Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. INTRODUCTION: Fragility  fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). METHODS: This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). RESULTS: Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. CONCLUSION: Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.

Sex differences of burosumab in children with X-linked hypophosphataemic rickets.

BACKGROUND: The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8 mg/kg every 2 weeks). PATIENTS AND METHODS: In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. RESULTS: We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5 years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18 mmol/L in males and 0.86 ± 0.22 mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11 mmol/L in males and 0.76 ± 0.23 mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19 mg/kg subcutaneously every 14 days (males: 0.79 ± 0.19 mg/kg; females: 0.87 ± 0.21 mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21 mmol/L) and females (1.27 ± 0.25 mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41 mg/kg to achieve a phosphate of 0.87 ± 0.11 mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79 days, the mean burosumab dose/kg in males was 1.68 ± 0.61 mg/kg, mean serum phosphate was 1.08 ± 0.23 mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6 nmol/L. CONCLUSIONS: Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses.

Mental health in children and adolescents with overweight or obesity.

BACKGROUND: Overweight and obesity represent huge concerns for children's physical and mental well-being. This study examined the relationship between body mass index (BMI) and health-related quality of life (HRQoL), somatoform complaints, and behavioral problems in children and adolescents. Additionally, the influence of sex, age, and socioeconomic status (SES) on these associations was considered. METHODS: In total, we studied 2350 participants between the ages of 4 and 18 years (1213 4- to 10-years-old (child sample) and 1137 11-to 18-year-olds (adolescent sample)). To assess HRQoL, somatoform complaints, and behavioral difficulties, we applied the KIDSCREEN-27, a short form of the Giessen Complaints Questionnaire, and the Strengths and Difficulties Questionnaire (SDQ). The BMI was transformed to BMI standard deviation scores (BMI-SDS), according to German gender- and age-specific reference data. Associations were investigated using linear regression analyses. Each association was checked for interaction with sex, age, and SES. RESULTS: Regarding HRQoL, we found worsening scores in physical well-being and psychological well-being with increasing BMI-SDS. Somatoform complaints were not significantly associated with BMI-SDS. Conduct problems, peer relationship problems, and emotional problems (the latter only in the adolescent sample) were positively associated with BMI-SDS. While we did not observe any significant interactions with sex, we found some significant interactions with age and/or SES. CONCLUSION: Our findings highlight the importance of mental difficulties in children and adolescents with higher BMI and, consequently, underline the relevance of including psychological interventions in the treatment of overweight or obesity.

A Modern Assessment of Cancer Risk in Adrenal Incidentalomas: Analysis of 2219 Patients.

OBJECTIVE: The aim of this study was to analyze the incidence of and risk factors for adrenocortical carcinoma (ACC) in adrenal incidentaloma (AI). SUMMARY OF BACKGROUND DATA: AI guidelines are based on data obtained with old-generation imaging and predominantly use tumor size to stratify risk for ACC. There is a need to analyze the incidence and risk factors from a contemporary series. METHODS: This is a retrospective review of 2219 AIs that were either surgically removed or nonoperatively monitored for ≥12 months between 2000 and 2017. Multivariate logistic regression was performed to define risk factors. ROC curves constructed to determine optimal size and attenuation cut-offs for ACC. RESULTS: 16.8% of AIs underwent upfront surgery and rest initial nonoperative management. Of conservatively managed patients, an additional 7.7% subsequently required adrenalectomy. Overall, ACC incidence in AI was 1.7%. ACC rates by size were 0.1%, 2.4%, and 19.5% for AIs of <4, 4 to 6, and >6 cm, respectively. The optimal size cut-off for ACC in AI was 4.6 cm. ACC risks by Hounsfield density were 0%, 0.5%, and 6.3% for lesions of <10, 10 to 20, and >20 HU, with an optimal cut-off of 20 HU to diagnose ACC. 15.5% of all AIs and 19.2% of ACCs were hormonally active. Male sex, large tumor size, high Hounsfield density, and >0.6 cm/year growth were independent risk factors for ACC. CONCLUSION: This contemporary analysis demonstrates that ACC risk per size in AI is less than previously reported. Given these findings, modern management of AIs should not be based just on size, but a combination of thorough hormonal evaluation and imaging characteristics.

Candidate Tidal Disruption Event AT2019fdr Coincident with a High-Energy Neutrino.

The origins of the high-energy cosmic neutrino flux remain largely unknown. Recently, one high-energy neutrino was associated with a tidal disruption event (TDE). Here we present AT2019fdr, an exceptionally luminous TDE candidate, coincident with another high-energy neutrino. Our observations, including a bright dust echo and soft late-time x-ray emission, further support a TDE origin of this flare. The probability of finding two such bright events by chance is just 0.034%. We evaluate several models for neutrino production and show that AT2019fdr is capable of producing the observed high-energy neutrino, reinforcing the case for TDEs as neutrino sources.

Immune modulating effects of receptor interacting protein 2 (RIP2) in autoinflammation and immunity.

Receptor-interacting protein 2 (RIP2) is a kinase that is involved in downstream signaling of nuclear oligomerization domain (NOD)-like receptors NOD1 and 2 sensing bacterial peptidoglycans. RIP2-deficiency or targeting of RIP2 by pharmaceutical inhibitors partially ameliorates inflammatory diseases by reducing pro-inflammatory signaling in response to peptidoglycans. However, RIP2 is widely expressed and interacts with several other proteins suggesting additional functions outside the NOD-signaling pathway. In this review, we discuss the immunological functions of RIP2 and its possible role in autoinflammation and immunity.

How Human Factors Can Help Preserve Democracy in the Age of Pandemics.

OBJECTIVE: To describe user-centered voting systems that would support the safe conduct of voting in a pandemic environment. BACKGROUND: The COVID-19 pandemic has complicated our democratic processes. Voters and poll workers feel threatened by the potential dangers of voting in business-as-usual polling stations. Indeed, significant problems were encountered in the recent 2020 primary elections in Wisconsin, where the National Guard had to be mobilized because so few poll workers reported to work, and more than 90% of polling places had to remain closed. METHOD: We describe a number of possible user-centered solutions that would help protect voters and poll workers in times of pandemic, and also report the results of a survey that asked voters and poll workers about what kinds of systems might make them willing to vote. RESULTS: Political as well as safety considerations will need to be considered as these safer voting solutions are designed since, surprisingly, the kinds of solutions preferred depend on the political affiliation of the voters. CONCLUSION: Human factors professionals have a large role to play in realizing the safe, successful implementation of these user-centered systems. Good human factors analysis can help minimize the risk to voters and poll workers. Moreover, human factors methods can help safeguard democracy by creating safe and well-engineered environments that are conducive to voting in the age of pandemics. APPLICATION: Creating safe and effective voting solutions that protect voters and poll workers during pandemic outbreaks is crucial to the preservation of democracy.

CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability.

CASP1 variants result in reduced enzymatic activity of procaspase-1 and impaired IL-1ß release. Despite this, affected individuals can develop systemic autoinflammatory disease. These seemingly contradictory observations have only partially been explained by increased NF-κB activation through prolonged interaction of variant procaspase-1 with RIP2. To identify further disease underlying pathomechanisms, we established an in vitro model using shRNA-directed knock-down of procaspase-1 followed by viral transduction of human monocytes (THP-1) with plasmids encoding for wild-type procaspase-1, disease-associated CASP1 variants (p.L265S, p.R240Q) or a missense mutation in the active center of procaspase-1 (p.C285A). THP1-derived macrophages carrying CASP1 variants exhibited mutation-specific molecular alterations. We here provide in vitro evidence for abnormal pyroptosome formation (p.C285A, p.240Q, p.L265S), impaired nuclear (pro)caspase-1 localization (p.L265S), reduced pro-inflammatory cell death (p.C285A) and changes in macrophage deformability that may contribute to disease pathophysiology of patients with CASP1 variants. This offers previously unknown molecular pathomechanisms in patients with systemic autoinflammatory disease.

cT1a Renal Masses Less Than 2 versus 2 cm or Greater Managed by Robotic Partial Nephrectomy: A Propensity Score Matched Comparison of Perioperative Outcomes.

PURPOSE: We performed a single center evaluation to compare perioperative, pathological and functional outcomes of robotic partial nephrectomy of T1a renal masses less than vs greater than 2 cm. MATERIALS AND METHODS: Propensity score 1:1 matching of queried patients was performed using the institutional robotic partial nephrectomy database from January 2007 to January 2017. Matching was done by patient age, gender, race, body mass index, the Charlson comorbidity index, smoking status, diabetes, hypertension, hyperlipidemia, ASA® (American Society of Anesthesiologists®) score, estimated glomerular filtration rate, chronic kidney disease stage and R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar line and abutting main renal artery or vein) score. We analyzed the records of 524 patients, including 262 with a renal mass less than 2 cm vs 262 with a renal mass 2 cm or greater. Perioperative, pathological and functional outcomes were evaluated. RESULTS: Smaller renal masses (less than 2 cm) were associated with significantly lower operative time, blood loss, ischemia time (mean ± SD 14.3 ± 9.58 vs 21.5 ± 9.51 minutes, p <0.001) and intraoperative transfusions (0% vs 2.7%, p = 0.015). Moreover, we found superior early renal functional outcomes as assessed by the estimated glomerular filtration rate on postoperative day 1 (mean 83.1 ± 21.3 vs 76.6 ± 22.0 mg/ml/1.73 m, p = 0.001), greater parenchymal preservation (mean 89.9% ± 9.45% vs 83.6% ± 8.20%, p <0.001) and a trend toward a lower rate of postoperative complications (13.5% vs 19.5%, p = 0.080). A higher incidence of malignancy was found in larger tumors (85.9% vs 74.8%, p = 0.002) but no difference was recorded in positive surgical margins. CONCLUSIONS: Robotic partial nephrectomy tends to be a low morbidity treatment modality for renal masses less than 2 cm. Although active surveillance is a common option for such tumors, robotic partial nephrectomy remains an alternative in select patients.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features.

PURPOSE: We determined the effect of 5α-reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. MATERIALS AND METHODS: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. RESULTS: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5α-reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5α-reductase inhibitors (p <0.01). Men on 5α-reductase inhibitors received them for a median of 23 months (IQR 6-37). On actuarial analysis there was no significant difference in grade reclassification for 5α-reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5α-reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31-1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). CONCLUSIONS: Among our cohort of men on active surveillance 5α-reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Hilar Parenchymal Oversew: a novel technique for robotic partial nephrectomy hilar tumor renorrhaphy.

INTRODUCTION: A renorrhaphy technique which is effective for hemostasis but does not place undue tension on the branch vessels of the renal sinus remains one of the challenging steps after hilar tumor resection during robotic partial nephrectomy (RPN). The published V-hilar suture (VHS) technique is one option for reconstruction after an RPN involving the hilum. The objective of this video is to show a novel renorrhaphy technique, Hilar Parenchymal Oversew that has been effective for such cases. MATERIALS AND METHODS: We present two cases of RPN for renal hilar tumors. The first case depicts use of the VHS renorrhaphy technique for a tumor that abuts the renal hilum along 20% of its diameter. The second case demonstrates tumor resection and reconstruction for a tumor that has >50% involvement of the hilum along its diameter. After tumor resection, individual sinus vessels can be selectively oversewn with 2-0 Vicryl suture on SH needle. The remaining exposed parenchyma is controlled using the Hilar Parenchymal Oversew technique with a #0 Vicryl on CT-1 needle. RESULTS: For the Hilar Parenchymal Oversew surgery operative time was 225 min, estimated blood loss was 140 ml, warm ischemia time was 19 minutes, and there were no intraoperative complications. Pathology was consistent with clear cell renal cancer with negative margins. CONCLUSION: Robotic partial nephrectomy with the Hilar Parenchymal Oversew technique is a good alternative to VHS renorrhaphy in the management of renal hilar tumors "bulging" into the renal sinus with >50% of the tumor diameter abutting the hilum.

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.

Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division.

Caspase-1 is a key player during the initiation of pro-inflammatory innate immune responses, activating pro-IL-1ß in so-called inflammasomes. A subset of patients with recurrent febrile episodes and systemic inflammation of unknown origin harbor mutations in CASP1 encoding caspase-1. CASP1 variants result in reduced enzymatic activity of caspase-1 and impaired IL-1ß secretion. The apparent paradox of reduced IL-1ß secretion but systemic inflammation led to the hypothesis that CASP1 mutations may result in variable protein interaction clusters, thus activating alternative signaling pathways. To test this hypothesis, we established and characterized an in vitro system of transduced immortalized murine macrophages expressing either WT or enzymatically inactive (p.C284A) procaspase-1 fusion reporter proteins. Macrophages with variant p.C284A caspase-1 did not secrete IL-1ß and exhibited reduced inflammatory cell death, referred to as pyroptosis. Caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) formed cytosolic macromolecular complexes (so-called pyroptosomes) that were significantly increased in number and size in cells carrying the p.C284A caspase-1 variant compared with WT caspase-1. Furthermore, enzymatically inactive caspase-1 interacted with ASC longer and with increased intensity compared with WT caspase-1. Applying live cell imaging, we documented for the first time that pyroptosomes containing enzymatically inactive variant p.C284A caspase-1 spread during cell division. In conclusion, variant p.C284A caspase-1 stabilizes pyroptosome formation, potentially enhancing inflammation by two IL-1ß-independent mechanisms: pyroptosomes convey an enhanced inflammatory stimulus through the recruitment of additional proteins (such as RIP2, receptor interacting protein kinase 2), which is further amplified through pyroptosome and cell division.

When Partial Nephrectomy is Unsuccessful: Understanding the Reasons for Conversion from Robotic Partial to Radical Nephrectomy at a Tertiary Referral Center.

PURPOSE: We sought to identify the preoperative factors associated with conversion from robotic partial nephrectomy to radical nephrectomy. We report the incidence of this event. MATERIALS AND METHODS: Using our institutional review board approved database, we abstracted data on 1,023 robotic partial nephrectomies performed at our center between 2010 and 2015. Standard and converted cases were compared in terms of patients and tumor characteristics, and perioperative, functional and oncologic outcomes. Logistic regression analysis was done to identify predictors of radical conversion. RESULTS: The overall conversion rate was 3.1% (32 of 1,023 cases). The most common reasons for conversion were tumor involvement of hilar structures (8 cases or 25%), failure to achieve negative margins on frozen section (7 or 21.8%), suspicion of advanced disease (5 or 15.6%) and failure to progress (5 or 15.6%). Patients requiring conversion were older and had a higher Charlson score (both p <0.01), including an increased prevalence of chronic kidney disease (p = 0.02). Increasing tumor size (5 vs 3.1 cm, p <0.01) and R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and hilar location) score (9 vs 8, p <0.01) were also associated with an increased risk of conversion. Worse baseline renal function (OR 0.98, 95% CI 0.96-0.99, p = 0.04), large tumor size (OR 1.44, 95% CI 1.22-1.7, p <0.01) and increasing R.E.N.A.L. score (p = 0.02) were independent predictors of conversion. Compared to converted cases, at latest followup standard robotic partial nephrectomy cases had similar short-term oncologic outcomes but better renal functional preservation (p <0.01). CONCLUSIONS: At a high volume center the rate of robotic partial nephrectomy conversion to radical nephrectomy was 3.1%, including 2.2% of preoperatively anticipated nephrectomy cases. Increasing tumor size and complexity, and poor preoperative renal function are the main predictors of conversion.

Do Renin-Angiotensin Blockers Affect Renal Function and Cardiac Outcomes in Patients Undergoing Partial Nephrectomy?

PURPOSE: Currently no data exist to guide renal surgeons on the perioperative use of renin-angiotensin blockers despite potential cardiorenal benefits. We aimed to assess the impact of resuming renin-angiotensin blockers on postoperative renal function and adverse cardiac events following partial nephrectomy. MATERIALS AND METHODS: This is an observational analysis of patients who underwent robot-assisted laparoscopic partial nephrectomy from 2006 to 2014 at a single institution. The Wilcoxon rank sum and chi-square tests, and logistic regression were used to assess the risk of adverse renal and cardiac events stratified by history and pattern of renin-angiotensin blockade perioperatively. RESULTS: We identified 900 patients with a median followup of 16.3 months (IQR 1.4-39.1). There were no significant differences in severe renal dysfunction at last followup on univariate analysis or adverse cardiac events at 30 days on multivariate analysis in patients stratified by a history of renin-angiotensin blockade. Of the 338 patients 137 (41.9%) resumed renin-angiotensin blockade immediately after surgery, which did not result in any significant difference in the postoperative glomerular filtration rate (p >0.05). Resuming renin-angiotensin blockade at discharge home was associated with a decreased risk of heart failure within 30 days of surgery (0.3% vs 11.8% of cases) and stage IV/V chronic kidney disease at last followup (2.6% vs 25.5%, each p <0.001). CONCLUSIONS: Renin-angiotensin blockers appear safe to continue immediately after renal surgery. Discharge home with angiotensin converting enzyme inhibitors/angiotensin receptor blockers was associated with a decreased risk of heart failure and severe renal dysfunction. However, this risk may be overstated as a result of the small number of patients discharged without resuming the home medication.

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance.

PURPOSE: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. MATERIALS AND METHODS: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1-80.3). Time to event analysis was performed for our clinical end points. RESULTS: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10-year all cause survival was 98% and 94%, respectively. Cumulative metastasis-free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5-year progression-free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. CONCLUSIONS: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

Optimum outcome achievement in partial nephrectomy for T1 renal masses: a contemporary analysis of open and robot-assisted cases.

OBJECTIVES: To compare optimum outcome achievement in open partial nephrectomy (OPN) with that in robot-assisted partial nephrectomy (RAPN). PATIENTS AND METHODS: Using our institutional partial nephrectomy (PN) database, we reviewed 605 cases performed for unifocal clinical T1 renal masses in non-solitary kidneys between 2011 and 2015. Tetrafecta, which was defined as negative surgical margins, freedom from peri-operative complications, ≥80% renal function preservation, and no chronic kidney disease upstaging, was chosen as the composite optimum outcome. Factors associated with tetrafecta achievement were assessed using multivariable logistic regression, with adjustment for age, gender, race, Charlson comorbidity score, body mass index, chronic kidney disease, tumour size, tumour complexity and approach. RESULTS: The overall tetrafecta achievement rate was 38%. Negative margins, freedom from complications, and optimum functional preservation were achieved in 97.1%, 73.6% and 54.2% of cases, respectively. For T1a masses, the tetrafecta achievement rate was similar between approaches (P = 0.97), but for T1b masses, the robot-assisted approach achieved significantly higher tetrafecta rates (43.0% vs 21.3%; P < 0.01). On multivariable analysis, the robot-assisted approach had 2.6-fold higher odds of tetrafecta achievement than the open approach, primarily because of lower peri-operative morbidity, specifically related to wound complications. Positive surgical margin rates and renal function preservation were similar in the two approaches. CONCLUSIONS: Optimum outcomes are readily achieved regardless of PN approach. The robot-assisted approach may facilitate optimum outcome achievement for 4-7-cm masses by minimizing wound complications.

Robot-assisted approach improves surgical outcomes in obese patients undergoing partial nephrectomy.

OBJECTIVES: To assess the impact of approach on surgical outcomes in otherwise healthy obese patients undergoing partial nephrectomy for small renal masses. PATIENTS AND METHODS: Using our institutional partial nephrectomy database, we abstracted data on otherwise healthy (Charlson comorbidity score ≤1 and bilateral kidneys), obese patients (body mass index >30 kg/m2 ) with small renal masses (<4 cm) treated between 2011 and 2015. The primary outcomes were intra-operative transfusion, operating time, length of hospital stay (LOS), and postoperative complications. The association between approach, open (OPN) vs robot-assisted partial nephrectomy (RAPN), and outcomes was assessed by univariable and multivariable logistic regression analyses. Covariates included age, gender, obesity severity, tumour size and tumour complexity. RESULTS: Of 237 obese patients undergoing partial nephrectomy, 25% underwent OPN and 75% underwent RAPN. Apart from larger tumour size in the OPN group (2.8 vs 2.5 cm; P = 0.02), there was no significant difference between groups. The rate of intra-operative blood transfusion (1.1 vs 10%; P = 0.01), the median operating time (180 vs 207 min; P < 0.01) and the median ischaemia time (19.5 vs 27 min; P < 0.01) were all greater for OPN. The LOS was significantly shorter for RAPN (3 vs 4 days; P < 0.01). While the overall complication rate was higher for OPN (15.8 vs 31.7%; P < 0.01), major complications were not significantly different (5.6 vs 1.7%; P = 0.20). On multivariable analyses, OPN independently predicted longer operating time, longer length of stay, and more overall complications. CONCLUSIONS: At a high-volume centre, the robot-assisted approach offers less blood transfusion, shorter operating time, faster recovery, and fewer peri-operative complications compared with the open approach in obese patients undergoing partial nephrectomy for small renal masses. In this setting, RAPN may be a preferable treatment option.

Assessing the effects of modality of surgery on postoperative weight loss in patients undergoing partial nephrectomy.

PURPOSE: To compare the early BMI changes postoperatively between patients undergoing open partial nephrectomy (OPN) and robotic partial nephrectomy (RPN). METHODS: Patients undergoing open NSS for a single renal tumor between 2010 and 2013 were retrospectively selected for the study. These patients were matched with RPN patients based on preoperative BMI and tumor R.E.N.A.L nephrometry score (1:1 matching). RESULTS: A total of 568 patients (284 pairs) met our inclusion criteria. The median time to lowest BMI was comparable between the OPN and RPN groups (24 vs. 29 days; p = 0.7). The mean BMI preservation was lower for the OPN group (96.8 ± 4.4 vs. 98.1 ± 4.7 %). On multivariable analysis after controlling for age, CCI, gender, tumor size, nephrometry score, estimated blood loss, occurrence of major complications and preoperative renal function, the modality of surgery favoring the RPN approach and the occurrence of major complications remained significant predictors for BMI preservation after surgery. CONCLUSIONS: Occurrence of major complications is associated with weight loss after NSS. Minimally invasive NSS delivered by RPN had lower impact on BMI loss in patients undergoing the procedure compared to OPN. This finding further suggests that RPN delivers minimally invasive surgery beyond the boundaries of just smaller incision sites.

Robot-assisted ureteral reconstruction using a tubularized peritoneal flap: a novel technique in a chronic porcine model.

OBJECTIVE: To evaluate the feasibility and functional outcomes in porcine models of a novel robotic surgical technique for the treatment of complex ureteral injuries and strictures. MATERIALS AND METHODS: Six pigs underwent robotic ureteral reconstruction using a long tabularized peritoneal flap and followed for 6-9 weeks after the surgery. Ureteral flap vascularity, intra-renal pressure, patency of the conduct, endoscopic aspect of the flap, renal function and histopathology were evaluated. RESULTS: All animals successfully underwent ureteral reconstruction using a tubularized peritoneal flap. Median operative time was 223 min (162-360). Flap tubularization suture took 31 min (19-47), and proximal anastomosis took 20 min (15-38). Bladder mobilization with psoas hitch and distal anastomosis took 9 min (7-12) and 23 min (13-46), respectively. On follow-up, significant shrinkage of the ureteral flap in both length and width was observed. Antegrade pyelograms confirmed dilation and tortuosity of the proximal ureter, dilation of the renal pelvis, and major and minor calyxes without any definitive strictures. Microscopically, focal urothelial lining was seen in the neoureter. Creatinine level was significantly higher at the end of the follow-up period (p = 0.003). CONCLUSIONS: Robot-assisted ureteral reconstruction using a tubularized peritoneum flap is technically feasible and reproducible. The flap sustained abundant vascular supply after different intervals of follow-up and the peritoneal mesenchymal cells differentiated into urothelium and myofibroblasts. Further studies are needed to address the issue of functional obstruction to improve long-term renal function outcomes.