Severe hypertensive flare-up after intravitreal injection of ranibizumab for retinal venous branch occlusion.

Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of angiogenesis. Systemic adverse effects of some anti-VEGF include hypertension, proteinuria and cardiovascular complications which could involve lower systemic VEGF levels. However, the question regarding intravitreal administration of anti-VEGF remains controversial given that the patients receiving these drugs are often elderly and present cardiac risk factors such as arterial hypertension or atrial fibrillation. We report a case of hypertensive flare-up following intravitreal injection of ranibizumab for retinal vein occlusion. The outcome was favourable after adapted antihypertensive treatment. This case report adds to the growing body of evidence suggesting that intravitreal administration of anti-VEGF, regardless of agents, may result in hypertensive episodes in some predisposed patients. Listing this adverse effect should help to minimize risks by heightening clinician and patient awareness and to improve blood pressure monitoring following the intravitreal administration of anti-VEGF agents.

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer.

BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.

Electrostatic Deposition of Large-Surface Graphene.

This work describes a method for electrostatic deposition of graphene over a large area using controlled electrostatic exfoliation from a Highly Ordered Pyrolytic Graphite (HOPG) block. Deposition over 130 × 130 µm² with 96% coverage is achieved, which contrasts with sporadic micro-scale depositions of graphene with little control from previous works on electrostatic deposition. The deposition results are studied by Raman micro-spectroscopy and hyperspectral analysis using large fields of view to allow for the characterization of the whole deposition area. Results confirm that laser pre-patterning of the HOPG block prior to cleaving generates anchor points favoring a more homogeneous and defect-free HOPG surface, yielding larger and more uniform graphene depositions. We also demonstrate that a second patterning of the HOPG block just before exfoliation can yield features with precisely controlled geometries.

Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity.

OBJECTIVES: Obesity, typically defined as a body mass index (BMI)≥30kg/m2, is an established risk factor for renal cell carcinoma (RCC) but is paradoxically linked to less advanced disease at diagnosis and improved outcomes. However, BMI has inherent flaws, and alternate obesity-defining metrics that emphasize abdominal fat are available. We investigated 3 obesity-defining metrics, to better examine the associations of abdominal fat vs. generalized obesity with renal tumor stage, grade, or R.E.N.A.L. nephrometry score. METHODS AND MATERIALS: In a prospective cohort of 99 subjects with renal masses undergoing resection and no evidence of metastatic disease, obesity was assessed using 3 metrics: body mass index (BMI), radiographic waist circumference (WC), and retrorenal fat (RRF) pad distance. R.E.N.A.L. nephrometry scores were calculated based on preoperative CT or MRI. Univariate and multivariate analyses were performed to identify associations between obesity metrics and nephrometry score, tumor grade, and tumor stage. RESULTS: In the 99 subjects, surgery was partial nephrectomy in 51 and radical nephrectomy in 48. Pathology showed benign masses in 11 and RCC in 88 (of which 20 had stage T3 disease). WC was positively correlated with nephrometry score, even after controlling for age, sex, race, and diabetes status (P = 0.02), whereas BMI and RRF were not (P = 0.13, and P = 0.57, respectively). WC in stage T2/T3 subjects was higher than in subjects with benign masses (P = 0.03). In contrast, subjects with Fuhrman grade 1 and 2 tumors had higher BMI (P<0.01) and WC (P = 0.04) than subjects with grade 3 and 4 tumors. CONCLUSIONS: Our data suggest that obesity measured by WC, but not BMI or RRF, is associated with increased renal mass complexity. Tumor Fuhrman grade exhibited a different trend, with both high WC and BMI associated with lower-grade tumors. Our findings indicate that WC and BMI are not interchangeable obesity metrics. Further evaluation of RCC-specific outcomes using WC vs. BMI is warranted to better understand the complex relationship between general vs. abdominal obesity and RCC characteristics.

Prevalence and bother of patient-reported lower urinary tract symptoms in the muscular dystrophies.

INTRODUCTION: Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) are characterized by progressive muscle weakness and eventual loss of ambulation, and result from mutations in the dystrophin gene. Dystrophin is essential for skeletal muscle functioning but its role in smooth muscle function is not as well established. In a retrospective review, our group previously demonstrated that roughly half of these patients have at least one documented urologic diagnosis, most commonly being lower urinary tract symptoms (LUTS) and nephrolithiasis. To better understand the frequency of LUTS and the degree to which they impact quality of life in this patient population, we performed a cross-sectional evaluation. METHODS AND MATERIALS: Following IRB approval, a survey modified from multiple validated surveys was distributed to DMD and BMD patients. The survey contained questions derived from multiple validated questionnaires, including the American Urological Association Symptom Score and the Dysfunctional Voiding Symptoms Score, which assessed both the frequency of lower urinary tract symptoms (i.e. urinary urgency, frequency, enuresis, dysuria, and bowel function) as well as how bothersome patients found these symptoms. RESULTS: Of the 56 respondents (mean age 15.3; range 4-33), 40 (71.4%) reported at least one LUTS, most commonly urgency (n = 31, 55%) and hesitancy of stream (n = 32, 57%) (Figure). Although the majority of the patients reported being happy with their symptoms, 16% (n = 9) expressed dissatisfaction. We did not find any correlation between LUTS and disease progression, as measured by years non-ambulatory, on chi-square analysis. CONCLUSIONS: In this cross-sectional study of the frequency and degree of bother of LUTS in D/BMD patients, we found that a high percentage experience LUTS. Despite this high prevalence, the majority report that they are not especially bothered by these symptoms; however, over 16% express dissatisfaction with their current LUTS. With this patient population now living longer, this may become even more prevalent. Screening for bothersome LUTS in patients with DMD and BMD should be a part of disease management, with appropriate treatment or referral to a urologist for those bothered by their symptoms to positively impact their quality of life.

Measuring and Predicting Patient Dissatisfaction after Anterior Urethroplasty Using Patient Reported Outcomes Measures.

PURPOSE: Subjective measures of success after urethroplasty have become increasingly valuable in postoperative monitoring. We examined patient reported satisfaction following anterior urethroplasty using objective measures as a proxy for success. MATERIALS AND METHODS: Men 18 years old or older with urethral strictures undergoing urethroplasty were prospectively enrolled in a longitudinal, multi-institutional urethroplasty outcomes database. Preoperative and postoperative assessment included questionnaires to assess lower urinary tract symptoms, pain, satisfaction and sexual health. Analyses controlling for stricture recurrence (defined as the inability to traverse the reconstructed urethra with a flexible cystoscope) were performed to determine independent predictors of dissatisfaction. RESULTS: At a mean followup of 14 months we found a high 89.4% rate of overall postoperative satisfaction in 433 patients and a high 82.8% rate in those who would have chosen the operation again. Men with cystoscopic recurrence were more likely to report dissatisfaction (OR 4.96, 95% CI 2.07-11.90) and men reporting dissatisfaction had significantly worse uroflowmetry measures (each p <0.02). When controlling for recurrence, multivariate analysis revealed that urethra and bladder pain (OR 1.71, 95% CI 1.05-2.77 and OR 2.74, 95% CI 1.12-6.69, respectively), a postoperative decrease in sexual activity (OR 4.36, 95% CI 2.07-11.90) and persistent lower urinary tract symptoms (eg straining to urinate OR 3.23, 1.74-6.01) were independent predictors of dissatisfaction. CONCLUSIONS: Overall satisfaction after anterior urethroplasty is high and traditional measures of surgical success strongly correlate with satisfaction. However, independently of the anatomical appearance of the reconstructed urethra, postoperative pain, sexual dysfunction and persistent lower urinary tract symptoms were predictors of patient dissatisfaction.

Functional Conservation in the SIAMESE-RELATED Family of Cyclin-Dependent Kinase Inhibitors in Land Plants.

The best-characterized members of the plant-specific SIAMESE-RELATED (SMR) family of cyclin-dependent kinase inhibitors regulate the transition from the mitotic cell cycle to endoreplication, also known as endoreduplication, an altered version of the cell cycle in which DNA is replicated without cell division. Some other family members are implicated in cell cycle responses to biotic and abiotic stresses. However, the functions of most SMRs remain unknown, and the specific cyclin-dependent kinase complexes inhibited by SMRs are unclear. Here, we demonstrate that a diverse group of SMRs, including an SMR from the bryophyte Physcomitrella patens, can complement an Arabidopsis thaliana siamese (sim) mutant and that both Arabidopsis SIM and P. patens SMR can inhibit CDK activity in vitro. Furthermore, we show that Arabidopsis SIM can bind to and inhibit both CDKA;1 and CDKB1;1. Finally, we show that SMR2 acts to restrict cell proliferation during leaf growth in Arabidopsis and that SIM, SMR1/LGO, and SMR2 play overlapping roles in controlling the transition from cell division to endoreplication during leaf development. These results indicate that differences in SMR function in plant growth and development are primarily due to differences in transcriptional and posttranscriptional regulation, rather than to differences in fundamental biochemical function.

Urologic and gastrointestinal symptoms in the dystroglycanopathies.

OBJECTIVE: To determine the frequency of urologic and gastrointestinal (GI) symptoms in a cohort of individuals with dystroglycanopathy compared with healthy household controls. METHODS: Participants in a North American dystroglycanopathy natural history study (NCT00313677) and other members of their households completed a questionnaire modified from validated instruments and clinical criteria. Urologic and GI symptom frequency, effect on patient life, and medications taken for these symptoms were assessed. Those younger than 4 years or not toilet trained were excluded. Healthy human bladder, esophagus, and duodenum from surgical specimens were immunostained for glycosylated α-dystroglycan. RESULTS: Thirty of 58 potential participants with dystroglycanopathy (51.7%) and 16 household controls participated. Subjects were aged 6 to 51 years (mean 26.7); 60.0% were female. Controls were aged 7 to 55 years (mean 34.6); 56.3% were female. The dystroglycanopathy cohort had higher frequency of urinary voiding symptoms (p = 0.02), higher urologic symptom scores (p = 0.05), and higher dysphagia symptom scores (p = 0.04). A correlation existed between urologic symptom score and effect on life (r = 0.71; 95% confidence interval 0.46, 0.85; p < 0.0001) and between dysphagia symptom score and effect on life (r = 0.72; 95% confidence interval 0.48, 0.86; p < 0.0001). Glycosylated α-dystroglycan was present in visceral smooth muscle of all normal tissues analyzed. CONCLUSIONS: Urologic symptoms and dysphagia are reported more frequently by individuals with dystroglycanopathies than by household controls. These symptoms can cause a perceived negative effect on patient life. Our results suggest urologic and GI dysfunction may be part of the dystroglycanopathy phenotype, and that questions about these symptoms should be incorporated into routine care because they may influence medical management.

Lower urinary tract pain and anterior urethral stricture disease: prevalence and effects of urethral reconstruction.

PURPOSE: Anterior urethral stricture disease most commonly presents as urinary obstruction. Lower urinary tract pain is not commonly reported as a presenting symptom. We prospectively characterized lower urinary tract pain in association with urethral stricture disease and assessed the effects of urethroplasty on this pain. MATERIALS AND METHODS: Men (18 years old or older) with anterior urethral stricture disease were prospectively enrolled in a longitudinal, multi-institutional, urethral reconstruction outcomes study from June 2010 to January 2013 as part of TURNS (Trauma and Urologic Reconstruction Network of Surgeons). Preoperative and postoperative lower urinary tract pain was assessed by the validated CLSS. Voiding and sexual function was assessed using validated patient-reported measures, including I-PSS. RESULTS: Preoperatively 118 of 167 men (71%) reported urethral pain and 68 (41%) reported bladder pain. Age was the only predictor of urethral pain with men 40 years or younger reporting more pain than those 60 years old or older (81% vs 58%, p = 0.0104). Lower urinary tract pain was associated with worse quality of life and overall voiding symptoms on CLSS and I-PSS (each p <0.01). Postoperatively lower urinary tract pain completely resolved in 64% of men with urethral pain and in 73.5% with bladder pain. There were no predictive factors for changes in lower urinary tract pain after urethral reconstruction. CONCLUSIONS: Lower urinary tract pain is common in urethral stricture disease, especially in younger men. It is associated with worse quality of life and voiding function. In most men lower urinary tract pain resolves after urethral reconstruction.