Current status of hypertension care and management in the Philippines.

AIMS: In this paper, we discuss the existing data on the burden of hypertension in the Philippines and present the status of management, prevention, and control of hypertension in the country. METHODS: A literature review was conducted to synthesize the status of hypertension care in the Philippines. RESULTS: Hypertension continues to contribute to the country's leading causes of death. Similar to the global trend, almost half of hypertensive Filipinos are still not aware of their condition, and only 27 % have it under control. The prevalence of hypertension has steadily increased from 22 % in 1993 to 25.15 % in 2013. The 2020 Philippine Society for Hypertension clinical practice guideline defines hypertension as an office BP of 140/90 mm Hg or above following the proper standard BP measurement. During the past decade, monotherapy has been the mode of treatment in more than 80 % of Filipino patients. This could also explain why the BP control rates have been low. The most prevalent complications of hypertension in the Philippines were stroke (11.6 %), ischemic heart disease (7.7 %), chronic kidney disease (6.30 %), and hypertensive retinopathy (2.30 %). Hypertension causes economic tolls on patients, from the cost of drugs to hospitalization and complications. Hospitalization from hypertensive complications can easily wipe out the savings of middle-class families and is catastrophic for lower-income Filipinos. CONCLUSION: In this review, we summarize the existing data on the burden of hypertension among Filipinos and the risk factors associated with the disease. We present the current screening tools, diagnostics, treatment, and prevention strategies for hypertension in the Philippines. Lastly, we propose solutions to meet the global targets of hypertension management and help relieve the growing burden of this disease.

High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

Spider Bite Wound Care and Review of Traditional and Advanced Treatment Options.

Background: Approaches to chronic wound care are worlds apart: In developing nations, the care of chronic wounds often involves traditional management with local products (eg, honey, boiled potato peels, aloe vera gel, banana leaves); whereas in developed nations, more expensive and technologically advanced products are available (eg, wound vacuum, saline wound chamber, hyperbaric oxygen therapy, antibacterial foam). The cost for wound care plays a significant role in total health care costs, and that cost is expected to rise dramatically. Case Presentation: A healthy, 60-year-old man presented after being bitten by a spider 6 days earlier. He was treated and prescribed clindamycin 300 mg 4 times daily for 14 days. Despite treatment, the wound continued to enlarge, and the patient showed symptoms of septicemia. The patient was admitted to the hospital and remained for 3 days. On discharge the patient was given a prescription for doxycycline 100 mg twice a day for 10 days and instructed to use iodoform gauze to pack the wound during daily dressing changes. However, the gauze was ineffective. The patient's dressing was switched to an antibacterial foam dressing impregnated with gentian violet and methylene blue. Conclusions: There is a disparity in available wound care product availability. Modern products may yield faster healing times with fewer adverse effects than traditional products. Products used by local healers can produce satisfactory results when more modern products are unavailable and at a fraction of the cost.

Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners.

Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.

Comparison of Frailty Indices and the Charlson Comorbidity Index in Traumatic Brain Injury.

BACKGROUND: Comorbidity scales for outcome prediction in traumatic brain injury (TBI) include the 5-component modified Frailty Index (mFI-5), the 11-component modified Frailty Index (mFI-11), and the Charlson Comorbidity Index (CCI). OBJECTIVE: To compare the accuracy in predicting clinical outcomes in TBI of mFI-5, mFI-11, and CCI. METHODS: The National Trauma Data Bank (NTDB) of the American College of Surgeons (ACS) was utilized to study patients with isolated TBI for the years of 2017 and 2018. After controlling for age and injury severity, individual multivariable logistic regressions were conducted with each of the 3 scales (mFI-5, mFI-11, and CCI) against predefined outcomes, including any complication, home discharge, facility discharge, and mortality. RESULTS: All 3 scales demonstrated adequate internal consistency throughout their individual components (0.63 for mFI-5, 0.60 for CCI, and 0.56 for mFI-11). Almost all studied complications were significantly more likely in frail patients. mFI-5 and mFI-11 had similar areas under the curve (AUC) for all outcomes, while CCI had lower AUCs (0.62-0.61-0.53 for any complication, 0.72-0.72-0.52 for home discharge, 0.78-0.78-0.53 for facility discharge, and 0.71-0.70-0.52 for mortality, respectively). CONCLUSION: mFI-5 and mFI-11 demonstrated similar accuracy in predicting any complication, home discharge, facility discharge, and mortality in TBI patients across the NTDB. In addition, CCI's performance was poor for the aforementioned metrics. Since mFI-5 is simpler, yet as accurate as the 2 other scales, it may be the most practical both for clinical practice and for future studies with the NTDB.

Evaluating an ACT-Based Brief Intervention for Educators Treatment Package on Reported Well-Being and ACT-Consistent Language in the Classroom.

Educators continue to experience stress and burnout, both of which have been negatively impacted by the COVID-19 pandemic, and there continues to be a need to develop interventions that support not only educators' well-being, but a climate within school buildings that fosters psychological well-being for students and school staff alike. Acceptance and Commitment Therapy (ACT) is one promising approach to interventions for both educator and student psychological well-being. The present study sought to evaluate the effect of a low-dosage, online, and remotely delivered ACT intervention for educators on self-reported burnout, psychological flexibility, ACT knowledge, and frequency of use of ACT-consistent language while teaching in an alternative educational setting. The ACT-based intervention targeted the development of educator psychological flexibility, but the analysis provided an evaluation of non-targeted participants' use of ACT-consistent language in the classroom, as well. Results suggest an overall improvement in participants' self-reported burnout and psychological flexibility, an increase in participants' ACT knowledge following each phase of the study, and an increase in the frequency of ACT-consistent language for all participants following the onset of a feedback component. We discuss potential implications of practical ACT-based interventions for educators in an applied setting and related increases in ACT-consistent verbal stimuli within the classroom setting.

Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8H-purin-8-one Inhibitors of DNA-PK.

The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10-15 µM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pK a, to identify compound 18, which combines low hERG activity (IC50 = 75 µM) with excellent kinome selectivity and favorable pharmacokinetic properties.

Upright versus supine MRI: effects of body position on craniocervical CSF flow.

BACKGROUND: Cerebrospinal fluid (CSF) circulation between the brain and spinal canal, as part of the glymphatic system, provides homeostatic support to brain functions and waste clearance. Recently, it has been observed that CSF flow is strongly driven by cardiovascular brain pulsation, and affected by body orientation. The advancement of MRI has allowed for non-invasive examination of the CSF hydrodynamic properties. However, very few studies have addressed their relationship with body position (e.g., upright versus supine). It is important to understand how CSF hydrodynamics are altered by body position change in a single cardiac phase and how cumulative long hours staying in either upright or supine position can affect craniocervical CSF flow. METHODS: In this study, we investigate the changes in CSF flow at the craniocervical region with flow-sensitive MRI when subjects are moved from upright to supine position. 30 healthy volunteers were imaged in upright and supine positions using an upright MRI. The cranio-caudal and caudo-cranial CSF flow, velocity and stroke volume were measured at the C2 spinal level over one cardiac cycle using phase contrast MRI. Statistical analysis was performed to identify differences in CSF flow properties between the two positions. RESULTS: CSF stroke volume per cardiac cycle, representing CSF volume oscillating in and out of the cranium, was ~ 57.6% greater in supine (p < 0.0001), due to a ~ 83.8% increase in caudo-cranial CSF peak velocity during diastole (p < 0.0001) and extended systolic phase duration when moving from upright (0.25 ± 0.05 s) to supine (0.34 ± 0.08 s; p < 0.0001). Extrapolation to a 24 h timeframe showed significantly larger total CSF volume exchanged at C2 with 10 h spent supine versus only 5 h (p < 0.0001). CONCLUSIONS: In summary, body position has significant effects on CSF flow in and out of the cranium, with more CSF oscillating in supine compared to upright position. Such difference was driven by an increased caudo-cranial diastolic CSF velocity and an increased systolic phase duration when moving from upright to supine position. Extrapolation to a 24 h timeframe suggests that more time spent in supine position increases total amount of CSF exchange, which may play a beneficial role in waste clearance in the brain.

Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance.

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs.

PURPOSE: Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood-brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy. EXPERIMENTAL DESIGN: We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models. RESULTS: In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (C max %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth. CONCLUSIONS: These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.

Reducing 30-day post gastrostomy insertion mortality with a feeding issues multidisciplinary team meeting.

INTRODUCTION: Decision-making regarding percutaneous endoscopic gastrostomy (PEG) insertion can be complex both medically and ethically. Thirty-day mortality following (PEG) insertion is an important quality indicator for endoscopy accreditation and for service evaluation. It also forms part of the measures assessed within the 'Getting It Right First Time' programme (GIRFT). We aimed to assess the impact of a newly adopted Feeding Issues MDT (FIMDT) and the clinical application of the Royal Free Gastrostomy Score (RFGS). METHOD: We adopted a retrospective observational methodology to assess the impact of a feeding issues MDT within our trust. The included study period ran from January 2016 to December 2019 (4 years). This formed part of a quality improvement (QI) project initiated upon receipt of the GIRFT report for our NHS trust. Statistical analysis and QI methodology was used to interpret and present the data. RESULTS: Two hundred and sixty eight PEG insertions occurred during the study period. 188 PEGs were inserted prior to the start of FIMDT and 45 following its inception. On average there were 66 PEGs performed per year. There was no significant difference in age for those undergoing PEG insertion pre (68 years) and post (69 years) FIMDT adoption. Prior to FIMDT those that died within 30 days post PEG were significantly older than those who did not (p < 0.001), whilst following FIMDT adoption there was no such difference. Prior to FIMDT the 30-day post PEG mortality was 10.64%, whilst following adoption of the FIMDT the mortality rate fell to 6.6% (p = 0.04). The mean number of procedures performed between a 30-day mortality occurring rose from 7.5 to 13.6. Furthermore, the mean number of days between a 30-day post insertion mortality occurring also rose from a mean of 53.0-111.8, pre and post FIMDT adoption. The Royal Free Gastrostomy Score (RFGS) for those discussed at FIMDT and declined for PEG insertion was significantly higher than those accepted for PEG insertion (p = 0.01). Over the entire study period those who died within 30 days following PEG insertion had a significantly greater RFGS (p < 0.0001). CONCLUSION: In our trust the adoption of a FIMDT has significantly reduced the 30-day mortality for PEG insertion. We have also demonstrated the clinical utility to assess mortality risk of the RFGS when making decisions around patient suitability for PEG insertion.

May Measurement Month 2018: an analysis of blood pressure screening in the Philippines.

Building on the gains of May Measurement Month 2017 (MMM17), the Philippine Society of Hypertension once again took part in MMM18 to raise awareness of high blood pressure (BP) in the country and to harness opportunistic BP screening in detecting unaware hypertensive individuals and referring them for treatment. We followed the standard MMM18 protocol designed by the International Society of Hypertension, utilizing convenience sampling with volunteer investigators, taking three sitting BP measurements of volunteer adults (≥18 years). Basic data on demographic, lifestyle, and environmental factors were also taken. We analysed 177 176 screened individuals from the Philippines. Of these, 29.1% (51 527) had also participated in MMM17, whereas 68.8% (121 893) were new screenees; and 14.2% (25 232) had their BP taken for the first time ever. After multiple imputation, 39.0% (69 126) were hypertensive. Of these, 50.3% (34 795) were aware they were hypertensive. 49.9% (34 491) were on antihypertensive medication, 58.0% (20 010) of whom had controlled BP <140/90 mmHg. Only 28.9% of all participants with hypertension had controlled BP. Systolic BPs and diastolic BPs were significantly higher in the overweight and obese, in those receiving antihypertensive medications, in patients with diabetes, and significantly lower in pregnant women. MMM18 has again shown that opportunistic BP screening, harnessing volunteers, is a pragmatic public health measure to improve awareness and treatment rates of raised BP.

Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures.

BACKGROUND: Three clusters of coronavirus disease 2019 (COVID-19) linked to a tour group from China, a company conference, and a church were identified in Singapore in February, 2020. METHODS: We gathered epidemiological and clinical data from individuals with confirmed COVID-19, via interviews and inpatient medical records, and we did field investigations to assess interactions and possible modes of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Open source reports were obtained for overseas cases. We reported the median (IQR) incubation period of SARS-CoV-2. FINDINGS: As of Feb 15, 2020, 36 cases of COVID-19 were linked epidemiologically to the first three clusters of circumscribed local transmission in Singapore. 425 close contacts were quarantined. Direct or prolonged close contact was reported among affected individuals, although indirect transmission (eg, via fomites and shared food) could not be excluded. The median incubation period of SARS-CoV-2 was 4 days (IQR 3-6). The serial interval between transmission pairs ranged between 3 days and 8 days. INTERPRETATION: SARS-CoV-2 is transmissible in community settings, and local clusters of COVID-19 are expected in countries with high travel volume from China before the lockdown of Wuhan and institution of travel restrictions. Enhanced surveillance and contact tracing is essential to minimise the risk of widespread transmission in the community. FUNDING: None.

Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.

DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.