Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

Rural versus urban commuting patients with stage III colon cancer: is there a difference in treatment and outcome?

BACKGROUND: To evaluate if there are differences in outcomes for patients with stage III colon cancer in those from urban vs. rural commuting areas. METHODS: Data were evaluated on patients diagnosed with stage III colon cancer between 2012 and2018 from the Louisiana Tumor Registry. Patients were classified into rural and urban groups. Data on overall survival, time from diagnosis to surgery and time from surgery to chemotherapy, and sociodemographic factors (including race, age, and poverty level) were recorded. RESULTS: Of 2652 patients identified, 2159 were urban (81.4%) and 493 rural (18.6%). No age difference between rural and urban patients (p = 0.56). Stage IIIB accounted for 66.7%, followed by IIIC (21.6%) and IIIA (11%), with a significant difference between rural and urban patients based on stage (p = 0.02). There was no difference in the extent of surgery (p = 0.34) or tumor size (p = 0.72) between urban and rural settings. No difference in undergoing chemotherapy (p = 0.12). There was a statistically significant difference in receiving timely treatment for hospital volume (p < 0.0001) and poverty level (p < 0.0001), but no difference in time from diagnosis to surgery (p = 0.48), and time from surgery to chemotherapy (p = 0.27). Non-Hispanic Blacks were less likely to receive timely treatment when compared with non-Hispanic Whites for both surgery and adjuvant chemotherapy, (aHR 0.91, 95% CI 0.83-0.99) and (aHR 0.86, 95% CI 0.77-0.97), respectively. There was no difference in Kaplan-Meier overall survival curves comparing rural vs. urban patients (p = 0.77). CONCLUSIONS: There was no statistical difference in overall survival, time to surgery, and time to adjuvant chemotherapy between rural and urban patients with Stage III colon cancer.

Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). INTERPRETATION: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration. FUNDING: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Value-based focused global population health management.

In 2018, approximately 18 million people worldwide were diagnosed with cancer and are predicted to double by 2040. The global quality chasm in improving health care worldwide requires "systems thinking" as the key to success. Aligning the goal around person-centered care captures the total needs of care of a population and not just disease categories. The integration of the Institute of Medicine's (IOM) six aims of quality termed "value-based focused" and population health management (PHM) provides all health care leaders grappling with improving the health care of the populations a framework for the communities they serve. In this context, the question becomes finding solutions to providing high quality, compassionate and patient-centered health care delivery. Over the last two decades, three paradigms have emerged; the six aims of quality, outcome-focused population health, and the "Quadruple Aim". We have termed the intersection of these concepts as Value-based focused Population Health Management (VBPHM). This review applies VBPHM across the geographic county and community levels in the United States. Specifically, we examine VBPHM at the county or county-equivalents and community levels within the United States. Lastly, the potential role of Community-based Participatory Research and it is applicability to our framework is discussed. VBPHM can comparably be applied globally to improve population health, especially in preventing and treating cancer better.

A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach.

The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.

Value-based chronic care model approach for vulnerable older patients with multiple chronic conditions.

"Old age, itself, is not a disease" (Suborne 2007). The rising rate of the global aging population is predicted to create a health care crisis within the next three decades. Vulnerable older adults suffer from multiple chronic conditions (MCCs) in addition to cognitive and physical decline during the process of aging resulting in an inability to optimally achieve self-management. In terms of resource utilization, complex inpatient, and outpatient care results in higher physician visits, polypharmacy, and higher prescription costs. Health literacy has become known as an important social determinant of health affecting the older population. Both reductions in health literacy and self-management are associated with poorer health outcomes. The patient activation measure (PAM) has been coined "a vital sign" to ascertain a patient activation level throughout the continuum of care with the introduction of an intervention's progress. In this review, we conceptualize a systematic approach of the development of a "tailored" integrated community and care team to develop a partnership in assisting senior adults with MCCs. Through this intervention the value-based chronic care model (CCM) and PAM allows for an adaptable integration between the activated patient, their caregivers, and the community. The Model for Improvement (MFI) serves as a well-recognized technique for developing and executing quality improvement strategies in this "tailored" engaged and activated individual and community care team approach in achieving health outcomes and quality of life among the vulnerable older adult population worldwide.

Esophageal cancer: the rise of adenocarcinoma over squamous cell carcinoma in the Asian belt.

Esophageal cancer is a common cancer worldwide with a high associated mortality rate. Amongst the two most frequent subsets of disease, squamous cell carcinoma (SCC) and adenocarcinoma (AC), there has been an epidemiologic shift towards adenocarcinoma over the last few decades. However, squamous cell carcinoma still predominates worldwide. Within Western countries, obesity has been associated with an increase in esophageal AC. A striking report from the World Health Organization (WHO) stated that worldwide obesity has tripled since 1975. In 2016, the WHO reported that greater than 1.9 billion adults are overweight and over 650 million were obese. In this review our goal is to analyze the esophageal cancer trends of China, which is the largest contributor among the esophageal cancer "Asian belt." Our intent is to evaluate whether there is a correlation between the rise in esophageal adenocarcinoma and obesity in this esophageal cancer "hotspot." With further analysis, the high-risk populations that are identified can be targeted to implement preventative strategies. This focus will aid in decreasing the burden of esophageal cancer at the global health level by addressing preventative strategies, such as screening endoscopy and lifestyle modifications. For example, WHO developed a global action plan on physical activity in response to the rise in obesity worldwide. Prevention is key to decreasing the rate of esophageal adenocarcinoma as majority of cases are diagnosed in the late stages leading to high mortality rates.

Implications of the growing incidence of global colorectal cancer.

The expanding worldwide burden of colorectal cancer (CRC) is a significant public health issue. Understanding the shift in the geo-demographic, socioeconomic, environmental, and biogenetic distribution of CRC is paramount. The Human Development Index (HDI) measuring life expectancy, education, and gross national income is a composite index comparing health outcomes between countries. This has been shown to be a useful comparison tool in measuring the health dimension among high, middle, and low-income countries. CRC has a wide global distribution in incidence and mortality with majority of cases occurring in countries with a high or very high HDI. However, in developing countries and in those undergoing rapid socioeconomic growth, there has also been a marked rise in CRC rates as well. This pattern is noted globally and seems to correlate with increase in a country's specific HDI. Additionally, another unique pattern of CRC incidence has emerged with more cancers being diagnosed in adults younger than 50 years old. Further investigation is needed to determine CRC risks reduction and implementation of primary prevention and early detection strategies within different country specific healthcare systems. Globally, improvement in healthcare equality, access to medical care and screening for CRC particularly in resource-limited (low HDI) countries is essential.

Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug-drug interaction predictions using a PBPK approach.

PURPOSE: Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically. METHODS: Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug-drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios. RESULTS: The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range. CONCLUSIONS: The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.

Mechanistic Modeling of Intra-Tumor Spatial Distribution of Antibody-Drug Conjugates: Insights into Dosing Strategies in Oncology.

Antibody drug conjugates (ADCs) provide targeted delivery of cytotoxic agents directly inside tumor cells. However, many ADCs targeting solid tumors have exhibited limited clinical efficacy, in part, due to insufficient penetration within tumors. To better understand the relationship between ADC tumor penetration and efficacy, previously applied Krogh cylinder models that explore tumor growth dynamics following ADC administration in preclinical species were expanded to a clinical framework by integrating clinical pharmacokinetics, tumor penetration, and tumor growth inhibition. The objective of this framework is to link ADC tumor penetration and distribution to clinical efficacy. The model was validated by comparing virtual patient population simulations to observed overall response rates from trastuzumab-DM1 treated patients with metastatic breast cancer. To capture clinical outcomes, we expanded upon previous Krogh cylinder models to include the additional mechanism of heterogeneous tumor growth inhibition spatially across the tumor. This expansion mechanistically captures clinical response rates by describing heterogeneous ADC binding and tumor cell killing; high binding and tumor cell death close to capillaries vs. low binding, and high tumor cell proliferation far from capillaries. Sensitivity analyses suggest that clinical efficacy could be optimized through dose fractionation, and that clinical efficacy is primarily dependent on the ADC-target affinity, payload potency, and tumor growth rate. This work offers a mechanistic basis to predict and optimize ADC clinical efficacy for solid tumors, allowing dosing strategy optimization to improve patient outcomes.

Social determinants of health associated with poor outcome for rural patients following resected pancreatic cancer.

BACKGROUND: The impact of rurality on outcome for patients who had resected pancreatic ductal adenocarcinoma (PDAC) is unclear. We hypothesize that poor outcomes for rural patients are associated with adverse social determinants of health (SDoH). The objective of this study is to assess the difference in overall survival (OS) of PDAC patients between rural, urban, and contributing factors. METHODS: A cohort of 25,536 patients diagnosed with stage I-III pancreatic adenocarcinoma from 2003 to 2011 and underwent resection were evaluated from the National Cancer Database. Socioeconomic/demographic, clinicopathological, and treatment variables were compared between rural and urban residences. The 5-year OS was calculated using the Kaplan-Meier method. The Cox regression model was used to assess factors associated with OS. P value <0.05 was considered significant. RESULTS: In univariate analysis, the rural residence was a predictor of poor OS. The 5-year OS for rural (N=4,389) and urban (N=21,147) was 18.8% (95% CI: 17.4-20.2%) and 22.3% (95% CI: 21.6-22.9%; P<0.0001), respectively. The risk of all causes of death was 10.3% higher (P<0.0001) in rural than urban patients. In multivariable analysis, rurality was not an independent predictor of OS (P=0.407). Independent predictors of worse OS included adverse social determinants of health associated with the rural population and these included a low income (P<0.0001), low education level (P<0.01), low insurance status (P<0.01), and treatment at a low-volume facility (P<0.0001). CONCLUSIONS: Rural/urban outcome disparities for resected stage I-III pancreatic cancer outcome can be explained by adverse social determinants of health associated with rural population.

Treatment at a high-volume academic research program mitigates racial disparities in pancreatic adenocarcinoma.

BACKGROUND: Racial disparities have long been a subject of concern between patients afflicted with pancreatic cancer in the United States. We believe that, in addition to a high-volume center, treatment at an academic research program (ARP) will mitigate racial outcome disparities. METHODS: A total of 12,950 patients diagnosed with stage I-III pancreatic adenocarcinoma from 2003-2011 and at ACS Commission on Cancer (COC) accredited facilities [e.g., high-volume (≥12 cases/year) ARPs] were evaluated from the National Cancer Data Base (NCDB). Sociodemographic, clinicopathological, and treatment variables were compared between Black (N=1,127) and White (N=11,823) patients. The Kaplan-Meier Estimator and Cox Proportional Hazards Model were used for survival analysis. P value ≤0.05 was considered significant. RESULTS: Black patients had a significantly higher overall survival (OS) than White patients, despite having a significantly lower household income, lower education level, more stage III disease, more Medicaid recipients, and higher comorbidity index (P<0.05). The 5-year unadjusted OS (28.6% versus 23.9%, a median survival time (months) was (25.2 versus 23.7 months for Black and White patients, respectively (P<0.05). There was no significant difference in surgical margin status or receipt of chemoradiation between the two cohorts. After adjusting for covariates, race was no longer a significant predictor of OS (P=0.096). CONCLUSIONS: Treatment at a high volume, ARP can mitigate racial disparities in pancreatic cancer.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.

Positive impact of the Patient Protection and Affordable Care Act Medicaid expansion on Louisiana women with breast cancer.

BACKGROUND: Louisiana is one of the few Southern states that enacted the Medicaid expansion of the Patient Protection and Affordable Care Act (ACA). To the authors' knowledge, the issue of how this has affected the breast cancer landscape in Louisiana is unknown. The authors have postulated that ACA expansion had a positive impact for Louisiana women diagnosed with breast cancer. METHODS: Data from the Louisiana Tumor Registry regarding 14,640 women aged 20 to 64 years who resided in Louisiana and were diagnosed with American Joint Committee on Cancer stage 0 to stage IV breast cancer between 2012 and 2018 were analyzed. The study period was divided into 2 groups: 1) before ACA expansion (January 1, 2012-May 31, 2016); and 2) after ACA expansion (June 1, 2016-December 31, 2018). The chi-square test and multivariable logistic regression models were used to assess the impact of ACA expansion. A P value <.05 was considered statistically significant. RESULTS: After ACA expansion, the rate of uninsured patients decreased from 5.4% to 3.0% (P < .0001), and the rate of Medicaid recipients increased from 11.6% to 17.7% (P < .0001). The diagnosis of stage I breast cancer increased from 36.8% to 44.7% (P < .0001), whereas the diagnosis of stage III breast cancer decreased from 10.7% to 8.5% (P < .0001). The receipt of radiotherapy after breast-conserving surgery increased from 81.2% to 84.0% (P = .0035), and the receipt of radiotherapy within 90 days increased from 57.2% to 61.7% (P = .0012). After adjustment for sociodemographic and clinical variables, the models demonstrated that ACA expansion decreased the uninsured rate by 48% (odds ratio [OR], 0.52; 95% CI, 0.43-0.63), increased the diagnosis of early-stage disease (stage0 to stage II) by 27% (OR, 1.27; 95% CI, 1.15-1.41), increased receipt of radiotherapy after breast-conserving surgery by 19% (OR, 1.19; 95% CI, 1.03-1.37), and reduced the delay of receipt of radiotherapy by 16% (OR, 0.84; 95% CI, 0.74-0.95). CONCLUSIONS: ACA expansion in Louisiana reduced the uninsured rate, increased the diagnosis of early-stage disease, and increased access to treatment.

Informing Development of Bispecific Antibodies Using Physiologically Based Pharmacokinetic-Pharmacodynamic Models: Current Capabilities and Future Opportunities.

Antibody therapeutics continue to represent a significant portion of the biotherapeutic pipeline, with growing promise for bispecific antibodies (BsAbs). BsAbs can target 2 different antigens at the same time, such as simultaneously binding tumor-cell receptors and recruiting cytotoxic immune cells. This simultaneous engagement of 2 targets can be potentially advantageous, as it may overcome disadvantages posed by a monotherapy approach, like the development of resistance to treatment. Combination therapy approaches that modulate 2 targets simultaneously offer similar advantages, but BsAbs are more efficient to develop. Unlike combination approaches, BsAbs can facilitate spatial proximity of targets that may be necessary to induce the desired effect. Successful development of BsAbs requires understanding antibody formatting and optimizing activity for both targets prior to clinical trials. To realize maximal efficacy, special attention is required to fully define pharmacokinetic (PK)/pharmacodynamic (PD) relationships enabling selection of dose and regimen. The application of physiologically based pharmacokinetics (PBPK) has been evolving to inform the development of novel treatment modalities such as bispecifics owing to the increase in our understanding of pharmacology, utility of multiscale models, and emerging clinical data. In this review, we discuss components of PBPK models to describe the PK characteristics of BsAbs and expand the discussion to integration of PBPK and PD models to inform development of BsAbs. A framework that can be adopted to build PBPK-PD models to inform the development of BsAbs is also proposed. We conclude with examples that highlight the application of PBPK-PD and share perspectives on future opportunities for this emerging quantitative tool.

Controlling the Speed of Light-Activated Colloids with a Constant, Uniform Magnetic Field.

It is demonstrated how the strength of activation for photocatalytic, self-propelled colloids can be enhanced with a constant, uniform magnetic field. When exposed to ultraviolet light and hydrogen peroxide, the titanium dioxide-based colloids become actively propelled. Due to the iron oxide core, a uniform field oriented perpendicular to the surface where motion takes place causes the asymmetrically shaped particles to rotate, which consequently leads to an increase in activity. The field-dependent dynamics of self-propulsion is quantified, and a qualitative description of how this effect arises is proposed. Since the application of the field is easily reversible, modulating the field on-and-off serves as a de facto "switch" that controls particle behavior.

Material-dependent performance of fuel-free, light-activated, self-propelling colloids.

Self-propelling, light-activated colloidal particles can be actuated in water alone. Here we study the effect of adding different amounts of a gold/palladium alloy to titanium dioxide-based, active colloids. We observe a correlation between alloy-thickness and the average speed of the particles, and we discover an intermediate thickness leads to the highest activity for this system. We argue that a non-continuous thin-film of the co-catalyst improves the efficiency of water-splitting at the surface of the particles, and in-turn, the performance of "fuel-free" self-propulsion.