Clinical laboratory and imaging evidence for effectiveness of agarose-agarose macrobeads containing stem-like cells derived from a mouse renal adenocarcinoma cell population (RMBs) in treatment-resistant, advanced metastatic colorectal cancer: Evaluation of a biological-systems approach to cancer therapy (U.S. FDA IND-BB 10091; NCT 02046174, NCT 01053013).

OBJECTIVE: The complexity, heterogeneity and capacity of malignant neoplastic cells and tumors for rapid change and evolution suggest that living-cell-based biological-systems approaches to cancer treatment are merited. Testing this hypothesis, the tumor marker, metabolic activity, and overall survival (OS) responses, to the use of one such system, implantable macrobeads [RENCA macrobeads (RMBs)], in phase I and IIa clinical trials in advanced, treatment-resistant metastatic colorectal cancer (mCRC) are described here. METHODS: Forty-eight mCRC patients (30 females; 18 males), who had failed all available, approved treatments, underwent RMB implantation (8 RMB/kg body weight) up to 4 times in phase I and phase IIa open-label trials. Physicals, labs [tumor and inflammation markers, lactate dehydrogenase (LDH)] and positron emission tomography-computed tomography (PET-CT) imaging to measure number/volume and metabolic activity of the tumors were performed pre- and 3-month-post-implantation to evaluate safety and initial efficacy (as defined by biological responses). PET-CT maximum standard uptake value (SUVmax) (baseline and d 90; SUVmax ≥2.5), LDH, and carcinoembryonic antigen (CEA) and/or cancer antigen 19-9 (CA 19-9) response (baseline, d 30 and/or d 60) were assessed and compared to OS. RESULTS: Responses after implantation were characterized by an at least 20% decrease in CEA and/or CA 19-9 in 75% of patients. Fluorodeoxyglucose (FDG)-positive lesions (phase I, 39; 2a, 82) were detected in 37/48 evaluable patients, with 35% stable volume and stable or decreased SUV (10) plus four with necrosis; 10, increased tumor volume, SUV. LDH levels remained stable and low in Responders (R) (d 0-60, 290.4-333.9), but increased steadily in Non-responders (NR) (d 0-60, 382.8-1,278.5) (d 60, P=0.050). Responders to RMBs, indicated by the changes in the above markers, correlated with OS (R mean OS=10.76 months; NR mean OS=4.9 months; P=0.0006). CONCLUSIONS: The correlations of the tumor marker, tumor volume and SUV changes on PET-CT, and LDH levels themselves, and with OS, support the concept of a biological response to RMB implantation and the validity of the biological-systems approach to mCRC. A phase III clinical trial is planned.

Multiparametric Quantitative Ultrasound Imaging in Assessment of Chronic Kidney Disease.

OBJECTIVES: To evaluate the value of multiparametric quantitative ultrasound imaging in assessing chronic kidney disease (CKD) using kidney biopsy pathologic findings as reference standards. METHODS: We prospectively measured multiparametric quantitative ultrasound markers with grayscale, spectral Doppler, and acoustic radiation force impulse imaging in 25 patients with CKD before kidney biopsy and 10 healthy volunteers. Based on all pathologic (glomerulosclerosis, interstitial fibrosis/tubular atrophy, arteriosclerosis, and edema) scores, the patients with CKD were classified into mild (no grade 3 and <2 of grade 2) and moderate to severe (at least 2 of grade 2 or 1 of grade 3) CKD groups. Multiparametric quantitative ultrasound parameters included kidney length, cortical thickness, pixel intensity, parenchymal shear wave velocity, intrarenal artery peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index. We tested the difference in quantitative ultrasound parameters among mild CKD, moderate to severe CKD, and healthy controls using analysis of variance, analyzed correlations of quantitative ultrasound parameters with pathologic scores and the estimated glomerular filtration rate (GFR) using Pearson correlation coefficients, and examined the diagnostic performance of quantitative ultrasound parameters in determining moderate CKD and an estimated GFR of less than 60 mL/min/1.73 m2 using receiver operating characteristic curve analysis. RESULTS: There were significant differences in cortical thickness, pixel intensity, PSV, and EDV among the 3 groups (all P < .01). Among quantitative ultrasound parameters, the top areas under the receiver operating characteristic curves for PSV and EDV were 0.88 and 0.97, respectively, for determining pathologic moderate to severe CKD, and 0.76 and 0.86 for estimated GFR of less than 60 mL/min/1.73 m2 . Moderate to good correlations were found for PSV, EDV, and pixel intensity with pathologic scores and estimated GFR. CONCLUSIONS: The PSV, EDV, and pixel intensity are valuable in determining moderate to severe CKD. The value of shear wave velocity in assessing CKD needs further investigation.

A zebrafish model for uremic toxicity: role of the complement pathway.

Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

Delivery of an at-home transcranial direct current stimulation intervention to mitigate pain in patients with end-stage kidney disease receiving hemodialysis (ESKD/HD).

Background: Poorly controlled pain remains a problem for many patients with end-stage kidney disease requiring hemodialysis (ESKD/HD) and customary approaches to pain management (e.g., opioids, non-steroidals) confer substantial risk. Accordingly, non-pharmacologic therapies are needed for use in this population. Non-invasive transcranial Direct Current Simulation (tDCS) constitutes a promising nonpharmacologic method for pain management in affected individuals. Aims: This study seeks to: 1) determine the effects of an 8-week course of at-home tDCS vs. sham tDCS on pain intensity, pain interference, medication usage, quality of life, and mood; 2) determine if tDCS effects vary by race/ethnicity; and 3) ascertain patient satisfaction with device use. Methods: This double-blind, randomized, sham-controlled clinical trial will enroll 100 ESKD/HD patients with moderate-to-severe (≥4 on 0-10 scale) chronic pain. The active study intervention consists of 20 min of tDCS delivered over the primary motor cortex 5 days/week for 8 weeks. The comparator is a sham procedure that provides no effective stimulation. The primary outcome analysis will evaluate efficacy of tDCS for pain reduction after two months of stimulation. We will also assess the effects of treatment on analgesic consumption, pain interference, depressed mood, and quality of life. The statistical plan will include fixed classification factors for treatment (vs. sham), clinic sites, and assessment time, and the interaction of these factors adjusting for covariates (e.g., race/ethnicity, pain level). Conclusion: At-home tDCS constitutes a promising nonpharmacologic treatment for pain mitigation in persons with ESKD/HD. This unique RCT could transform the way pain is managed in this vulnerable population. Trial Registration: NCT05311956.

More with Less: A Trial of Reduced-Intensity Treatment in Transplant-Ineligible Hemodialysis Patients.

BACKGROUND: An increasing proportion of hemodialysis patients are ineligible for transplant. Often these patients are elderly, with multiple comorbidities and decreased functional status. Such patients may benefit from modified treatment goals to reduce symptom burden. OBJECTIVE: To demonstrate the feasibility of a trial of reduced-intensity treatment in nontransplantable patients with end-stage renal disease (ESRD). STUDY DESIGN: A 6-week study randomized patients to a reduced-intensity intervention versus usual care. Intervention subjects were treated with liberalized goals for serum phosphorus and parathyroid hormone (PTH) as well as predialysis blood pressure in comparison with usual care subjects. Outcomes included assessed feasibility of recruitment, randomization, and data collection. SETTING AND POPULATION: Sixteen transplant-ineligible hemodialysis patients were recruited from two urban units. MEASUREMENTS: Blood pressure was recorded weekly, while serum PTH and phosphorus were assessed every 10 days. A quality-of-life measure was administered before and after the trial. RESULTS: Of 300 patients, 51 were eligible and 16 consented. All were randomized and completed the trial. Patients in the intervention group received significantly lower doses of phosphorus binders and vitamin D analogues, and were less likely to have their dry weight reduced. All patient surveys were completed. CONCLUSIONS: High-risk hemodialysis patients may benefit from liberalized treatment guidelines but larger studies are necessary.

First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors.

PURPOSE: Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. METHODS: Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RESULTS: RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. CONCLUSION: The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

End-of-life matters in chronic renal failure.

PURPOSE OF REVIEW: The population considered eligible for dialysis has expanded dramatically over the past 4 decades, so that a significant proportion of patients receiving renal replacement therapy are elderly, frail and infirm. These patients have an extremely limited life expectancy and suffer from significant symptom burden, similar to patients with other end-stage organ failure or cancer. As dialysis has been offered more broadly, it is now initiated earlier than in decades past, further adding to cost and patient burden. RECENT FINDINGS: The trend toward more expansive and intensive care has not been corroborated by robust data. In response, an increasing number of studies has focused on establishing reasonable limits to renal replacement therapy. Multiple authors have explored the role of conservative kidney management for high-risk dialysis patients as an alternative to dialysis, which may offer similar survival and improved quality of life in certain populations. For those who chose dialysis, deferring initiation until the patient becomes symptomatic may be a reasonable. Evidence-based symptom management guidelines for dialysis patients remain largely absent, with few proven approaches. Hospice and palliative care resources remain underutilized. SUMMARY: For a subset of dialysis patients, palliative care and conservative kidney management are appropriate and underutilized. VIDEO ABSTRACT: http://links.lww.com/COSPC/A8

Acute Renal Failure and Jaundice without Methemoglobinemia in a Patient with Phenazopyridine Overdose: Case Report and Review of the Literature.

Phenazopyridine is a commonly used urinary analgesic available throughout the United States. Ingestion of large quantities can lead to methemoglobinemia, hemolytic anemia, jaundice, and acute renal failure. We report a case of a 78-year-old male with previously normal renal function who developed acute renal failure and jaundice without methemoglobinemia or hyperbilirubinemia after taking nearly 8 g of phenazopyridine over the course of 4 days. Initially presenting with oliguria, the urine output began to increase by day 2 of his admission, and the creatinine peaked 11 days after he began taking phenazopyridine, and he was discharged safely soon after. To our knowledge, this is the first such case of renal failure and jaundice without methemoglobinemia or hemolytic anemia in an adult patient with normal renal function.

An isolated iliac wing stress fracture in a marathon runner.

Iliac stress fractures are uncommon and are usually insufficiency fractures related to osteoporosis. Only 2 previous case reports of iliac stress fractures in runners that extended into the sacroiliac joint, and 1 previous case of an isolated iliac wing stress fracture not involving the sacroiliac joint were found in the English language literature. We report on a second case of an isolated stress fracture of the iliac wing in a female marathon runner and the associated diagnosis of the female athlete triad. Iliac stress fractures can be an occult cause of hip pain in athletes and should be included in the differential diagnosis of hip pain in a marathon runner.

Disparities in symptom burden and renal transplant eligibility: a pilot study.

BACKGROUND: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) suffer from a high symptom burden. However, there is significant heterogeneity within the HD population; certain subgroups, such as the elderly, may experience disproportionate symptom burden. OBJECTIVES: The study's objective was to propose a category of HD patients at elevated risk for symptom burden (those patients who are not transplant candidates) and to compare symptomatology among transplant ineligible versus eligible HD patients. DESIGN: This was a cross-sectional study. SETTING/SUBJECTS: English-speaking, cognitively intact patients receiving HD and who were either transplant eligible (n=25) or ineligible (n=32) were recruited from two urban HD units serving patients in the greater New York City region. MEASUREMENTS: In-person interviews were conducted to ascertain participants' symptom burden using the Dialysis Symptom Index (DSI), perceived symptom bother and attribution (whether the symptom was perceived to be related to HD treatment), and quality of life using the SF-36. Participants' medical records were reviewed to collect demographic and clinical data. RESULTS: Transplant ineligible (versus eligible) patients reported an average of 13.9±4.6 symptoms versus 9.2±4.4 symptoms (p<0.01); these differences persisted after adjustment for multiple factors. A greater proportion of transplant ineligible (versus eligible) patients attributed their symptoms to HD and were more likely to report greater bother on account of the symptoms. Quality of life was also significantly lower in the transplant ineligible group. CONCLUSIONS: Among HD patients, transplant eligibility is associated with symptom burden. Our pilot data suggest that consideration be given to employing transplant status as a method of identifying HD patients at risk for greater symptom burden and targeting them for palliative interventions.

Improving symptom management in hemodialysis patients: identifying barriers and future directions.

BACKGROUND: Hemodialysis (HD) patients experience significant symptom burden that is often undertreated. OBJECTIVE: This study identified (1) barriers to symptom management in the HD population, (2) potential targets for improving symptom burden, (3) provider attitudes toward palliative care for HD patients, and (4) perceptions of how transplant eligibility impacts care. DESIGN: Semistructured, one-on-one interviews were conducted, audiotaped, and transcribed. Data were analyzed qualitatively by two investigators to identify discrete themes. SETTING/SUBJECTS: Health care providers (HCPs) and caregivers were recruited (June to October 2012) from three outpatient HD units in New York City. MEASUREMENTS: Open-ended questions were used with follow-up probes. RESULTS: Interviews were completed with 34 HCPs (8 physicians, 2 nurse practitioners, 4 social workers, 13 registered nurses, 7 patient care technicians) and 20 caregivers (14 family members, 5 home health aides, 1 friend). Barriers to symptom control were identified in three areas: (1) provider unawareness of symptoms, (2) provider's uncertainty as to whose responsibility it is to treat symptoms, and (3) inherent difficulty in symptom management. Ideas for ameliorating symptoms included enhancing systems for patient/caregiver education, improving systems for HCP communication with other disciplines, and encouraging alternative methods of dialysis when appropriate. HCPs also expressed discomfort with the term "palliative care." CONCLUSIONS: Renal HCPs are often unaware of the magnitude of symptom burden in their HD patients. This study found that there is lack of ownership for assessing and treating these symptoms. Providers also feel certain symptoms are "untreatable." Research is needed to develop effective treatment strategies for HD populations.