Opportunities For Disease Management Research Articles

Abstract P3-08-03: Establishment of patient-derived xenograft tumor models from breast cancer patients for quantitative elemental profiles and testing candidate therapies

Abstract Breast cancer (BC) is a heterogeneous disease comprising different clinical, histopathological, and molecular subtypes. Triple negative breast cancer (TNBC) is among the most aggressive clinical manifestations of breast cancer (BC), and represents a significant clinical challenge to the effective treatment of early metastatic and treatment-refractory disease because of its poor outcomes. Therefore, there exists a need to develop pre-clinical models that retain the characteristics of the original TNBC tumor—e.g., PDX tumor models—to better understand the mechanisms of drug resistance in metastatic TNBC and to effectively evaluate the effects of anti-cancer drugs on patients with this disease. Furthermore, quantitative changes in cellular element signatures, which indicate levels of enzymatic activity, are emerging new biomarkers for cancer in the clinic, but are of yet systematically understudied in tumor samples from breast cancer patients or/and PDX models of these tumors. Due to limitations in current cellular element signature quantitation profiles, there also exists a need to investigate further. Seven samples of advanced BC patient pleural effusion were obtained from Northwestern Memorial Hospital to establish a PDX tumor model in immunodeficient NSG female mice using breast fat pad xenografting and to develop derived 3D spheroid cultures for anti-cancer drug evaluation. To authenticate, STR profiling against with original patient tumor DNA was conducted. Five developed BC PDX tumor models were shown by pathology to have highly heterogeneous characteristics and the metastatic features of the origin patient tumor. Liver and lung metastases were observed in breast fat pad xenografted PDX tumor mice. 3D tumor spheroid cultures were successfully established from original BC pleural effusion or/and PDX tumor cultures. Using the newly developed, highly sensitive, and reliable Wash-Free Inductively Coupled Plasma Mass Spectrometry (WF ICP-MS) method, we evaluated the inorganic phenotypes from samples of breast cancer patient tumor tissue and of the established PDX tumor to quantify the mobile elements (Na, K, and Ca) and less mobile elements (P, Mg, Mn, Fe, Cu, and Zn) simultaneously within the same sample. The data was collected for further analysis of breast cancer inorganic signatures from normal and tumor cells. Our results suggested that BC 3D spheroid cultures and PDX tumor models could serve as models to further study the mechanisms of MBC and serve as promising tools for in vivo and in vitro quick testing and mechanistic studies of novel antitumor drugs respectively. Identifying quantitative elemental profiles is fundamental to understanding the pathologies of various metal-related cancers and thus opens up new opportunities for disease management and therapeutic intervention Citation Format: Wenan Qiang, Haimei Chen, Yi Yang, Andrew Crawford, Demirkan B. Gursel, Jian-Jun Wei, Thomas O’Halloran, Massimo Cristofanilli. Establishment of patient-derived xenograft tumor models from breast cancer patients for quantitative elemental profiles and testing candidate therapies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-03.

Abstract 2169: Tumor-myeloid cell interactions are dynamic and influence the evolutionary trajectory of adult diffuse glioma

Abstract Diffuse glioma is an aggressive brain cancer that is characterized by a poor prognosis and a universal resistance to therapy. The evolutionary processes behind this resistance remain unclear. Previous studies by the Glioma Longitudinal Analysis (GLASS) Consortium have indicated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the immune response and the administration of standard-of-care therapy. Interactions between these factors remain poorly understood, making it difficult to predict how a patient's tumor will evolve from diagnosis to recurrence. To investigate these factors, we collected RNAseq data from 151 pre- and post-treatment tumor pairs, 101 of which also had matched whole exome or whole genome sequencing. Together, this dataset represents the largest collection of longitudinal multiomic glioma data yet assembled. We integrated this dataset with representative glioma single cell RNAseq data to implement digital cytometry approaches that quantified the microenvironmental composition of each tumor and reconstructed their tumor and immune cell state-specific gene expression profiles. In both IDHwt and IDHmut glioma, the tumor microenvironment was dominated by myeloid cells. The myeloid compartment of IDHwt tumors more closely resembled blood-derived macrophages, while myeloid cells in IDHmut tumors were more similar to microglia. While therapy did not alter the balance between macrophages and microglia in IDHwt tumors, myeloid cells in IDHmut tumors that increased grade following therapy had fewer microglia characteristics. Myeloid cells in mesenchymal glioma exhibited a distinct gene expression signature compared to those in non-mesenchymal tumors, and this signature was upregulated in the myeloid cells of tumors that acquired this phenotype following therapy. Receptor-ligand analyses revealed that this mesenchymal phenotype was associated with interactions between differentiated-like tumor cells and myeloid cells, suggesting a potential mechanism of mesenchymal transformation. Radiation therapy did not alter the composition or transcriptional activity of the glioma microenvironment but did associate with increased synaptic plasticity in stem cell-like and differentiated-like tumor cells. Collectively, our results suggest that tumor-myeloid cell interactions in glioma are dynamic and capable of shaping tumor evolution following the administration of therapy. Clinically targeting these interactions may allow for better control of malignant cell state shifts over time, creating new opportunities for disease management. Citation Format: Frederick S. Varn, Kevin C. Johnson, Floris P. Barthel, Hoon Kim, Taylor Wade, Disha Lodha, Shoaib Ajaib, Nazia Ahmed, Luciano Garofano, Fulvio D'Angelo, Lucy Stead, Houtan Noushmehr, Antonio Iavarone, Roel Verhaak, The GLASS Consortium. Tumor-myeloid cell interactions are dynamic and influence the evolutionary trajectory of adult diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2169.

Awareness and Practices Relating to Zoonotic Diseases Among Smallholder Farmers in Nepal.

Increasing livestock production to meet growing demands has resulted in greater interactions at the livestock-wildlife-human interface and more opportunities for zoonotic disease spread. Zoonoses impose enormous burdens on low-income countries like Nepal, where populations are largely dependent on livestock production and access to shared grazing lands, often near protected areas, due to population pressures. Several livestock-associated zoonoses have been reported in Nepal; however, little is known regarding Nepali farmers' knowledge of zoonoses and opportunities for disease management. We conducted a cross-sectional study to investigate Nepali farmers' awareness of zoonoses, assess current health challenges, and evaluate disease prevention and control practices. We found that awareness of zoonotic pathogens was limited, especially in informally educated and illiterate farmers; the majority of which were women. Further, farmers' preventive herd health, food safety, and sanitation practices were not associated with their awareness. Several farmers reported high-risk practices despite being aware of zoonotic diseases, suggesting a disconnect between the farmers' awareness and practice. Our study highlights the need for improving Nepali farmers' knowledge of zoonoses and disease prevention measures. Closing these awareness-practice gaps will require an improved understanding of risk and effective drivers of behavior change, alongside engagement of farmers in development of zoonotic disease prevention programs that encourage participation of both male and female farmers across all levels of education.

Intratumoral CD14+ Cells and Circulating CD14+HLA-DRlo/neg Monocytes Correlate with Decreased Survival in Patients with Clear Cell Renal Cell Carcinoma.

Immunotherapeutic strategies to treat patients with renal cell carcinoma (RCC) offer new opportunities for disease management. Further improvements to immunotherapy will require additional understanding of the host response to RCC development. Using a novel approach to understanding the immune status of cancer patients, we previously showed that patients with a certain immune profile had decreased overall survival. Here, we examine in more detail the phenotypic changes in peripheral blood and the potential consequences of these changes in RCC patients. We found that CD14(+)HLA-DR(lo/neg) monocytes were the most predominant phenotypic change in peripheral blood of RCC patients, elevated nearly 5-fold above the average levels measured in healthy volunteers. Intratumoral and peritumoral presence of CD14 cells was an independent prognostic factor for decreased survival in a cohort of 375 RCC patients. The amount of peripheral blood CD14(+)HLA-DR(lo/neg) monocytes was found to correlate with the intensity of CD14 staining in tumors, suggesting that the measurement of these cells in blood may be a suitable surrogate for monitoring patient prognosis. The interaction of monocytes and tumor cells triggers changes in both cell types with a loss of HLA-DR expression in monocytes, increases of monocyte survival factors such as GM-CSF in tumors, and increased production of angiogenic factors, including FGF2. Our results suggest a model of mutually beneficial interactions between tumor cells and monocytes that adversely affect patient outcome.

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype.

Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism–epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin–proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.

The Cystic Fibrosis Lung Microbiome

The chronic colonization of the lower airways by bacterial pathogens is the leading cause of morbidity and mortality in patients with cystic fibrosis (CF). Pseudomonas aeruginosa is the most common CF pathogen, followed by Staphylococcus aureus. Improvements in airway clearance and more effective treatment of the conventional CF pathogens has led to the emergence of new airway pathogens such as Stenotrophomonas maltophilia, Mycobacterium abscessus, and Achromobacter. More recently, it has become appreciated that the lower airways in patients with CF are colonized by a more complex polymicrobial community composed primarily of bacteria found in the upper respiratory tract. This includes obligate anaerobes, most commonly Prevotella. Expanded culturing methods and culture-independent molecular methods are being used to characterize the composition and dynamics of these polymicrobial communities in patients with CF. The contribution of the CF microbiome to airway disease is actively being investigated and will present new opportunities for disease management in CF. However, there remain many challenges that must be overcome if microbiome profiling is going to inform clinical practice.

Focused Ultrasound to Expel Calculi from the Kidney: Safety and Efficacy of a Clinical Prototype Device

Focused ultrasound has the potential to expel small stones or residual stone fragments from the kidney, or move obstructing stones to a nonobstructing location. We evaluated the efficacy and safety of ultrasonic propulsion in a live porcine model. Calcium oxalate monohydrate kidney stones and laboratory model stones (2 to 8 mm) were ureteroscopically implanted in the renal pelvicalyceal system of 12 kidneys in a total of 8 domestic swine. Transcutaneous ultrasonic propulsion was performed using an HDI C5-2 imaging transducer (ATL/Philips, Bothell, Washington) and the Verasonics® diagnostic ultrasound platform. Successful stone relocation was defined as stone movement from the calyx to the renal pelvis, ureteropelvic junction or proximal ureter. Efficacy and procedure time was determined. Three blinded experts evaluated histological injury to the kidney in the control, sham treatment and treatment arms. All 26 stones were observed to move during treatment and 17 (65%) were relocated successfully to the renal pelvis (3), ureteropelvic junction (2) or ureter (12). Average ± SD successful procedure time was 14 ± 8 minutes and a mean of 23 ± 16 ultrasound bursts, each about 1 second in duration, were required. There was no evidence of gross or histological injury to the renal parenchyma in kidneys exposed to 20 bursts (1 second in duration at 33-second intervals) at the same output (2,400 W/cm(2)) used to push stones. Noninvasive transcutaneous ultrasonic propulsion is a safe, effective and time efficient means to relocate calyceal stones to the renal pelvis, ureteropelvic junction or ureter. This technology holds promise as a useful adjunct to surgical management for renal calculi.

Genetic Studies of Age-related Macular Degeneration: Lessons, Challenges, and Opportunities for Disease Management

Age-related macular degeneration (AMD) is a common cause of visual impairment in individuals >55 years of age worldwide. The varying clinical phenotypes of AMD result from contributions of genetic, epigenetic, and nongenetic (environmental) factors. Genetic studies of AMD have come of age as a direct result of tremendous gains from the human genome project, genome-wide association studies, and identification of numerous susceptibility loci. These findings have implicated immune response, high-density lipoprotein cholesterol metabolism, extracellular matrix, and angiogenesis signaling pathways in disease pathophysiology. Herein, we address how the wealth of genetic findings in AMD is expected to impact the practice of medicine, providing opportunities for improved risk assessment, molecular diagnosis, preventive, and therapeutic intervention. We propose that the potential of using genetic variants for monitoring treatment response (pharmacogenetics) may usher in a new era of personalized medicine in the clinical management of AMD. Proprietary or commercial disclosures may be found after the references.

Cost-Effectiveness of Primary Prevention Strategies for Nephrolithiasis

Stone disease is a highly prevalent condition associated with substantial cost and morbidity. We evaluated the cost-effectiveness of a primary prevention strategy. A decision analysis model was constructed to compare the cost of ad hoc management of symptomatic stones vs the cost of primary prevention. A literature search was performed to determine the incidence of stone disease, the effectiveness of nonmedical prevention strategies and cost associated with stone management. One and 2-way sensitivity analyses were performed to determine conditions under which a strategy of primary prevention might be cost-effective. Assuming a 1% incidence of stones, a 50% risk reduction and a $100 cost per individual per year for primary prevention, the model was used to calculate the overall costs per individual per year without and with a primary prevention strategy of $46 and $123, respectively. One-way sensitivity analyses indicated that primary prevention was cost-effective if the incidence of stones exceeded 4.3% yearly or the cost of prevention was less than $23 per person yearly. Varying other factors (risk reduction, probability of requiring surgery, hours of lost work, emergency room cost) failed to reach cost equivalence under any circumstances or required unrealistic assumptions. Preventive strategies were more costly than no prevention unless the incidence of stone disease was at least 1%, the cost did not exceed $20 per person per year and the prevention strategy was at least 50% effective in preventing stones. Primary prevention strategies for stone disease have not been sufficiently evaluated but can theoretically be cost-effective if the population has a sufficiently high incidence of stone disease and the strategy is of low cost and moderately effective.

Practice Variation in the Surgical Management of Urinary Lithiasis

Shock wave lithotripsy and ureteroscopy are highly effective treatments for urinary lithiasis. While stone size and location are primary determinants of therapy, little is known about other factors associated with treatment. We identified patient, provider and practice setting characteristics associated with the selection of ureteroscopy or shock wave lithotripsy. We used the Medicare 5% sample to identify beneficiaries with an incident stone encounter from 1997 to 2007. Within this group we identified beneficiaries undergoing shock wave lithotripsy or ureteroscopy for the management of urinary calculi. Multivariable regression models identified factors associated with the use of ureteroscopy. The cohort comprised 9,358 beneficiaries who underwent an initial procedure. Shock wave lithotripsy was used in 5,208 (56%) beneficiaries while ureteroscopy was used in 4,150 (44%). Female patients were less likely than males to undergo ureteroscopy (OR 0.844, p = 0.006). Providers who more recently completed residency training used ureteroscopy more often (p = 0.023). Provider and facility volume were associated with initial procedure selection. The odds of a second procedure following initial shock wave lithotripsy were 1.54 times those of ureteroscopy (p <0.001). Nonclinical factors are associated with the use of ureteroscopy or shock wave lithotripsy for initial stone management, which may reflect provider and/or patient preferences or experience. Further investigation is required to understand the impact of these outcomes on quality and cost of care.

Genetic Assignment Methods for Gaining Insight into the Management of Infectious Disease by Understanding Pathogen, Vector, and Host Movement

For many pathogens with environmental stages, or those carried by vectors or intermediate hosts, disease transmission is strongly influenced by pathogen, host, and vector movements across complex landscapes, and thus quantitative measures of movement rate and direction can reveal new opportunities for disease management and intervention. Genetic assignment methods are a set of powerful statistical approaches useful for establishing population membership of individuals. Recent theoretical improvements allow these techniques to be used to cost-effectively estimate the magnitude and direction of key movements in infectious disease systems, revealing important ecological and environmental features that facilitate or limit transmission. Here, we review the theory, statistical framework, and molecular markers that underlie assignment methods, and we critically examine recent applications of assignment tests in infectious disease epidemiology. Research directions that capitalize on use of the techniques are discussed, focusing on key parameters needing study for improved understanding of patterns of disease.

Determinants of Quality of Life for Patients With Kidney Stones

We evaluated various factors relating to quality of life in a population of patients with stones. A total of 155 patients seen at our urology clinic for stones between January and May 2007 were prospectively questioned regarding stone history and were administered the SF-36 questionnaire to assess quality of life. Age, body mass index, American Society of Anesthesiologists score, number of stone episodes, interval from the last stone episode, number of surgical procedures for stones and associated complications, missed days of work and long-term medical treatment were elicited from the patients. Individual SF-36 domains and composite scores were compared to those of the American general population. Univariate and multivariate regression analyses were performed to assess the impact of all covariates on quality of life scores. Patients with stones scored lower than the average American population in 5 of the 8 domains of the SF-36 as well as in the physical composite score. Multivariate regression modeling showed that increasing body mass index and age were the strongest predictors of decreased physical well-being. The number of stone episodes did not influence SF-36 scores, although the number of surgical procedures impacted physical and mental components. The number of ureteroscopy procedures and stent placements primarily impacted mental well-being. Medical therapy, particularly the use of potassium citrate, was associated with more favorable quality of life. Various factors impact quality of life in patients with urolithiasis but the most important are body mass index, age and the number of surgical procedures. Prospective longitudinal studies may further elucidate the determinants of quality of life and they might be used to optimize patient care.

Direct and indirect costs of nephrolithiasis in an employed population: Opportunity for disease management?

More than 5% of the United States population has been diagnosed with nephrolithiasis and about one half of (first-time) stone formers will have a recurrence within 5 years. The prevalence of nephrolithiasis is concentrated among working age adults, yet little prior work has examined the economic burden of the disease on employers and their employees. We sought to estimate the direct and indirect costs of nephrolithiasis for working age adults (18-64) with employer-provided insurance. This was an observational study using retrospective claims data. Detailed medical and pharmacy claims from 25 large employers and absentee data from a subset of firms were used to estimate the direct and indirect costs associated with nephrolithiasis in a privately insured, non-elderly population. Multivariate regression models were used to predict health care expenditures for persons with and without the condition, controlling for differences in patient (health status) and plan characteristics. More than 1% of working-age adults were treated for nephrolithiasis in 2000. Prevalence was considerably higher among men and employees age 55 to 64. About one third of employees treated for nephrolithiasis in 2000 missed work due to the condition, with an average work loss for the entire treated population of 19 hours per person. Conditional on receiving treatment, the incremental costs of nephrolithiasis were 3,494 US dollars per person in 2000. The direct and indirect costs of nephrolithiaisis are substantial among working-age adults. Interventions that prevent recurrence among known stone formers may be a cost-effective component of disease management programs.

Identifying patients with gastroesophageal reflux disease in a managed care organization.

The ability of various strategies to identify patients with gastroesophageal reflux disease (GERD) and the relative economic impact on disease management programs for GERD were studied. A telephone interview was conducted of a random sample of patients enrolled in any of three health plans in a 100,000-member managed care organization who had either a pharmacy claim or an encounter claim during 1997. The telephone interview identified patients with GERD and served as the standard by which the sensitivity, specificity, and predictive values of the following patient-identification strategies were compared: (1) telephone interview, (2) chart review, (3) use of encounter claims, (4) use of pharmacy claims, (5) use of both encounter claims, and pharmacy claims, and (6) use of encounter claims or pharmacy claims. Conservative estimates of costs and projected savings were then used to model the potential return on investment of the strategies. A total of 1186 patients completed the telephone interview, of whom 390 (33%) met the case definition of GERD. The most sensitive method for identifying patients with GERD was using either pharmacy or encounter claims (26%). The most specific strategy with the highest positive predictive value (PPV) (87%) was using both pharmacy and encounter claims, but this approach had a case-detection rate of only 3%. Encounter claims were significantly more sensitive than pharmacy claims and yielded a higher estimate of prevalence. The telephone interview identified the most subjects who could have benefited from a disease management program and cost 84% less than chart review. While use of administrative data (pharmacy and encounter claims) was the least costly strategy, it identified 74% fewer patients expected to benefit from disease management. The efficiency of disease management programs for GERD may depend on the method of patient identification, which in turn may depend on whether PPV or negative predictive value (NPV) should be maximized. If there is a need to identify all cases (i.e., sensitivity and NPV are most important), then telephone interview may provide the greatest opportunity for disease management with the greatest return on investment, but at the expense of enrolling many patients who may not benefit.

DM and pharma companies

A s mentioned in a previous feature article,* disease management (DM) may become the dominant strategy for healthcare delivery in the US. And a number of other countries are exploring DM strategies, including the UK. While ongoing structural reforms in the UK National Health Service (NHS) provide new opportunities for DM, a recent report suggests there are several hurdles to overcome before the approach is widely adopted - not least a pervasive culture of suspicion within the NHS towards the pharmaceutical industry.

Interactive Voice Response in Disease Management

Interactive voice response (IVR) phone systems offer unique opportunities for disease management. This technology can address challenges in patient care, including how to provide personalised assessment and intervention to large populations in a cost efficient manner. Furthermore, the IVR point of contact yields critical patient data which can be used for outcomes management, identification, referral and triage for at-risk patients. The real-time database allows a clinical encounter to proceed through a path of questions and feedback which mimic the type of individualised care typical of face-to-face visits with a healthcare provider.

Effects of cover crops, weeds and plant debris on development ofMycocentrospora acerinain caraway

SummaryThis paper reports on the search for inoculum sources ofMycocentrospora acerinaon caraway (Carum carviL.). Obvious suspects are cover crops of biennial caraway and preceding crops of annual caraway. Other suspects are weeds in or alongside the field. Finally, survival structures of the fungus, chlamydospore chains, packed in plant debris or naked, are suspected.M. acerinais able to infect many plant species, including cover crops of caraway such as spinach for seed production and peas. However, the agronomical suitability of a crop to serve as a cover crop of biennial caraway proved to be a more important factor in determining caraway yield than the susceptibility of the cover crop toM. acerina.This finding was corroborated by the fact that spinach and peas as preceding crops had no significant effects onM. acerinadevelopment in spring caraway sown the next year. Dill, barley and four weed species were found as new hosts ofM. acerina.The role of weed hosts, susceptible crops and plant debris in the survival of the fungus in years without caraway is discussed. Caraway sown on soil containing infested caraway straw, infested debris of other plant species or chlamydospores grown in pure culture, became infected byM. acerina.Only high inoculum densities of chlamydospores in the soil caused severe damping‐off of caraway seedlings. The opportunity for disease management by agronomical means is quite limited.