International Journal of Clinical Case Reports 2026, Vol.16 http://medscipublisher.com/index.php/ijccr © 2026 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
International Journal of Clinical Case Reports 2026, Vol.16 http://medscipublisher.com/index.php/ijccr © 2026 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in clinical case, clinical medicine, new variations in disease processesregistered at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Edited by Editorial Team of International Journal of Clinical Case Reports Email: edit@ijccr.medscipublisher.com Website: http://medscipublisher.com/index.php/ijccr Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada International Journal of Clinical Case Reports (ISSN 1927-579X) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is considering all the latest and outstanding research articles, letters and reviews in all aspects of clinical case, containing clinical medicine which advance general medical knowledge; the event in the course of observing or treating a patient; new variations in disease processes; as well as the expands the field of clinical relating to case reports. All the articles published in International Journal of Clinical Case Reports are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
International Journal of Clinical Case Reports (online), 2026, Vol. 16, No.1 ISSN 1927-579X http://medscipublisher.com/index.php/ijccr © 2026 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Early Clinical Applications, Pitfalls, and Imaging Integration of ctDNA-MRD in Early-Stage Solid Tumors Hui Xu International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 1-10 Concentration and Heterogeneity of Medication Combination Patterns for Common Diseases in Retail Pharmacies: Evidence from Xiongcheng Jianmin Pharmacy in Zhuji City, 2023-2024 Caijuan Shuo, Xiaoping Cai International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 11-18 The Role of Nurses in Medication Reconciliation, Patient Education, and Adherence Management Wei Shi, Mingzi Huang, Yeli Huan International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 19-30 Nursing Assessment Tools for Postpartum Pelvic Floor Dysfunction and Their Appropriate Use Scenarios DanXu International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 31-41 Genomics-Metabolomics Integration in Neurometabolic And Rare Neurologic Disorders: Diagnostic Pathways and Clinical Impact ManmanLi International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 42-52 Genomics-Metabolomics Integration in Neurometabolic And Rare Neurologic Disorders: Diagnostic Pathways and Clinical Impact Tiantian Li, Jie Zhang International Journal of Clinical Case Reports, 2026, Vol. 16, No. 1, 53-65
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 1 Research Article Open Access Early Clinical Applications, Pitfalls, and Imaging Integration of ctDNA-MRD in Early-Stage Solid Tumors Hui Xu Tianjin Medical University Cancer Institute and Hospital, Hexi, 300210, Tianjin, China Corresponding email: xuhui@163.com International Journal of Clinical Case Reports 2026, Vol.16, No.1 doi: 10.5376/ijccr.2026.16.0001 Received: 16Nov., 2025 Accepted: 21 Dec., 2026 Published: 03 Jan., 2026 Copyright © 2026 Xu, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Xu H., 2026, Early clinical applications, pitfalls, and imaging integration of ctDNA-MRD in early-stage solid tumors, International Journal of Clinical Case Reports, 16(1): 1-10 (doi: 10.5376/ijccr.2026.16.0001) Abstract This study explores the latest advancements in circulating tumor DNA (ctDNA) testing and discusses the clinical significance of ctDNA-based minimal residual disease (ctDNA-MRD). As a liquid biopsy marker, ctDNA-MRD can capture the signals of trace residual diseases at the molecular level and is gradually being used to assess the risk of recurrence and guide follow-up management. Numerous studies have shown that patients with positive ctDNA test results after treatment are more likely to experience recurrence and have poorer survival outcomes. In many cases, the changes in ctDNA prece de imaging findings, providing doctors with earlier reference for adjusting treatment plans and follow-up strategies. In practical applications, ctDNA-MRD also has certain limitations. Factors such as individual biological differences, low ctDNA release levels, clonal hematopoiesis interference, and differences in detection platforms can all affect the accuracy of the results, potentially leading to false negatives or false positives. If one relies too heavily on a single test result, it may result in insufficient or excessive treatment. ctDNA is suitable for dynamic monitoring, while imaging is still indispensable for locating lesions. The combined application of the two is considered a more reliable approach. With further clinical validation, ctDNA-MRD is expected to gradually evolve fro m a predictive indicator to a more practically meaningful decision support tool. Keywords Circulating tumor DNA; Minimal residual disease; Early-stage solid tumors; Molecular relapse; Imaging integration 1 Introduction In the treatment of early-stage solid tumors, determining whether the disease has been completely cured has always been a challenge. Even after surgery or systemic treatment, there may still be residual malignant cells at the molecular level in the body, which is what we commonly refer to as minimal residual disease (MRD). These lesions are difficult to detect clinically, but they may eventually lead to cancer recurrence or metastasis (Pantel and Alix-Panabières, 2024). Currently, the recurrence rate of early-stage solid tumors is still not low, which indicates that traditional imaging examinations and serum markers are not sensitive enough in monitoring molecular-level residual lesions. Over the years, high-throughput sequencing and error correction technologies have become increasingly mature, and the sensitivity of circulating tumor DNA (ctDNA) detection has also significantly improved. Therefore, micro-residual disease assessment based on ctDNA (ctDNA-MRD) has become an important alternative indicator for evaluating molecular residual disease (Semenkovich et al., 2023; Quinn et al., 2025). Many prospective studies and systematic reviews have confirmed that if ctDNA remains positive after radical treatment, the risk of recurrence and death for patients will significantly increase, and this positive signal often appears earlier than imaging abnormalities or clinical symptoms. In various solid tumors, ctDNA signals can predict the risk of recurrence 4 to 12 months in advance, and its prognostic value is very stable (Zhu et al., 2023; Zheng et al., 2024). However, there are still many challenges to be addressed in the practical clinical application of ctDNA-MRD. For instance, there are differences in results among different detection platforms, and the criteria for positive determination are not uniform. Moreover, there is currently no mature framework that can effectively integrate it with imaging, clinical pathological indicators (Boukouris et al., 2025). Imaging is crucial for lesion localization, but its sensitivity in detecting minor lesions is limited; while ctDNA can better reflect the overall tumor burden and clonal evolution. The complementarity of their time and information aspects can improve the accuracy of
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 2 recurrence risk assessment, especially when imaging results are unclear, and it can also provide reference for decision-making on adjuvant therapy (Pantel and Alix-Panabières, 2024). This study will explore the current clinical application status of ctDNA-MRD in early solid tumors, analyze the common misunderstandings and actual challenges that may arise during its interpretation process, and also discuss the feasible paths for its combination with multimodal imaging. By integrating existing research evidence and related controversies, it is hoped to promote the transformation of ctDNA-MRD from a research tool to a standardized clinical application method, providing support for the precise treatment of early solid tumors. 2 Technical Foundation and ctDNA-MRD Detection Strategy 2.1 Biological source and dynamic characteristics of ctDNA Circulating tumor DNA (ctDNA) accounts for a relatively small proportion in circulating free DNA (cfDNA). It mainly comes from the apoptosis, necrosis, or active release of tumor cells, carrying the unique characteristics of the tumor, such as somatic mutations, copy number alterations, and abnormal methylation. The fragments of ctDNA in plasma are mostly concentrated around 160-180 base pairs. This characteristic of the fragments is also utilized in fragmentomics and multi-omics MRD detection (Zhu et al., 2023). In the early stages of tumors or after patients undergo radical treatment, the proportion of ctDNA is usually less than 0.1%. It is indeed quite challenging to find such a very low-frequency signal in the background of a large amount of normal DNA (Semenkovich et al., 2023). Moreover, the half-life of ctDNA is only a few hours, which actually has an advantage as it can quickly reflect the treatment effect and the changes in post-treatment tumor burden. Before tumor recurrence, the level of ctDNA tends to increase exponentially, and its doubling time is closely related to the detection sensitivity (Isbell et al., 2024). In various solid tumors, ctDNA-negative residual disease can usually indicate the risk of recurrence 4 to 12 months earlier than imaging examinations (Zhu et al., 2023). However, it should be noted that the release amount of ctDNA is affected by tumor type, growth location, blood supply, and treatment conditions. If the release amount is low or there is inflammation after surgery, it may lead to false-negative results in the detection (Chen and Zhou, 2023). Therefore, when interpreting the test results, one should not only consider a single test but also combine continuous monitoring and clinical reality for judgment (Semenkovich et al., 2023). 2.2 Main detection methods of ctDNA-MRD The commonly used clinical strategies for ctDNA-MRD detection currently can be broadly classified into two categories: one is information-based detection based on tissues, and the other is non-tissue-based detection. Let's start with the information-based detection. In simple terms, it involves sequencing the primary tumor (usually accompanied by germline samples) to identify the patient-specific mutation sites, and then conducting ultra-deep tracking detection on plasma samples. By combining UMI tagging and error correction techniques, the false positive rate can be reduced even when the tumor burden is low (Kasi et al., 2022). This method has demonstrated clinical value in risk stratification and adjuvant treatment decision-making for diseases such as colorectal cancer (Chidharla et al., 2023), but it also has limitations-it relies on high-quality tissue samples, has high detection costs, and may miss newly emerging clonal variations (Semenkovich et al., 2023). There is another type of non-organ-based detection. This method does not rely on specific organs and directly analyzes the free DNA in the plasma. Based on the preset mutation panel, copy number abnormalities, or methylation characteristics, it determines whether MRD exists. In recent years, by integrating fusion mutations and methylation signals, the ability of this method to detect ultra-low abundance ctDNA has been enhanced (Zhu et al., 2023; Quinn et al., 2025), and the operation is also simpler and more suitable for situations without tissue samples. However, it is prone to interference from background noise, especially the impact of clonal hematopoiesis. Therefore, it usually needs to be combined with white blood cell sequencing or filtered using strict algorithms (Semenkovich et al., 2023). 2.3 The impact of pre-analysis processing on detection accuracy In the MRD detection scenario, the content of ctDNA is already extremely low. Therefore, the pre-analysis
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 3 processing steps in the early stage have a particularly significant impact on the accuracy of the final detection results. For instance, the type of collection tube, centrifugation conditions, the time of plasma separation, the sample storage method, and the sample volume all can change the background level of cfDNA. If the operation is improper, it may lead to white blood cell lysis, increase genomic DNA contamination, reduce the proportion of ctDNA, and thereby increase the risk of false negatives (Chen and Zhou, 2023). Therefore, using dedicated cfDNA collection tubes and strictly controlling the processing time window are the key to ensuring the consistency of the detection results (Quinn et al., 2025). In addition, the performance of the detection is not only related to the sequencing depth, but also influenced by error suppression techniques (such as UMI, double-strand sequencing, algorithm noise reduction), the number of target sites, and the multi-signal integration method. To accurately identify ultra-low-frequency genetic changes, systematic errors must be controlled within the order of 10⁻⁵. Currently, different detection platforms have differences in positive thresholds and interpretation rules, which also limits the comparability of the detection results of each platform. At the same time, biological factors such as clonal hematopoiesis may lead to false positive results, which requires a comprehensive judgment combined with paired controls, longitudinal follow-up, as well as imaging and clinical information (Semenkovich et al., 2023). 3 Clinical Application of Blood-Free DNA (ctDNA)-Minimal Residual Disease (MRD) in Early Solid Tumors 3.1 Detection of postoperative minimal residual disease and risk stratification of recurrence Even if radical resection surgery is performed on patients with early-stage solid tumors, the risk of recurrence cannot be completely eliminated. In my research, I found that some early-stage patients did not detect any abnormalities during postoperative imaging examinations, but their conditions still progressed during the follow-up period. This situation occurs mostly because there are still molecular-level lesions remaining in the body. Relevant studies have confirmed that during the "microscopic residual disease window period" of approximately 2 to 10 weeks after surgery, if ctDNA is positive during the test, it has a strong correlation with subsequent recurrence, and it usually occurs much earlier than the changes shown on imaging (Elliott et al., 2025). Specifically for different types of tumors, for instance localized lung cancer, using deep sequencing based on tissue information can detect recurrence signs earlier than imaging examinations; while for resectable colorectal cancer, the status of ctDNA after surgery, in predicting the risk of recurrence, is even better than the traditional pathological staging, which also makes ctDNA-MRD an important molecular stratification tool (Chidharla et al., 2023). Unlike the static TNM staging system, ctDNA can reflect the dynamic changes of residual tumor clones. Large-scale prospective studies like GALAXY have confirmed that early positive ctDNA after surgery can independently predict disease-free survival and overall survival (Nakamura et al., 2024). However, it should be noted that the interpretation of these results requires considering signal intensity, duration, and clinical reality, and a negative ctDNA result does not mean there is absolutely no recurrence risk. 3.2 Application of ctDNA-MRD in treatment guidance and efficacy monitoring Traditional adjuvant treatments are usually stratified based on population risk, which can easily lead to over-treatment or under-treatment issues. However, ctDNA-MRD can precisely provide a basis for individualized treatment decisions: if ctDNA remains positive, it indicates that there are still active tumor lesions in the body, and it may be necessary to strengthen the treatment or extend the treatment period; if it remains negative, unnecessary treatment interventions can be reduced, avoiding patients from bearing excessive treatment burdens (Semenkovich et al., 2023; Abidoye et al., 2025). In patients with non-small cell lung cancer and colorectal cancer, patients with positive MRD showed more significant benefits from adjuvant therapy, while patients with negative MRD benefited less from chemotherapy. Currently, there are relevant randomized studies exploring strategies to adjust treatment intensity based on ctDNA test results (Vellanki et al., 2023). A longitudinal analysis of the GALAXY cohort also further demonstrated that continuous ctDNA clearance was associated with improved disease-free survival (DFS) and overall survival (OS), and a recurrence risk increase was indicated when ctDNA turned positive again (Nakamura et al., 2024).
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 4 Additionally, the dynamic changes of ctDNA have been regarded as potential alternative endpoints and trial screening tools for research (Semenkovich et al., 2023; Vellanki et al., 2023; Kobayashi et al., 2025). However, there are differences among different tumor types and different detection platforms. Without evidence from randomized controlled studies, relying solely on ctDNA results to adjust treatment still carries certain risks (Figure 1). Figure 1 Role of ctDNA-MRD in Postoperative Recurrence Risk Assessment and Treatment Monitoring 3.3 Clinical significance of ctDNA dynamics for early recurrence prediction One of the most compelling clinical advantages of ctDNA-MRD lies in its ability to predict recurrence ahead of conventional methods. Longitudinal studies across multiple cancers consistently demonstrate that conversion from ctDNA-negative to ctDNA-positive status, or persistent positivity during follow-up, predicts clinical recurrence with high sensitivity and specificity and typically precedes radiographic detection by several months, creating a “molecular recurrence window”. In colorectal cancer, dynamic ctDNA monitoring detects recurrence earlier than carcinoembryonic antigen (CEA) testing and routine imaging, with lead times commonly ranging from 2 to 11.5 months; systematic reviews further show that patients who convert to or remain ctDNA-positive after surgery or adjuvant therapy have significantly worse recurrence-free or disease-free survival than those who remain ctDNA-negative (Chidharla et al., 2023; Negro et al., 2025). Similar findings have been reported in localized NSCLC, where persistent ctDNA positivity during surveillance precedes imaging-confirmed relapse by months and can be incorporated into time-to-event models for individualized risk estimation. Beyond binary positivity, ctDNA trajectories convey additional clinically relevant information. Rates of increase, changes in mutational profiles, and the emergence of new variants can reflect clonal evolution and biological progression, and serial monitoring is better suited than single measurements to distinguish transient fluctuations from true relapse trends. These dynamic features provide a practical framework for integrating ctDNA with imaging over time—for example, using ctDNA conversion to trigger intensified imaging or biopsy, or reducing the posterior probability of “true recurrence” when imaging is equivocal but ctDNA remains persistently negative. Importantly, however, earlier detection of molecular recurrence does not automatically translate into survival benefit. Definitive evidence is still lacking to show that ctDNA-triggered early intervention universally improves outcomes, with unresolved questions regarding molecular recurrence thresholds, optimal timing of intervention, and the risk of overtreatment (Comino-Méndez et al., 2025). Consequently, the optimal role of ctDNA-MRD in
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 5 recurrence surveillance is likely as part of an integrated, verifiable decision-support framework that combines staging, treatment history, imaging, and other biomarkers (Kasi et al., 2022; Kobayashi et al., 2025). 4 Clinical Misunderstandings and Challenges in the Practical Application of ctDNA-MRD 4.1 Biological differences and false-negative results caused by low ctDNA release In clinical practice, many people mistakenly believe that a negative postoperative ctDNA result indicates the absence of residual lesions in the body. However, this is not the case. ctDNA-MRD testing relies on capturing the DNA released by residual tumor clones to predict the risk of recurrence. However, this core biological assumption is not applicable in all situations. Especially in early-stage tumors or after radical treatment, the ctDNA levels in the body are already very low. Tumors that are small in size, grow slowly, have a mild degree of necrosis, or are located in areas with limited release capabilities (such as the central nervous system or abdominal cavity) are difficult to release sufficient DNA into the bloodstream. Even if there are residual lesions, the signals may not be detectable (Pellini and Chaudhuri, 2022; Zhong et al., 2023). Although the specificity of ctDNA-MRD is usually quite high, its sensitivity is only 40% to 70%, and this problem becomes more obvious when conducting a single test (Pellini and Chaudhuri, 2022; Sato, 2025). In my research, I found that continuous multiple samplings can improve the accuracy of the detection. Additionally, the heterogeneity of tumors and clonal evolution make the interpretation of results more complex-those residual subclonal lesions that were not tracked or new dominant clones that emerged may not be captured by the preset detection panel (Semencovich et al., 2023). Moreover, postoperative inflammation, tissue repair, and adjuvant therapy can temporarily change the background environment of cfDNA, so the negative results in the early postoperative period are not reliable and cannot be regarded as evidence of complete cfDNA clearance (Faulkner et al., 2022; Zhong et al., 2023). Therefore, for low-release tumors, a negative ctDNA result can only be understood as "not detected", not equivalent to "absent", and must be combined with pathological risk factors and imaging follow-up for comprehensive judgment (Zhu et al., 2023; Wang et al., 2025). 4.2 Technical noise, chip interference and platform differences Apart from the biological factors mentioned earlier, technical issues also introduce considerable uncertainty to the ctDNA-MRD detection. The core of MRD detection is to capture extremely subtle frequency changes, which makes the detection results highly susceptible to various factors, such as errors in polymerase chain reaction products, sequencing errors, oxidative damage, and various interferences during the in vitro processing. Even with the use of UMI tagging, dual-end sequencing, and computational noise reduction techniques, background errors cannot be completely eliminated. Once the true variant signal approaches the detection threshold, the risks of false negatives and false positives will significantly increase (Semenkovich et al., 2023). Among them, the ambiguous potential clonal hematopoiesis (CHIP) is a crucial interfering factor. Genes such as DNMT3A, TET2, ASXL1, and TP53, which are age-related mutations, often appear in plasma cfDNA and can overlap with the tumor mutation profile. Without paired leukocyte sequencing or without a strict screening process, these mutations may be misidentified as ctDNA from tumor sources, thereby leading to false positive results (Kasi et al., 2022; Sato, 2025). In addition, the differences between different detection platforms are also significant, such as target design, library preparation, cfDNA input volume, sequencing depth, error models, and positive thresholds. These differences limit the comparability of the detection results. Low VAF variations may also lead to different results from different platforms, causing difficulties in individual result interpretation and cross-study integration (Figure 2). Therefore, standardized operating procedures and cross-platform validation are still necessary to improve the reliability of the detection (Pellini and Chaudhuri, 2022; Zhong et al., 2023; Hoang et al., 2025). 4.3 Risks of over-reliance on ctDNA-MRD in clinical decision-making As the prognostic value of ctDNA-MRD has been increasingly recognized by more and more people, in clinical decision-making, sometimes its role is overemphasized. However, from the perspective of practical application, due to its limited sensitivity, a negative ctDNA result does not mean that the patient has completely recovered. I have found that some patients who later relapsed had negative ctDNA test results at key follow-up time points. If
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 6 the treatment intensity is prematurely reduced based solely on this negative result, it may affect the long-term treatment outcome (Faulkner et al., 2022; Hoang et al., 2025). Figure 2 Biological and Technical Determinants of ctDNA-MRD Accuracy Conversely, relying solely on positive ctDNA results and blindly intensifying high-cost and high-risk treatments will also expose patients to unnecessary risks, especially when there is no reliable evidence from randomized controlled studies to support it (Zhu et al., 2023). Over-interpreting ctDNA results can also lead to excessive imaging examinations, invasive surgeries, or prolonged systemic treatment times, which not only increase the economic burden on patients but also bring additional clinical risks (Semenkovich et al., 2023). Therefore, ctDNA-MRD can only serve as an auxiliary tool for clinical decision-making and cannot be used as the sole basis for decision-making. It must be combined with the patient's pathological characteristics, imaging results, treatment history, and other biomarkers, and also requires confirmation through prospective trials to determine whether MRD-guided intervention measures can truly improve the survival benefits of patients (Chen et al., 2025). 5 The Integrated Application of ctDNA-MRD and Imaging Technology 5.1 Complementarity in time and information ctDNA-MRD and imaging do not look at the tumor from the same angle. ctDNA focuses on molecular signals circulating in the whole body and often raises an alarm before structural changes become visible. Imaging, on the other hand, shows where the lesion is, how large it is, and how it should be staged—information that remains essential for treatment planning (Pantel and Alix-Panabières, 2024). In non-small cell lung cancer and colorectal cancer, ctDNA conversion from negative to positive frequently precedes radiographic relapse by several months, a period described as the “molecular recurrence window” (Zheng et al., 2024; Azzi et al., 2025). Imaging abnormalities usually appear only after the tumor reaches a detectable size or metabolic threshold. From a practical perspective, ctDNA reflects residual tumor burden, clonal shifts, and emerging resistance, while imaging answers a more direct clinical question: where is the disease and can it be treated locally? (Semenkovich
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 7 et al., 2023). Neither approach is sufficient alone. ctDNA lacks spatial resolution, and imaging may miss small or diffuse lesions. For this reason, several studies advocate placing ctDNA results alongside imaging and conventional markers within the same follow-up pathway, using molecular changes to prompt more focused radiological evaluation and guide intervention (Bent et al., 2022; Chidharla et al., 2023; Pantel and Alix-Panabières, 2024). 5.2 Managing discordant results In real-world follow-up, discrepancies between ctDNA and imaging are not unusual. Rather than treating one test as definitive, it is more reasonable to interpret both within a structured clinical context. When both ctDNA and imaging are positive, the likelihood of residual or recurrent disease is high, and timely restaging with multidisciplinary discussion is warranted (Wang et al., 2025). Positive imaging but negative ctDNA may be related to low release or detection sensitivity, or it could be caused by inflammation or post-operative changes. Repeated imaging, tissue biopsy, or dynamic ctDNA monitoring can help clarify (Semenkovich et al., 2023). On the contrary, a single positive ctDNA result often indicates molecular recurrence below the resolution of imaging (Zheng et al., 2024), and the recurrence risk has significantly increased before imaging diagnosis (Zhu et al., 2023; Azzi et al., 2025; Negro et al., 2025). Enhanced imaging or shortening the follow-up interval may detect hidden lesions (Dasari et al., 2023; Maddalena et al., 2024). At present, a more reliable approach is to repeat confirmation and dynamic follow-up rather than immediately upgrading treatment (Pantel and Alix-Panabières, 2024). 5.3 Integration of functional imaging and artificial intelligence Functional imaging techniques such as PET-CT, DWI-MRI and dynamic enhancement technology can capture metabolic or perfusion abnormalities before structural changes occur, thereby shortening the time gap between molecular and imaging recurrence (Semenkovich et al., 2023; Pantel and Alix-Panabières, 2024). In cases where ctDNA is positive but conventional imaging is negative, functional imaging is helpful for localization; if ctDNA and functional indicators decrease simultaneously, it can also support the judgment of therapeutic efficacy (Emiloju et al., 2024). Radiomics and artificial intelligence enhance the ability of individualized recurrence prediction by integrating imaging features, ctDNA dynamics, and clinical variables (Semenkovich et al., 2023; Hoang et al., 2025). Multimodal omics models that integrate ctDNA, protein markers, and imaging information show certain predictive gains (Sabit et al., 2025). However, inconsistent imaging collection standards, differences in ctDNA platforms, and the lack of prospective validation still limit its widespread application. To achieve the integrated application of multimodal MRD, a unified process, standardized time points, and clear clinical endpoints are required (Pantel and Alix-Panabières, 2024; Wang et al., 2025). 6 Concluding Remarks Over the years, the emergence of ctDNA-MRD has led us to re-evaluate how "residual lesions" should be assessed. In the past, more reliance was placed on imaging, and only visible lesions were considered valid; now, there is an additional molecular perspective. Especially during the uncertain period following radical treatment for early solid tumors, ctDNA can capture extremely low levels of tumor molecular traces throughout the body, which are difficult to cover by imaging and traditional pathological indicators. A large number of prospective studies and systematic reviews have repeatedly proven that if ctDNA remains positive after treatment, the risk of recurrence and death will significantly increase. In cancers such as colorectal cancer and non-small cell lung cancer, the performance of ctDNA-MRD in risk classification often outperforms traditional staging and pathological high-risk factors, and thus has gradually become an important reference in postoperative stratification, adjuvant treatment decision-making, and follow-up optimization. However, when it comes to actual clinical application, problems arise. The sensitivity of a single test remains limited in MRD or early disease scenarios. Although longitudinal monitoring can increase the detection rate, false negatives still exist. Low tumor release, limited lesions confined to specific anatomical regions, inappropriate
International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 1-10 http://medscipublisher.com/index.php/ijccr 8 sampling time, and failing to meet the required detection sensitivity can all lead to the actual residual being "missed". Therefore, a more accurate understanding of ctDNA negativity should be "no signal detected at present", rather than complete clearance. On the other hand, CHIP, technical noise, and threshold differences between different platforms may also lead to false positives. If there is a lack of strict preprocessing procedures and variant filtering strategies, the interpretation of results can easily be disturbed, and even unnecessary examinations or treatment intensification may be triggered. ctDNA-MRD does not work well as a standalone decision tool. In practice, its results need to be interpreted alongside imaging findings, pathological features, and the broader clinical context. ctDNA may signal molecular relapse earlier than structural changes appear, but it cannot indicate where the lesion is or how extensive it is— questions that imaging still answers more directly. Looking at both together usually provides a clearer and more dependable picture of residual disease. With further integration of multi-omics data, functional imaging, and artificial intelligence models, ctDNA-MRD may gradually move beyond simple risk estimation toward a more practical role in clinical decision-making. However, until stronger prospective evidence is available, a cautious approach remains advisable—combining multiple modalities, discussing cases within multidisciplinary teams, and, whenever possible, enrolling patients in clinical trials to ensure that potential benefits do not come at the expense of safety. Acknowledgments The author extends sincere thanks to Dr. Shou for his feedback on the manuscript. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Abidoye O., Ahn D., Borad M., Wu C., Bekaii-Saab T., Chakrabarti S., and Sonbol M., 2025, Circulating Tumor DNA testing for minimal residual disease and its application in colorectal cancer, Cells, 14(3): 161. https://doi.org/10.3390/cells14030161 Azzi G., Slavin T., Izaguirre-Carbonell J., Sloane H.S., Edelstein D., and Ma C.X., 2025, Advanced minimal residual disease detection using a novel circulating tumor DNA assay: a report of two cases, Case Reports in Oncology, 18: 1105-1110. https://doi.org/10.1159/000547249 Bent A., Raghavan S., Dasari A., and Kopetz S., 2022, The future of ctDNA-defined minimal residual disease: personalizing adjuvant therapy in colorectal cancer, Clinical Colorectal Cancer, 21(2): 89-95. https://doi.org/10.1016/j.clcc.2022.03.004 Boukouris A., Michaelidou K., Joosse S., Charpidou A., Mavroudis D., Syrigos K., and Agelaki S., 2025, A comprehensive overview of minimal residual disease in the management of early-stage and locally advanced non-small cell lung cancer, NPJ Precision Oncology, 9(1): 178. https://doi.org/10.1038/s41698-025-00984-9 Chen H., and Zhou Q., 2023, Detecting liquid remnants of solid tumors treated with curative intent: circulating tumor DNA as a biomarker of minimal residual disease (Review), Oncology Reports, 49(5): 106. https://doi.org/10.3892/or.2023.8543 Chen J., Geng Y., and Lucci A., 2025, Applications of ctDNA testing to monitor and detect residual disease in breast cancer, Expert Review of Molecular Diagnostics, 25: 263-274. https://doi.org/10.1080/14737159.2025.2498545 Chidharla A., Rapoport E., Agarwal K., Madala S., Linares B., Sun W., Chakrabarti S., and Kasi A., 2023, Circulating tumor DNA as a minimal residual disease assessment and recurrence risk in patients undergoing curative-intent resection with or without adjuvant chemotherapy in colorectal cancer: a systematic review and meta-analysis, International Journal of Molecular Sciences, 24(12): 10230. https://doi.org/10.3390/ijms241210230 Comino-Méndez I., Velasco-Suelto J., Pascual J., López-López E., Quirós-Ortega M., Gaona-Romero C., Martín-Muñoz A., Losana P., Heredia Y., Alba E., and Guerrero-Zotano A., 2025, Identification of minimal residual disease using the clonesight test for ultrasensitive ctDNA detection to anticipate late relapse in early breast cancer, Breast Cancer Research, 27(1): 65. https://doi.org/10.1186/s13058-025-02016-7 Dasari A., Bent A., Alfaro-Munoz K., Huey R., Johnson B., Lee M., Morelli M., Morris V., Overman M., Parseghian C., Raghav K., Shen J., Willis J., Newhook T., Uppal A., You Y., Konishi T., Chang G., Kopetz S., and Wolff R., 2023, Association of positive ctDNA-based minimal residual disease assays during surveillance and undiagnosed concomitant radiographic recurrences in colorectal cancer (CRC): results from the MD Anderson INTERCEPT program, Journal of Clinical Oncology, 41(16_suppl): 3522. https://doi.org/10.1200/JCO.2023.41.16_suppl.3522
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International Journal of Clinical Case Reports, 2026, Vol.16, No.1, 11-18 http://medscipublisher.com/index.php/ijccr 11 Research Report Open Access Concentration and Heterogeneity of Medication Combination Patterns for Common Diseases in Retail Pharmacies: Evidence from Xiongcheng Jianmin Pharmacy in Zhuji City, 2023-2024 Caijuan Shuo, Xiaoping Cai Xiongcheng Jianmin Med. Ltd., Zhuji, 311800, Zhejiang, China Corresponding author: 2985757244@qq.com International Journal of Clinical Case Reports 2026, Vol.16, No.1 doi: 10.5376/ijccr.2026.16.0002 Received: 03 Dec., 2025 Accepted: 04 Jan., 2026 Published: 13 Jan., 2026 Copyright © 2026 Shuo and Cai, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Shuo C.J., and Cai X.P., 2026, Concentration and heterogeneity of medication combination patterns for common diseases in retail pharmacies: evidence from Xiongcheng Jianmin Pharmacy in Zhuji City, 2023–2024, International Journal of Clinical Case Reports, 16(1): 11-18 (doi: 10.5376/ijccr.2026.16.0002) Abstract This study systematically characterizes the concentration and heterogeneity of medication-use structures for common diseases in retail pharmacies from a “medication combination” perspective, aiming to reveal real-world decision-making logic in primary care medication use and to identify potential risks of inappropriate medication use. Using health insurance settlement sales and electronic dispensing data from Xiongcheng Jianmin Pharmacy in Zhuji City, Zhejiang Province, covering 2023–2024, transaction records were taken as the unit of analysis to construct disease-level indicators of medication combination concentration. Drawing on industrial organization theory, the Herfindahl–Hirschman Index (HHI) was introduced to quantitatively measure the degree of concentration or dispersion of medication combinations across different diseases based on sales revenue, and to compare structural differences among disease categories. A total of 19,661 valid purchase records were included during the study period, with cumulative sales of approximately RMB 4.376 million. The results indicate pronounced disease-specific differentiation in medication combination concentration in retail pharmacies: chronic conditions such as hypertension and hyperlipidemia exhibit highly concentrated medication use centered on a small number of core drugs, forming a stable structure characterized by a “single core drug plus a limited number of adjunctive medications”; in contrast, gastrointestinal diseases, sleep disorders, and functional conditioning conditions show lower concentration, with the coexistence of traditional Chinese medicines and chemical drugs, more dispersed structures, and marked heterogeneity, which are more susceptible to patients’ individual preferences, pharmacists’ recommendations, and price factors. Overall, medication combinations for common diseases in retail pharmacies display a structural pattern in which high-frequency core combinations dominate alongside numerous low-frequency long-tail combinations. Indicators of medication combination concentration and heterogeneity effectively capture real-world primary care medication behaviors and provide new quantitative tools and empirical evidence for identifying potential drug-related problems, optimizing pharmacist interventions, and advancing rational medication management. Keywords Retail pharmacy; Medication combinations; Concentration; Heterogeneity; Rational drug use 1 Introduction With the continued advancement of China’s tiered diagnosis and treatment system and the ongoing improvement of the primary healthcare service network, the role of retail pharmacies in the supply of medicines for common and frequently occurring diseases has become increasingly prominent. Compared with medical institutions, retail pharmacies are characterized by wide geographic distribution, high accessibility, and convenient access to medicines, and have thus emerged as important healthcare service nodes for community residents to meet initial medication needs for acute minor illnesses and chronic conditions (Miller and Goodman, 2016). Previous studies have shown that, particularly in Asia and in low- and middle-income countries, patients are more inclined to obtain medications for common diseases through retail pharmacies. In China’s urban and rural primary care settings, the functions of retail pharmacies have gradually expanded from simple drug sales to include a certain degree of pharmaceutical consultation and preliminary medication guidance, making them important venues for self-medication and primary health management among residents. Against the backdrop of a continuously increasing burden of chronic diseases and the growing prevalence of multimorbidity, the complexity of medication regimens among primary care populations has risen markedly. Retail pharmacies have assumed an increasingly central role in the routine medication management of conditions
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