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Selecting study endpoints in prospective cancer cachexia trials remains poorly defined. The aim of this study was to further evaluate associations in changes in weight, body composition, functional outcomes, and patient-reported outcomes (PROs) in patients with metastatic cancer. We completed a 2-year (2016–2018) observational study in patients with metastatic solid cancer and ECOG performance status 0 to 2 while receiving chemotherapy and/or immunotherapy. We completed assessments at study enrollment and 3 months from enrollment. We analyzed longitudinal changes in weight and body composition using validated methods. Functional assessments included the 6-Min Walk Test, Timed Up and Go Test, and Short Physical Performance Battery. PROs included the Functional Assessment of Anorexia/Cachexia Therapy and Functional Assessment of Cancer Therapy Fatigue. We analyzed changes in body composition and functional assessment using paired t tests. Additionally, we utilized linear regression models to assess relationships between changes in body composition and function outcomes and PROs, adjusting for age and sex. A total of 57 patients completed baseline assessments, but 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data, the mean age was 61.8 years and 47% were female. Metastatic cancer types included 71% gastrointestinal, 13% lung, and 8% gynecologic. Half received chemotherapy, 16% immunotherapy, and 34% a combination. From enrollment to 3 months, we did not observe a change in weight or skeletal muscle but did find an increase in total adipose tissue (16.9 ± 52.4 cm2, 95% CI − 33.79–0.63; p = 0.059; ~ 1.5 pounds). We did not observe any association with changes in weight with any functional outcomes or PROs. However, greater losses in skeletal muscle were associated with greater declines in physical function (6-Min Walk Test [B = 0.04, p = 0.01], Short Physical Performance Battery [B = 2.44, p

Purpose To evaluate the clinical outcome of patients with non–small-cell lung cancer treated by targeting low variant allelic frequency (VAF) driver mutations identified through cell-free DNA (cfDNA) next-generation sequencing (NGS). Detection of driver mutations in cancer is critically important in the age of targeted therapy, where both tumor-based as well as cfDNA sequencing methods have been used for therapeutic decision making. We hypothesized that VAF should not be predictive of response and that low VAF alterations detected by cfDNA NGS can respond to targeted therapy. Patients and Methods A multicenter retrospective case review was performed to identify patients with non–small-cell lung cancer who received targeted molecular therapy on the basis of findings of low VAF alterations in cfDNA NGS. Mutations at low VAF were defined as < 0.2% mutated cfDNA molecules in a background of wild-type cfDNA. Results One hundred seventy-two patients underwent cfDNA NGS testing. Of the 172 patients, 12 were identified as having low VAF driver alterations and were considered for targeted therapy. The median progression-free survival (PFS) for all patients was 52 weeks (range, 17 to 88 weeks). For patients with EGFR exon 19 deletion (n = 7), the median PFS was 52 weeks (range, 17 to 60.5 weeks). For patients with EML4-ALK fusions (n = 3), the median PFS was 60 weeks (range, 18 to 88 weeks). The median overall survival for all patients after diagnosis was 57.6 weeks. Conclusion Targeted treatment response for driver mutations detected by cfDNA may be independent of VAF, even in relation to other higher VAF aberrations in plasma, and directly dependent on the underlying disease biology and ability to treat the patient with appropriate targeted therapy.

Acute myeloid leukemia (AML), which is the most common acute adult leukemia and the second most common pediatric leukemia, still has a poor prognosis. Human C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90% of AML patient myeloid blasts and in leukemic stem cells. Here, we describe the synthesis of a novel bispecific antibody, αCLL1-αCD3, using the genetically encoded unnatural amino acid, p-acetylphenylalanine. The resulting αCLL1-αCD3 recruits cytotoxic T cells to CLL1 positive cells, and demonstrates potent and selective cytotoxicity against several human AML cell lines and primary AML patient derived cells in vitro. Moreover, αCLL1-αCD3 treatment completely eliminates established tumors in an U937 AML cell line xenograft model. These results validate the clinical potential of CLL1 as an AML-specific antigen for the generation of a novel immunotherapeutic for AML.

Colonoscopic perforation is a rare complication. We sought to determine its risk factors in patients with inflammatory bowel disease (IBD).The study group consisted of 19 IBD patients who had perforation secondary to diagnostic or therapeutic colonoscopy from January 2002 to October 2010. The control group consists of 76 IBD patients undergoing colonoscopy and no perforations that were matched based on indication in a 4:1 ratio to the study group. Demographic and clinical variables as well as perforation outcomes were analyzed by univariate and multivariate analyses.There were a total of 5295 colonoscopies done during the study period in IBD patients of which 19 patients had perforation. The prevalence of perforation in IBD patients was 0.3%. Of the 19 patients, 12 had Crohn's disease (CD) and 7 had ulcerative colitis (UC). Patients in the perforation group were more likely treated with steroids (68.4% vs. 21.1%, p0.001) and had severe disease on endoscopy (31.6% vs. 10.1%, p=0.03) than that in the control groups. On multivariate analysis, severe disease on endoscopy (adjusted odds ratio [aOR]=3.82, 95% confidence interval [CI]=1.03-15.24) and steroid treatment (aOR=7.68; 95% CI=1.48, 39.81) were independently associated with the risk of perforation. The median length of stay in the perforation group was 10 days (range 2-23 days). There was no mortality in our study.There appears to be a higher risk of colonoscopy-associated perforation in IBD patients with active disease and on steroids.

Study Type – Therapy (case control) Level of Evidence 3b What's known on the subject? and What does the study add? Angiotensin II is the main effector peptide in the bladder local renin-angiotensin system. This experiment demonstrates the role of this local renin-angiotensin system with respect to bladder outlet obstruction. OBJECTIVE • To determine if treatment with an angiotensin II type 1 (AT-1) receptor antagonist, losartan, can prevent the structural and functional changes that occur in a mouse model of bladder outlet obstruction (BOO). MATERIALS AND METHODS • Twenty-four Balb/CAN mice underwent partial urethral obstruction for 6 weeks. • Twelve mice were given oral losartan (10 mg/kg/day), and 12 were not. Six mice served as unobstructed controls, and six unobstructed mice were given oral losartan (10 mg/kg/day) to determine the effect of angiotensin II inhibition on the normal bladder. • Bladder capacity (C), detrusor pressure during voiding (Pdet) and volume at first non-voiding contraction (NVC1) as a percentage of C were recorded after 6 weeks. • Bladders were stained with haematoxylin and eosin for measurement of detrusor muscular thickness, and graded as 1 = atrophy ( 200 µm thick) compared with controls. RESULTS • Compared with controls, BOO mice had greater C (153.5 ± 20.9 vs 57.5 ± 7.4 µl, P < 0.01), higher Pdet (28.8 ± 2.1 vs 12.1 ± 2.1 mm Hg), lower NVC1 (median = 24% vs 54% P= 0.03). BOO mice manifested greater bladder weight (93.2 ± 11.7 mg vs 26.8 ± 2.40 mg, P < 0.01) and greater detrusor muscle thickness (median 3 vs 2, P= 0.02). • Compared with untreated BOO mice, mice treated with losartan had greater mean C (248.8 ± 28.6 vs 153.5 ± 20.9 µL, P= 0.01), no significant change in mean Pdet (24.7 ± 1.6 vs 28.8 ± 2.1 mm Hg, P= 0.2) and a higher mean NVC1 (47% vs 24%, P= 0.02). • Treatment with losartan mediated an insignificant reduction in mean bladder weight (68.1 ± 9.1 mg vs 93.2 ± 11.7 mg, P= 0.10), but a significant reduction in detrusor muscle thickness (median 2 vs 3, P= 0.02). Losartan did not mediate any significant structural or functional changes in the unobstructed mouse bladder. CONCLUSION • In a mouse model of BOO, treatment with an AT-1 antagonist partially prevented the urodynamic and structural changes that otherwise occur with BOO.

208 Background: Despite multiple cancer cachexia (CC) trials evaluating novel agents, the FDA has not approved a single drug to date. One key challenge in CC trials is selection of endpoints. The aim of this study was to explore changes in body composition and associations with functional and patient-reported outcomes (PROs) to clarify CC trial endpoint selection. Methods: We identified metastatic solid tumor cancer patients receiving cancer-directed therapies at a single cancer center (2016-2018). Patients completed all assessments at study enrollment and 3 months from enrollment. We analyzed body composition utilizing cross-sectional computed tomography (CT) scans at the third lumbar vertebra. Functional assessments included the 6-minute walk test (6MWT), Timed Up-and-Go (TUG) test, and Short Physical Performance Battery (SPPB). PROs included the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) and Functional Assessment of Cancer Therapy Fatigue (FACT-F). We examined changes in body composition and functional assessments from enrollment to 3 months using paired t-tests. We utilized linear regression models to assess the relationship between changes in body composition and changes in functional assessment adjusting for age and sex. Results: A total of 57 patients completed baseline assessments; 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data (mean age 61.8 years, 47% female, 71% GI malignancy), 50% received chemotherapy, 16% immunotherapy, and 34% combination therapy. From enrollment to 3 months, we observed an increase in total adipose tissue (16.9±52.4 cm2, 95% CI -33.79-0.63; p = 0.059), but not weight or skeletal muscle. Greater losses in skeletal muscle were associated with greater declines in 6MWT (B = 0.036, p = 0.014) and SBBP (B = 2.444, p = 0.002), but not the TUG. We observed no association with change in weight with all functional outcomes or PROs. Moreover, we found no association with body composition and PROs from enrollment to 3 months. Conclusions: In future CC trials, changes in longitudinal body composition rather than weight should be utilized. Furthermore, changes in skeletal muscle and the 6MWT and/or SBBP may be preferred endpoints.

209 Background: Given body composition predicts toxicity for patients receiving cytotoxic chemotherapy, we explored changes in body composition and biomarkers as predictors of immune-related adverse events (irAEs) and health care utilization. Methods: We conducted a longitudinal study of patients with metastatic solid tumor receiving immunotherapy (07/2014-10/2017). Eligible patients had a computed tomography (CT) scan prior to first-line immunotherapy with at least two additional CT scans at three, six or nine months after immunotherapy initiation. We analyzed body composition using cross-sectional CT scans at the third lumbar vertebra. We utilized mixed effect linear regression models to assess longitudinal changes in body composition (weight, skeletal muscle, total adipose). We examined associations of baseline body composition and biomarkers (albumin, neutrophil-lymphocyte ratio (NLR)) with the incidence of irAEs and healthcare utilization (hospitalizations/ED visits) using logistic regression. Results: Of 140 patients treated with immunotherapy, 61 met inclusion criteria. The majority (80%) received prior chemotherapy and the most common malignancies included lung (26%), head and neck (20%), and melanoma (20%). We found that one-third (n=19) experienced an irAE and colitis (53%) was the most common irAE. Patients experienced substantial weight loss over time (B= -1.88, p

Aims Bladder outlet obstruction (BOO) can mediate structural and functional detrusor changes, which can lead to bothersome lower urinary tract symptoms. We investigate if sacral nerve stimulation (SNS) can prevent these structural and functional changes in a rat model of BOO. Methods 24 female Sprague-Dawley rats (250 gm) were divided into 4 groups: control (CTRL), BOO, SNS, and both (BOO/SNS). BOO was achieved by partially occluding the proximal urethra. SNS involved stimulating the S1–S4 dorsal roots with a unipolar S1 lead, 8 hours daily. Urodynamics were performed at baseline and after 6 weeks. Bladders were harvested, stained, and scored for detrusor hypertrophy and fibrosis (scale = 1–5). Results BOO caused an increase in mean voiding pressure (Pdet = 35 ± 2 mmHg vs. 23 ± 1 mmHg, p = 0.02), an increase in mean bladder capacity (C = 1230 ± 250 μl vs. 484 ± 60 μl, p = 0.03), and a decrease in mean volume at first non-voiding contraction (67 ± 16 μl vs. 110 ± 24 μl, p = 0.02) compared to CTRL. Addition of SNS neither significantly affected Pdet (30 ± 3 mm Hg vs. 35 ± 2 mmHg, p = 0.2), nor C (630 ± 90 μl vs. 1230 ± 250 μl, p = 0.06) compared to BOO, but eliminated non-voiding contractions. Detrusor hypertrophy and fibrosis were both significantly greater in BOO vs. CTRL and vs. BOO/SNS. Conclusions Partial BOO caused functional and structural changes in the rat bladder. SNS in obstructed rats prevents these alterations, without adversely affecting detrusor contractility. Neurourol. Urodynam. 29:783–788, 2010. © 2010 Wiley-Liss, Inc.

To investigate if sildenafil citrate can inhibit the functional and structural changes of the detrusor in a murine model of bladder outlet obstruction (BOO). Phosphodiesterase type 5 (PDE-5) inhibitors have recently been used for treating urinary symptoms associated with prostatic obstruction, but it is unclear whether PDE-5 inhibition acts on the prostatic urethra or the bladder.In 18 male Balb/CAN mice, partial BOO was created and the mice allowed to survive for 6 weeks. Half of the mice (nine) were treated with oral sildenafil citrate daily (10 mg/kg) by oral lavage (BOO + V), and half (nine) were not (BOO). Six mice were used as sham-operated controls and received no sildenafil. The mice were assessed by urodynamics at baseline and after 6 weeks, with a measurement of volume at first uninhibited non-voiding contraction (V(DO1)), bladder capacity (BC), and detrusor pressure during void (Pdet). At 6 weeks, bladders were harvested, fixed and sectioned, and stained with haematoxylin and eosin (HE) and trichrome stain. Detrusor muscle hypertrophy and fibrosis were evaluated on a scale of 1 (decreased) to 3 (increased), by two urologists and one pathologist unaware of the treatment group; the results were compared with those from normal controls.BOO mice had a significantly greater BC than control mice, with a mean (SD) of 153 (66) vs 58 (13) microL (P = 0.004). Treatment with sildenafil did not significantly alter BC. BOO caused an increase in Pdet compared to controls, with a mean (SD) of 25 (7) vs 12 (5) cm H2O. P(det) was not significantly different after treatment with sildenafil. The median V(DO1) as a percentage of BC was significantly lower in BOO than in control mice (20% vs 53%, P0.03) and increased significantly after sildenafil treatment (20% vs 44%, P = 0.04). BOO was associated with a greater bladder weight than in control mice, with a mean (SD) of 89 (32) vs 27 (6) mg (P = 0.001), which was decreased with sildenafil treatment, to 40 (14) vs 89 (32) mg (P = 0.013). BOO caused an increase in detrusor muscular hypertrophy vs control mice, with a median HE score of 3 vs 2 (P = 0.01) and an increase in fibrosis vs control mice, with a median trichrome score of 3 vs 2 (P = 0.01). BOO + V mice had reduced muscular hypertrophy and fibrosis, with a median HE score of 3 vs 2 (P = 0.01) and a median trichrome score of 3 vs 1 (P = 0.01).BOO mediates both functional and structural changes in the mouse bladder. Six weeks of obstruction caused an increase in BC, detrusor overactivity and voiding pressure, and mediated an increase in bladder weight, detrusor muscle hypertrophy and collagen deposition in the lamina propria and smooth muscle. Treatment with 6 weeks of oral sildenafil beginning at the time of BOO prevented the increase in detrusor overactivity without affecting voiding pressures, and prevented the increase in detrusor muscle hypertrophy and collagen deposition that otherwise occurred with BOO. It appears therefore that sildenafil citrate acts on the bladder rather than on the outlet.

Objectives Ischemia/reperfusion injury is a leading cause of renal damage which can be improved with antisense oligonucleotide gene therapy. We have shown that polyethylene glycol (PEG) hydrogel, which also functions as a tissue sealant, is an effective topical delivery vehicle for oligonucleotides in a murine partial nephrectomy model. The objective of this study was to use and evaluate this method against intercellular adhesion molecule-1 ( ICAM-1 ) to prevent tissue damage. Methods Sixty mice underwent left upper pole partial nephrectomy with 45 minutes of warm ischemia, randomized to treatment with 50 μg ICAM-1 antisense oligonucleotides embedded in PEG hydrogel, no therapy, or sham surgery. Kidneys were harvested at 24 hours and 3, 4, and 5 days. The specimens were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) for ICAM-1 messenger ribonucleic acid (mRNA), immunohistochemical staining for ICAM-1 protein, and standard histology. Results At 24 hours, qRT-PCR and immunohistochemistry data showed a significant reduction in ICAM-1 mRNA and protein expression in the antisense group versus the ischemia group, but no difference at 3 to 5 days. Histologically there was reduced inflammation and necrosis in the cortex at 24 hours. The outer and inner medulla also showed improvement at 3 to 5 days in the antisense group as opposed to the ischemia group. Conclusions Topical PEG hydrogel delivery of antisense ICAM-1 oligonucleotides demonstrated decreased ICAM-1 mRNA expression, reduced ICAM-1 protein staining, and decreased cellular damage. The application of gene therapy through this novel topical delivery system holds potential for a highly specific, localized method of preventing tissue damage after ischemia/reperfusion injury.

OBJECTIVES To investigate whether angiotensin II (AII) receptor antagonism decreases the inflammation and oedema in acute murine experimental autoimmune cystitis (EAC), as interstitial cystitis (IC) might have an autoimmune component and AII has been implicated in autoimmune-mediated vascular congestion, oedema and scarring. MATERIALS AND METHODS Female Balb/cAN mice were divided into three treatment groups (eight in each group) that were autoimmunized with bladder homogenate to induce EAC. One group received an AII type 1 receptor (AT1) antagonist, one group an AII type 2 receptor (AT2) antagonist, and one group remained untreated (EAC). A control and sham-injected group were also included. After 10 weeks, bladders were removed, sectioned, and stained with haematoxylin and eosin. RESULTS Grossly, there was no thickening or adhesions in the bladders of the control or sham-injected mice. In five of seven surviving EAC bladders, there were dense adhesions to surrounding peritoneal structures. There were also adhesions and bladder thickening in all of the AT2 antagonist-treated mice (though in a milder form) but in only two of seven surviving AT1 antagonist-treated mice. There was no inflammation or oedema in the sham and control groups. All the EAC bladders were inflamed, with submucosal oedema and urothelial detachment from the lamina propria. In the AT1 antagonist-treated mice there was no inflammation or oedema. By contrast, all AT2 antagonist-treated mice had moderate inflammation and minor detachment of the urothelium from the lamina propria. CONCLUSIONS AT1 receptor blockade ameliorated the inflammatory infiltration, submucosal oedema, and urothelial detachment associated with EAC in mice. This was achieved to a lesser extent by AT2 receptor blockade. If some patients with IC have a pathophysiology similar to that of EAC mice, there might be potential benefit from AII receptor blockade.

Aims Pharmacological treatment for stress urinary incontinence (SUI) is limited to the use of non-selective alpha-agonists, which are often ineffective. Non-adrenergic mechanisms have also been implicated in urethral closure, including angiotensin II (Ang-II), which has been demonstrated throughout the urinary tract. We investigate the role of Ang-II in urethral tone in a rat model of SUI. Methods Abdominal leak point pressure (ALPP) and retrograde urethral pressure profilometry (RLPP) were measured in 70 female virgin rats. Thirty rats underwent pudendal nerve injury (PNT), 30 had circumferential urethrolysis (U-Lys), and 10 had sham surgery. Rats received daily doses of Angiotensin Type 1 (AT-1) receptor inhibitor (20 mg/kg), Angiotensin Type 2 (AT-2) receptor antagonist (10 mg/kg), or Ang-II (2 mg/kg). Results Following U-Lys, RLPP and ALPP decreased from 21.4 ± 2.0 and 39.2 ± 3.3 mm Hg, to 13.1 ± 1.5 and 21.6 ± 1.9 mmHg, respectively (P

Ischemia/reperfusion injury is a leading cause of renal damage and antisense gene therapy has been shown to ameliorate its effects. However, this approach has been limited by current delivery methods that require high concentrations of intravenous nucleic acids lacking specificity for targeting tissues. To overcome these limitations we developed a novel murine partial nephrectomy model to evaluate polyethylene-glycol (PEG) hydrogel tissue sealant as a topical oligonucleotide delivery system.A total of 18 male C57BL/6 mice underwent left partial nephrectomy with vascular occlusion. Hydrogel primer and then sealant were applied to the cut surface and photopolymerized. Using this method 16 additional mice received hydrogel primer mixed with Cy5 labeled fluorescent oligonucleotide (10 to 100 microg). Kidneys were harvested at various time points and assessed for oligonucleotide penetration using fluorescence microscopy.A survival rate of 100% (34 subjects) was obtained using this mouse model of partial nephrectomy. PEG hydrogel provided adequate protection against renal hematoma and intraperitoneal blood. Fluorescent images revealed that 50 microg was the minimum dose resulting in complete progressive cellular penetration with time. In addition to direct diffusion from the application site, movement of oligonucleotide through the subcapsular space into the cortex was an observed mechanism of distribution.A murine partial nephrectomy model was successfully created using PEG hydrogel. In addition to achieving hemostasis, hydrogel served as a successful depot for delivering oligonucleotides throughout the kidney.

Rapid diagnosis of urinary tract infection would have a significant beneficial impact on clinical management, particularly in patients with structural or functional urinary tract abnormalities who are highly susceptible to recurrent polymicrobial infections. We examined the analytical validity of an electrochemical biosensor array for rapid molecular diagnosis of urinary tract infection in a prospective clinical study in patients with neurogenic bladder.The electrochemical biosensor array was functionalized with DNA probes against 16S rRNA of the most common uropathogens. Spinal cord injured patients at a Veterans Affairs hospital were recruited into the study. Urine samples were generally tested on the biosensor within 1 to 2 hours of collection. Biosensor results were compared with those obtained using standard clinical microbiology laboratory methods.We successfully developed a 1-hour biosensor assay for multiplex identification of pathogens. From July 2007 to December 2008 we recruited 116 patients, yielding a total of 109 urine samples suitable for analysis and comparison between biosensor assay and standard urine culture. Of the samples 74% were positive, of which 42% were polymicrobial. We identified 20 organisms, of which Escherichia coli, Pseudomonas aeruginosa and Enterococcus species were the most common. Biosensor assay specificity and positive predictive value were 100%. Pathogen detection sensitivity was 89%, yielding a 76% negative predictive value.To our knowledge we report the first prospective clinical study to successfully identify pathogens within a point of care time frame using an electrochemical biosensor platform. Additional efforts to improve the limit of detection and probe design are needed to further enhance assay sensitivity.

not Available.

RESULTS: Thirty-four hypospadias patients (77.2%) and 13 controls (65%) completed the questionnaire. The hypospadias patients were divided into 2 groups based on the preoperative position of the meatus: proximal (P) (n = 24) and distal (D) (n = 9). One patient could not be classified into any of the groups. The mean age of the patients at the time of the initial operation was 3.3 years (range: 1-10 years) and the mean duration after the initial operation was 11.3 years (range: 4-27 years). The mean current age of both the patients and controls was 14.6 years. All subjects could void in the standing position: 8.3% patients in group P, 11.1% in group D, and 7.6% of the controls reported spraying of the urinary stream. Two patients in group P (8.3%) were dissatisfied with the appearance of their penis, and 8.7% in group P, 22.2% in group D, and 8.3% of the controls were disappointed with the size of their penis. The percentages of subjects who expressed interest in watching adult videos were 53.8% in group P, 50.0% in group D, and 100% of the controls (over 13 years old). None of the patients complained of penile pain during erection. CONCLUSIONS: We found that the repair of severe hypospadias could result in different problems and dissatisfaction, particularly regarding penile size and erection, therefore, we concluded that patients undergoing hypospadias repair require long-term follow-up and adequate counseling for future voiding and sexual dysfunction.

analysis, we used the prolapse (POPDI) and urinary (UDI) subscales of the PFDI. We used Wilcoxon ranked test and McNemar test for repeated parametric and categorical variables, respectively. RESULTS: Thirty-three women with a mean age of 79 years (65-90) were included in the analysis. The median follow-up was 9 months (3-23 months). Prior to surgery, the median POP-Q stage was 3 (range 2-4). Nearly all (91%) had some incontinence symptoms, and 80% reported symptoms of stress urinary incontinence (SUI). Preoperative urodynamic diagnoses included: urodynamic stress incontinence (USI)