volume. Of the 90 patients (4.9%) with microscopic bladder neck involvement, 63 were further classified as true bladder neck involvement and 27 as false bladder neck involvement. In univariate model, both types of bladder neck involvement (P<0.001), true (P<0.001), and false (P=0.040), were significantly associated with increased PSA-recurrence risk compared to bladder neck negative cases. In multivariate model the PSA-recurrence relative risk associated with bladder neck involvement (true or false) was not a significant independent prognostic factor. Extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, PSA, and Gleason score were significant independent predictors of PSA recurrence. The time to biochemical recurrence in patients with bladder neck involvement was similar to that of pT2 with positive surgical margin or pT3a with negative surgical margin patients (Kaplan-Meier curves). Bladder neck involvement was associated with other adverse pathologic features, but was not an independent predictor of PSA recurrence. In view of the previous and current data, the staging system for bladder neck involvement should be revised and patients may be best categorized as having pT3a disease.

Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET-1 and TARGET-2 studies.

AIMS: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF. METHODS AND RESULTS: The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment. CONCLUSIONS: The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.

Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research.

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.

Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience.

Radiological characterization of an adrenal tumor as adenoma may decrease the need for follow-up imaging studies, biopsies, and unnecessary adrenalectomies. We retrospectively reviewed 299 adrenalectomies in 290 patients at Cleveland Clinic Foundation over a recent 5-yr period to assess the value of noncontrast Hounsfield units (HU) in characterizing whether an adrenal mass is adenoma or nonadenoma. The mean (+/- SD) HU value for the adrenocortical adenoma/hyperplasia group was 16.2 +/- 13.6 and significantly lower (P < 0.0001) than primary adrenocortical cancers (36.9 +/- 4.1), metastases (39.2 +/- 15.2), and pheochromocytomas (38.6 +/- 8.2). The sensitivity and specificity for 10- and 20-HU cutoff values to differentiate adenomas/hyperplasias from nonadenomas were 40.5 and 100% and 58.2 and 96.9%, respectively. The size of the adrenal tumor had less value with only 40.7 and 81.3% sensitivity and 94.7 and 61.4% specificity for 2- and 4-cm cutoff values. A combination of less than or equal to 4-cm adrenal mass size and noncontrast computed tomography HU less than or equal to 20 had 42.1% sensitivity and 100% specificity. Our study, the largest with surgical histopathology as the gold standard for diagnosis, supports a noncontrast computed tomography attenuation value of 10 HU as a safe cutoff value to differentiate adrenal adenomas/hyperplasias from nonadenomas.

Preoperative combined nested reverse transcriptase polymerase chain reaction for prostate-specific antigen and prostate-specific membrane antigen does not correlate with pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy.

PURPOSE: We report a prospective study examining the ability of preoperative nested reverse transcriptase polymerase chain reaction (RT-PCR) for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) to predict pathologic stage and biochemical recurrence in patients with clinically localized prostate cancer treated with radical prostatectomy. PATIENTS AND METHODS: One hundred forty-one patients were entered onto the study. Preoperative evaluation included clinical T stage, serum PSA, biopsy Gleason score, and serum RT-PCR for PSA/PSM. Univariate and multivariate logistic regression models, Kaplan-Meier estimates, and Cox proportional hazards modeling were used to identify predictors of pathologic stage and biochemical failure. RESULTS: Seventy-three patients (51.8%) were RT-PCR positive for PSA, PSM, or both. In the multivariate logistic regression model, only initial PSA was an independent predictor of pathologic stage as defined by organ-confined disease (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00 to 1.13; P =.026) or organ-/specimen-confined disease (OR, 1.09; 95% CI, 1.02 to 1.16; P =.009). Overall Kaplan-Meier biochemical relapse-free survival (bRFS) was 85% at 59 months. Multivariate analysis of predictors for bRFS with the Cox proportional hazards model indicated that only initial PSA (OR, 1.05; 95% CI, 1.02 to 1.09; P =.004) and biopsy Gleason score (OR, 3.57; 95% CI, 1.37 to 9.58; P =.009) were independent predictors of biochemical failure. RT-PCR status did not predict pathologic stage or biochemical failure. Repeat analysis excluding 27 patients who received preoperative androgen-deprivation therapy did not change the results. CONCLUSION: Combined nested RT-PCR for PSA and PSM is not an independent predictor of pathologic stage or biochemical failure in patients with localized prostate cancer undergoing radical prostatectomy. This assay has no clinical utility in this patient population.

Prostate cancer aggressiveness locus on chromosome 7q32-q33 identified by linkage and allelic imbalance studies.

The biologic aggressiveness of prostate tumors is an important indicator of prognosis. Chromosome 7q32-q33 was recently reported to show linkage to more aggressive prostate cancer, based on Gleason score, in a large sibling pair study. We report confirmation and narrowing of the linked region using finer-scale genotyping. We also report a high frequency of allelic imbalance (AI) defined within this locus in a series of 48 primary prostate tumors from men unselected for family history or disease status. The highest frequency of AI was observed with adjacent markers D7S2531 (52%) and D7S1804 (36%). These two markers delineated a common region of AI, with 24 tumors exhibiting interstitial AI involving one or both markers. The 1.1-Mb candidate region contains relatively few transcripts. Additionally, we observed positive associations between interstitial AI at D7S1804 and early age at diagnosis (P=.03) as well as a high combined Gleason score and tumor stage (P=.06). Interstitial AI at D7S2531 was associated with a positive family history of prostate cancer (P=.05). These data imply that we have localized a prostate cancer tumor aggressiveness loci to chromosome 7q32-q33 that is involved in familial and nonfamilial forms of prostate cancer.

Assessment of synchrony relationships between the native left ventricle and the HeartMate left ventricular assist device.

BACKGROUND: It has been suggested that the cardiac cycle becomes synchronized with the LVAD. Synchronization between the left ventricle and the LVAD may be important for ventricular unloading and coronary flow. In this study, we assessed the synchrony between the cardiac and LVAD cycles. METHODS: We studied 24 patients with HeartMate LVAD support. Native heart rate from an electrocardiogram and LVAD rate were measured at rest and peak exercise. Three patients underwent simultaneous invasive pressure measurement from the left ventricle and the aorta, and 3 patients underwent simultaneous recording of electrocardiogram and LVAD electrical signal. RESULTS: Resting heart rate was significantly higher than LVAD rate (96 +/- 17 vs 66 +/- 15 beats [b]/min, p < 0.0001), with no correlation between the 2 (r = 0.25). Peak heart rate was significantly higher than LVAD rate (142 +/- 16 vs 102 +/- 14 b/min, p < 0.0001), with no correlation observed (r = 0.31). Electrical signal recording confirmed the absence of cardiac-LVAD synchrony. Pressure measurements revealed a cyclical intraventricular pressure variation, determined by the relationship between the cardiac and LVAD cycles. Intraventricular pressure was lowest when left ventricular systole occurred during pump filling and highest when left ventricular systole occurred during pump ejection. CONCLUSIONS: The cardiac and LVAD cycles are not in synchrony at rest or at peak exercise. However, a cyclical variation in left ventricular pressure exists, dependent upon the phasic relationship of the cardiac-LVAD cycles, which significantly effects ventricular loading. Better understanding of this relationship may be important in developing assist devices for optimal left ventricular unloading and improvement of myocardial recovery.

Continuing trends in pathological stage migration in radical prostatectomy specimens.

Prostate-specific antigen (PSA) screening has resulted in a profound clinical stage migration. Extracapsular extension (ECE) presents a poor prognosis after radical prostatectomy (RP). In this study the trends in rate of ECE for cancers detected by PSA screening between 1987, when PSA screening became routine in the United States, and 2001, were examined. The clinical outcome of patients (total 1505; 888 clinical Tlc, 614 clinical T2, and 3 clinical T3) with prostate cancer diagnosed by PSA screening and treated with RP without neoadjuvant hormonal therapy was analyzed. The primary outcome variable was ECE rate with respect to year of treatment for a given tumor stage, preoperative PSA level, biopsy Gleason score, and surgical Gleason score. Logistic regression analysis was used to identify predictors of ECE. Biochemical relapse-free survival (bRFS) by year of treatment was analyzed by Kaplan-Meier Curve. Rate of ECE decreased from 65.8 to 25.2% during the 15-year study duration. Multivariate analysis of clinical tumor stage, age, preoperative serum PSA level, and Gleason score confirmed that year of treatment was an independent predictor of ECE. Six-year bRFS rates (by years of treatment) were 75.1% for 1987 to 1994 and 82.6% for 1995 to 2001 (P-value = 0.0022). PSA screening has resulted in a downward pathological stage migration. These observations demonstrate improved biochemical failure rates in more recently treated patients.

Adrenal insufficiency attributable to adrenal hemorrhage: long-term follow-up with reference to glucocorticoid and mineralocorticoid function and replacement.

OBJECTIVE: To describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage. METHODS: We performed a retrospective review of medical records of four patients who underwent follow-up for 6(1/2) to 19 years. RESULTS: Despite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6(1/2) to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5(1/2) to 11(1/2) years after bilateral adrenal hemorrhage in three of the four patients. CONCLUSION: Long-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients.

Change in adrenal mass size as a predictor of a malignant tumor.

OBJECTIVE: To assess the value of adrenal mass absolute growth, growth rate, and percentage growth rate on serial imaging for distinguishing benign from malignant adrenal masses. METHODS: We retrospectively reviewed the Cleveland Clinic medical record data on 136 adrenalectomies or biopsies in 132 patients with 2 imaging studies performed more than 2 months apart (during 1997 to 2008). RESULTS: There were 111 benign (81.6%) and 25 malignant (18.4%) adrenal masses. With use of receiver operating characteristic curve analysis, all 3 aforementioned growth measures showed similar levels of discrimination for the entire study group as well as for the subgroups with 3 to 12 months of follow-up (n = 75 masses) and noncontrast computed tomography Hounsfield units >10 or not reported (n = 111 masses). After adjustment for other factors, the 3 growth measures remained statistically significant predictors of a malignant tumor. The absolute growth cutoff value of 0.8 cm had the highest sum of sensitivity and specificity of 72% and 81.1%, respectively. We could not identify an adrenal mass growth cutoff value to provide 100% sensitivity or specificity to confirm or exclude the presence of a malignant lesion. In 3 patients with metastatic lesions, no growth or a decrease in mass size during a period of 4 to 36 months was observed. CONCLUSION: In this study, the largest with surgical histopathology findings as the "gold standard" for diagnosis, change in adrenal mass size was a significant predictor of a malignant tumor. Nevertheless, we could not identify an adrenal mass growth cutoff value for reliable confirmation or exclusion of a malignant lesion. Change in adrenal mass size should be used in conjunction with other imaging and clinical characteristics when surgical resection is being considered.

Preoperative PSA is still predictive of cancer volume and grade in late PSA era.

OBJECTIVES: To examine the relationship between preoperative prostate-specific antigen (PSA) and pathologic characteristics of the prostate gland and prostate cancer at radical prostatectomy in patients with clinically localized disease in the early (1993 to 1998) and late (1999 to 2004) PSA eras. METHODS: From January 1, 1993 to December 31, 2004, 2067 patients aged 40 to 80 years with clinically localized prostate cancer underwent radical prostatectomy without neoadjuvant therapy at the Cleveland Clinic. The correlation among the preoperative PSA level, prostate volume, percentage of Gleason pattern 4/5, surgical Gleason score, and cancer volume was calculated using Pearson's and Spearman's tests for the early (1993 to 1998) and late (1999 to 2004) PSA eras. Logistic regression analyses were performed to identify independent predictors of the percentage of Gleason pattern 4/5 and cancer volume during each era. RESULTS: In both eras, the PSA level correlated positively with the percentage of Gleason pattern 4/5, surgical Gleason score, and prostate volume, with nearly identical r values. The PSA level also correlated with the cancer volume in the late PSA era (the only era for which cancer volume data were available). In the multivariate model, biopsy Gleason score, clinical T stage, and PSA level were independent predictors of percentage of Gleason pattern 4/5 in both eras and of cancer volume in the late PSA era. CONCLUSIONS: Even in the late PSA era, the preoperative PSA level has retained its predictive value for the percentage of Gleason pattern 4/5 and cancer volume. The PSA level continues to have prognostic value for men with clinically localized prostate cancer treated by radical prostatectomy.

Partial nephrectomy for renal urothelial tumors: clinical update.

OBJECTIVES: To evaluate the contemporary indications and outcome after partial nephrectomy for renal urothelial cancer. Partial nephrectomy is an established treatment for renal cell cancer but its use for renal urothelial tumors has been studied less extensively. METHODS: Records were reviewed for patients undergoing partial nephrectomy for renal urothelial tumors between January 1990 and December 2001. Partial nephrectomy was selected for those with a solitary kidney, chronic renal insufficiency, or bilateral synchronous tumors. Partial nephrectomy was performed according to the principles of partial nephrectomy. Follow-up included ultrasonography, intravenous urography, computed tomography, metastatic workup, and renal function evaluation. RESULTS: This study included 12 patients (12 kidneys, 10 solitary) with a mean age of 68.5 +/- 21 years and a mean follow-up of 40.8 +/- 32 months. The pathologic T stage was Tis in 1 patient, T1 in 3, T2 in 2, and T3 in 6 patients. Of the 12 patients, 6 had negative surgical margins, and 4 of the 12 patients (30%) were tumor free after a mean follow-up of 57.7 months. Of the 6 patients with positive surgical margins (Stage T1 in 2 and T3 in 4), 1 developed recurrence and 3 developed metastasis; 4 died after a mean of 31.3 months. Overall recurrence was seen in 5 (42%) and progression (metastasis) in 6 (50%) patients. Of the 12 patients, 6 were alive, 4 of them were well (mean serum creatinine 1.83 mg/dL) at 62 months of follow-up. Two patients required dialysis. The overall long-term survival rate was 50%. CONCLUSIONS: Partial nephrectomy for renal urothelial tumors is feasible and should be considered in a select population. Dialysis or renal replacement can be delayed or avoided in most of these patients, but strict surveillance remains mandatory.

Mucinous adenocarcinoma of the prostate does not confer poor prognosis.

OBJECTIVES: To report a series of patients with mucinous (colloid) adenocarcinoma (MC) at prostatectomy who were treated at a single institution from 1987 to 2005. MC is a rare form of prostate cancer reported in some cases to have a more aggressive clinical course than conventional adenocarcinoma (AC). METHODS: Radical prostatectomy specimens with mucinous features were identified from a database of 3613 consecutive patients. Each case was reviewed again by a single pathologist who confirmed the diagnosis of MC in 14 patients. MC was defined by the presence of pools of extracellular mucin in more than 25% of the tumor. Eighteen additional cases were identified in which the mucinous component occupied only a small portion of the tumor and were referred to as AC with focal mucin (AFM). The biochemical and overall survival of 26 patients with MC or AFM who had completed > or = 6 months of follow-up was analyzed using Kaplan-Meier estimates. RESULTS: No patients with MC or AFM died of disease, and 11 (91.7%) of 12 patients with MC and 9 (64.3%) of 14 patients with AFM were clinically and biochemically free of disease. No significant difference was found in biochemical recurrence or overall survival between those with MC or AFM and a matched group of patients with AC. CONCLUSIONS: We report what we believe to be the largest published series of cases of MC (n = 14) with a median overall follow-up of 6.4 years. MC appears to behave clinically in a similar fashion to AC, with no statistically significant difference in biochemical failure or survival.

The utility of epithelial membrane antigen and vimentin in the diagnosis of chromophobe renal cell carcinoma.

We evaluated the immunohistochemical expression of epithelial membrane antigen (EMA) and vimentin (VMT) in chromophobe renal cell carcinoma (CHRCC). We also studied the utility of EMA and VMT immunostains in helping differentiate CHRCC from renal oncocytoma and conventional (clear cell) renal cell carcinoma with granular morphology (GCRCC). Immunohistochemical staining for EMA and VMT was performed on 21 cases of CHRCC, 16 cases of renal oncocytoma, and 28 cases of GCRCC. The diagnosis in all cases was by concurrence of all pathologists involved in the study and was based entirely on examination of routinely stained slides. All cases were classic examples of these tumor types and presented no diagnostic difficulties. The intensity of immunohistochemical staining was graded on a scale of 0 to 3 (0 = no staining; 1 = equivocal; 2 = unequivocal, moderate intensity; and 3 = unequivocal, high intensity). Positive immunohistochemical staining was defined as unequivocal staining of at least 20% of the neoplastic cells. All cases of CHRCC were positive for EMA and negative for VMT. The same immunophenotype was observed in 75% of renal oncocytoma and 21% of GCRCC. In summary, all CHRCC cases in our study demonstrated immunohistochemical staining for EMA and not VMT. However, we also found that the same immunophenotype is observed in 75% of renal oncocytoma and in 21% of GCRCC, precluding its utility for positive identification of CHRCC. Nevertheless, the lack of such an immunophenotype is a reliable indication that a neoplasm under consideration is not CHRCC.