Delivery of an at-home transcranial direct current stimulation intervention to mitigate pain in patients with end-stage kidney disease receiving hemodialysis (ESKD/HD)
Jordan Van Zyl, Helena Knotkova, Patricia Kim, Charles R Henderson, Russell K Portenoy, Nathaniel Berman, Melissa W Frederic, M Carrington Reid...
Front Pain Res (Lausanne). 2023 Apr 5;4:1132625. doi: 10.3389/fpain.2023.1132625. eCollection 2023.
ABSTRACT
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.
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)
Barry H Smith, Lawrence S Gazda, Thomas J Fahey, Angelica Nazarian, Melissa A Laramore, Prithy Martis, Zoe P Andrada, Joanne Thomas, Tapan Parikh, Sudipta Sureshbabu, Nathaniel Berman, Allyson J Ocean, Richard D Hall, David J Wolf...
Chin J Cancer Res. 2018 Feb;30(1):72-83. doi: 10.21147/j.issn.1000-9604.2018.01.08.
ABSTRACT
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.
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.
First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors
Barry H Smith, Tapan Parikh, Zoe P Andrada, Thomas J Fahey, Nathaniel Berman, Madeline Wiles, Angelica Nazarian, Joanne Thomas, Anna Arreglado, Eugene Akahoho, David J Wolf, Daniel M Levine, Thomas S Parker, Lawrence S Gazda, Allyson J Ocean...
Cancer Growth Metastasis. 2016 Aug 2;9:9-20. doi: 10.4137/CGM.S39442. eCollection 2016.
ABSTRACT
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.
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.
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