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Comorbidities and socioeconomic barriers often limit patient adherence and self-management with hemodialysis. Missed sessions, often associated with communication barriers, can result in emergency dialysis and avoidable hospitalizations. This proof of concept study explored using a novel digital-messaging platform, EpxDialysis, to improve patient-to-dialysis center communication via widely available text messaging and telephone technology. A randomized controlled trial was conducted through Washington University-affiliated hemodialysis centers involving ESRD patients with poor attendance, defined as missing 2–6 sessions over the preceding 12 weeks. A cross-over study design evaluated appointment adherence between intervention and control groups. Comparing nonadherence rates eight weeks prior to enrollment, median appointment adherence after using the system increased by 75%, and median number of unintended hospitalization days fell by 31%. A conservative cost-benefit analysis of EpxDialysis demonstrates a 1:36 savings ratio from appointment adherence. EpxDialysis is a low-risk, cost-effective, intervention for increasing hemodialysis adherence in high-risk patients, especially at centers caring for vulnerable and low-income patients.

Background: Medication adherence remains a difficult problem to both assess and improve in patients. It is a multifactorial problem that goes beyond the commonly cited reason of forgetfulness. To date, eHealth (also known as mHealth and telehealth) interventions to improve medication adherence have largely been successful in improving adherence. However, interventions to date have used time- and cost-intensive strategies or focused solely on medication reminding, leaving much room for improvement in using a modality as flexible as eHealth. Objective: Our objective was to develop and implement a fully automated short message service (SMS)-based medication adherence system, EpxMedTracking, that reminds patients to take their medications, explores reasons for missed doses, and alerts providers to help address problems of medication adherence in real time. Methods: EpxMedTracking is a fully automated bidirectional SMS-based messaging system with provider involvement that was developed and implemented through Epharmix, Inc. Researchers analyzed 11 weeks of de-identified data from patients cared for by multiple provider groups in routine community practice for feasibility and functionality. Patients included were those in the care of a provider purchasing the EpxMedTracking tool from Epharmix and were enrolled from a clinic by their providers. The primary outcomes assessed were the rate of engagement with the system, reasons for missing doses, and self-reported medication adherence. Results: Of the 25 patients studied over the 11 weeks, 3 never responded and subsequently opted out or were deleted by their provider. No other patients opted out or were deleted during the study period. Across the 11 weeks of the study period, the overall weekly engagement rate was 85.9%. There were 109 total reported missed doses including “I forgot” at 33 events (30.3%), “I felt better” at 29 events (26.6%), “out of meds” at 20 events (18.4%), “I felt sick” at 19 events (17.4%), and “other” at 3 events (2.8%). We also noted an increase in self-reported medication adherence in patients using the EpxMedTracking system. Conclusions: EpxMedTracking is an effective tool for tracking self-reported medication adherence over time. It uniquely identifies actionable reasons for missing doses for subsequent provider intervention in real time based on patient feedback. Patients enrolled on EpxMedTracking also self-report higher rates of medication adherence over time while on the system. [JMIR Res Protoc 2017;6(5):e87]

The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors. Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) dissolution in vivo increases pH asymptotically to 7.4. We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pH over time. The associated induction of tumor growth stasis is putatively interpreted as a pHe increase. This study establishes an approach to prepare nano-CaCO3 over a wide particle size range, a formulation that stabilizes the nanomaterials in aqueous solutions, and a pH-sensitive nano-platform capable of modulating the acidic environment of cancer for potential therapeutic benefits.

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer.

Background: The bone-forming metastases of prostate cancer result from complex stromal–epithelial interactions within the tumour microenvironment. Autocrine–paracrine signalling pathways between prostate cancer epithelial cells, osteoblasts, and osteoclasts stimulate aberrant bone remodelling, and the activity of these three cell populations can be quantitatively measured using prostate-specific antigen (PSA), bone-specific alkaline phosphatase (BAP) and urine N-telopeptide (uNTx), respectively. The purpose of the present study was to test the hypothesis that serial measurements of BAP and uNTx during therapy would facilitate monitoring of disease activity and predict the overall survival (OS) in patients with metastatic prostate cancer receiving therapy. Methods: Radionuclide bone scan, PSA, BAP, and uNTx data were retrospectively analysed from three clinical trials in patients with metastatic prostate cancer conducted at our institution. Qualitative changes in bone scans and quantitative changes in PSA, BAP, and uNTx concentrations during therapy were correlated with OS. Results: Baseline levels of BAP, but not PSA, were prognostic for OS in both androgen-dependent and castrate-resistant disease. A reduction in PSA, BAP, uNTx, or BAP/uNTx on therapy was predictive of improved OS in both patient groups. Conversely, an increase in PSA, or BAP on therapy was predictive of worse OS in both patient groups. Baseline number of lesions and response on bone scan during therapy were neither prognostic nor predictive of OS in either patient group. Conclusion: These observations support the concept that serial measurements of bone turnover metabolites during therapy function as clinically informative predictive biomarkers in patients with advanced prostate cancer and skeletal metastases. PSA measurements and bone scans remain essential to monitor the overall disease activity and determine the anatomic distribution of skeletal metastases.

The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery and improve the accuracy of cancer staging.

Background: Patient noncompliance with therapy, treatments, and appointments represents a significant barrier to improving health care delivery and reducing the cost of care. One method to improve therapeutic adherence is to improve feedback loops in getting clinically acute events and issues to the relevant clinical providers as necessary (ranging from detecting hypoglycemic events for patients with diabetes to notifying the provider when patients are out of medications). Patients often don’t know which information should prompt a call to their physician and proactive checks by the clinics themselves can be very resource intensive. We hypothesized that a two-way SMS system combined with a platform web service for providers would enable both high patient engagement but also the ability to detect relevant clinical alerts. Objective: The objectives of this study are to develop a feasible two-way automated SMS/phone call + web service platform for patient-provider communication, and then study the feasibility and acceptability of the Epharmix platform. First, we report utilization rates over the course of the first 18 months of operation including total identified clinically significant events, and second, review results of patient user-satisfaction surveys for interventions for patients with diabetes, COPD, congestive heart failure, hypertension, surgical site infections, and breastfeeding difficulties. Methods: To test this question, we developed a web service + SMS/phone infrastructure (“Epharmix”). Utilization results were measured based on the total number of text messages or calls sent and received, with percentage engagement defined as a patient responding to a text message at least once in a given week, including the number of clinically significant alerts generated. User satisfaction surveys were sent once per month over the 18 months to measure satisfaction with the system, frequency and degree of communication. Descriptive statistics were used to describe the above information. Results: In total, 28,386 text messages and 24,017 calls were sent to 929 patients over 9 months. Patients responded to 80% to 90% of messages allowing the system to detect 1164 clinically significant events. Patients reported increased satisfaction and communication with their provider. Epharmix increased the number of patient-provider interactions to over 10 on average in any given month for patients with diabetes, COPD, congestive heart failure, hypertension, surgical site infections, and breastfeeding difficulties. Conclusions: Engaging high-risk patients remains a difficult process that may be improved through novel, digital health interventions. The Epharmix platform enables increased patient engagement with very low risk to improve clinical outcomes. We demonstrated that engagement among high-risk populations is possible when health care comes conveniently to where they are.

At Washington University, students and faculty have addressed challenges surrounding biomedical innovation and training through a novel and low-cost platform.

A small subset of young men die from seminoma. Studying these high risk, clinically atypical seminomas (CASs)-aggressive tumors with visceral metastases and chemotherapy resistance-may provide clues to the nature of drug resistance and the origin of testicular cancers. We explored the possibility that these seminomas are a unique clinical and biologic entity with intrinsic yolk sac tumor (YST) features.We assayed available archived tissue samples (n = 22) for chemotherapy-resistance markers found in YSTs. Specifically, we analyzed tissues and clinical histories from patients with CASs (those who had visceral metastases and recurrent disease), classical seminomas, and mixed germ-cell tumors containing YST. By using immunohistochemical testing, we evaluated the expression of bone morphogenetic protein 2, alpha fetoprotein, and glutathione S-transferase (pi) [GST (pi)].GST (pi) expression significantly predicted for overall survival (p = .036). In addition, according to the results of GST (pi) immunohistochemical staining, the CASs appeared to resemble YSTs more than they did classical seminomas (p = 0.043). Less-advanced tumors, both those that expressed GST (pi) and those that were negative for GST (pi), were more amenable to local therapies, and the patients who had those tumors had better clinical outcomes.Results from this exploratory study suggest that certain CASs that express GST (pi) are more similar to YST than they are to classical seminomas, and that GST (pi) expression may be able to be used as a prognosticator of disease-specific survival. Such CASs thus may have a unique biologic origin that differs from that of classical seminomas. Additional studies are needed to determine the natural history and therapeutic implications of these CASs.

Introduction A major question concerning cancer is its cells of origin. We hypothesized that distinct cancer subtypes arise from unique cancer-initiating cells. By performing a microarray meta-analysis of seminomas and spermatogonial stem cells, we investigated a putative cell of origin for seminoma. Materials and Methods We obtained published microarray data for 6 human adult germ cell lines, 16 embryonic stem cell lines, 3 normal testicular tissue samples, and 40 seminomas from the Gene Expression Omnibus database. By assessing correlations between various tissue microarrays, we determined the number of transitional events and the distance between seminomas and human spermatogonial stem cells. Results Our meta-analysis showed that spermatogonial stem cells correlated similarly with seminoma (95% CI of Spearman ρ, 0.33-0.44) and with normal somatic testicular tissue cells (95% CI, 0.39-0.40), which suggests parallel paths of cellular origins. Conclusion Analysis of our results suggests that a unique cancer subtype, namely seminoma, may have originated from an undifferentiated cell with stemness features rather than from a differentiated cell that acquired stemness features.

Introduction: The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors and restricts it growth. Methods: We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Biochemical simulations were used to simulate pH changes in vivo using the particle. In vitro and in vivo assays were used to determine pH changes. IV injections of the nanoparticles were implemented in a xenograft model of fibrosarcoma to determine growth changes. Results: Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) dissolution in vivo increases pH asymptotically to 7.4. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pHe over time. The persistent neutralization of tumor pHe from nano-CaCO3 induces tumor growth stasis. Conclusions: We have been able to create a novel nanoparticle based on widely existing in vivo components (Calcium and CO3) that safely equilibrates acidic pH of tumors up to normal physiological pH. As expected, this modulation restricts growth of implanted tumors in vivo. Future studies will study the effect of these particles on metastasis, and synergy with other therapeutic modalities. Citation Format: Avik Som, Ramesh Raliya, Walter Akers, Joseph Ippolito, Srikanth Singamaneni, Pratim Biswas, Samuel Achilefu. Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-232.

Background: Patients with prostate cancer tend to die from bone metastases. Until now, no evidence has shown that Paget's disease of bone (PDB) affects the progression of bone metastasis or overall survival of patients with prostate cancer. Methods: We searched our patient database for men who had presented with prostate cancer and PDB between June 1993 and March 2009, and identified best-matched control patients according to stage, grade, age, date of diagnosis, treatment, and race. Results: Among 1346 consecutive patients with prostate cancer diagnosed before 2008, 15 were confirmed to have comorbid PDB. Twenty-six more were identified from the institutional billing search. Including the 41 best-matched controls, our total study population was 82 patients. In the Kaplan–Meier analysis, we estimated median times from diagnosis of prostate cancer to bone metastasis to be 21.5 years for those with PDB and 9.4 years for those without PDB (P=0.044). Median overall survival times were 11.8 and 9.2 years for the two groups, respectively (P=0.008). Conclusion: For the first time, we have obtained evidence that patients with prostate cancer and PDB have delayed time to bone metastases and improved overall survival than do patients with prostate cancer alone.

Objectives Certain patients with seminoma and clinically atypical phenotypes—visceral metastases, elevated levels of β human chorionic gonadotropin (βHCG), and/or recurrent disease—have a poor prognosis. The primary goal of this pilot study was to characterize the clinical characteristics and treatment profile of these rare patients. We also wished to test whether these tumors expressed any specific biomarkers that might distinguish them as a unique subtype of seminoma. Materials and methods We retrospectively identified 25 patients with a history of seminoma plus visceral metastases, βHCG levels >200 mU/ml, and/or recurrent disease. We reviewed these patients' histories for treatment efficacy and clinical outcome. Tissue samples were available from 6 of those patients, and we studied them for expression of the markers OCT 3/4, PLAP, CD30, TRA-1-60, c-kit, and gp200. We compared our results with the expression of those markers in tissue samples from mixed seminoma/embryonal carcinomas and classic seminomas. Results Our analysis suggested that certain chemotherapeutic regimens (such as ifosfamide, paclitaxel, and cisplatin) are efficacious for the treatment of patients with these atypical seminomas. Further, specimens from the atypical seminomas generally had staining profiles that resembled those of classic seminomas and the seminoma components in mixed germ-cell tumors, but the profiles differed from those of the embryonal carcinoma components in the same mixed germ-cell tumors. Conclusions Although these atypical seminomas tend to be resistant to chemotherapy, they may still respond to certain chemotherapeutic regimens. Our pilot immunohistochemical study also suggested that the unique phenotypes associated with these atypical seminomas do not result from any relationship with embryonal carcinomas. More study is needed to confirm these initial findings.

Theranostic platforms allow the capability of both diagnostic level imaging and therapy for diseases such as cancer. The decreased pH found in the extracellular environment in cancer is an ideal target for cancer theranostics, because it is both a unique and universal hallmark that distinguishes tumor regions from normal tissue, but also that the decreased pH has been linked to tumor growth and metastasis. We describe herein the development of nano-CaCO3, a novel nanoparticle that can both increase pH in vivo resulting in therapeutic benefit, but also dissolves only at pHs less than 7.4 in vivo, creating a pH sensitivity to the nanoparticle that can be used to detect the more acidic pH ranges in vivo. As a result, nano-CaCO3 is pH sensitive theranostic platform for cancer detection and treatment in vivo.