Potential value of detection of minimal residual disease in colorectal cancer following radical resection

Although there has been significant advancement in the identification and management of colorectal cancer(CRC)in recent years,there is still room for improvement in the current standard treatment regimen.One area of concern is the lack of reliable tumor markers to predict treatment efficacy and guide tailored care.Due to its dynamic,effective,and non-invasive benefits over tissue biopsy,the detection of minimal or molecular residual lesions(MRD)based on circulating tumor DNA(ctDNA)is beneficial to the clinical development of drugs for patients with CRC after radical treatment,as well as for continuous monitoring of tumor recurrence and malignancy molecular gene evolution.The detection of ctDNA can currently be used to guide individual postoperative auxiliary treatment decisions(upgrade or downgrade treatment)in CRC,stratify the risk of clinical recurrence more precisely,and predict the risk of recurrence in advance of imaging examination,according to a large number of observational or prospective clinical studies.With increasing clarity comes the possibility of selecting a regimen of treatment based on postoperative ctDNA,which also improves the accuracy of clinical recurrence risk assessment for CRC.Therefore,it is anticipated that the identification of ctDNA would alter the current framework for dealing with CRC and lead to individualized,stratified precision therapy;however,additional confirmation will require subsequent high-quality,prospective,large-scale randomized controlled studies.This article will provide an overview of the definition and clinical significance of MRD,the primary indications and technological challenges for MRD detection,along with the advancement in clinical research about ctDNA detection following radical resection of the CRC.

Liquid biopsy and blood-based minimal residual disease evaluation in multiple myeloma

Novel drug availability has increased the depth of response and revolutionised the outcomes of multiple myeloma patients.Minimal residual disease evaluation is a surrogate for progression-free survival and overall survival and has become widely used not-only in clinical trials but also in daily patient management.Bone marrow aspiration is the gold standard for response evaluation,but due to the patchy nature of myeloma,false negatives are possible.Liquid biopsy and blood-based minimal residual disease evaluation consider circulating plasma cells,mass spectrometry or circulating tumour DNA.This approach is less invasive,can provide a more comprehensive picture of the disease and could become the future of response evaluation in multiple myeloma patients.

Prognostic relevance of minimal residual disease in colorectal cancer

Presence of occult minimal residual disease in patients with colorectal cancer(CRC)has a strong prognostic impact on survival.Minimal residual disease plays a major role in disease relapse and formation of metastases in CRC.Analysis of circulating tumor cells(CTC)in the blood is increasingly used in clinical practice for disease monitoring of CRC patients.In this review article the role of CTC,disseminated tumor cells(DTC)in the bone marrow and micrometastases and isolated tumor cells(ITC)in the lymph nodes will be discussed,including literature published until September 2013.Occult disease is a strong prognostic marker for patient survival in CRC and defined by the presence of CTC in the blood,DTC in the bone marrow and/or micrometastases and ITC in the lymph nodes.Minimal residual disease could be used in the future to identify patient groups at risk,who might benefit from individualized treatment options.

High-precision downward continuation of potential fi elds algorithm utilizing adaptive damping coeffi cient of generalized minimal residuals

The downward continuation of potential fields is a process of calculating their values in a lower plane based on those of a certain plane.This technology is not only a data processing method for resource exploration but also plays an extremely important role in military applications.However,the downward continuation of potential fields is a typical linear inverse problem that is ill-posed.Generalized minimal residuals(GMRES)is an eff ective solution to ill-posed inverse problems,but it is unstable under the condition wherein the GMRES is directly applied in the calculation process.Moreover,the long-term behavior of its iterative computation is a disordered,divergent result.Therefore,to obtain stable solutions,GMRES is applied to solve the normal equations of the downward continuation of potential fields;it is also used to prequalify for occasional interruptions in the operation process by adding the damping coefficient,thus strengthening the stability conditions of the equations of residual minimization.Finally,the stable downward continuation of the potential fields method is proposed.As indicated by the theoretical data and the measured testing data,the method proposed in this paper has the advantages of high-precision and excellent stability.Furthermore,compared with the Tikhonov iteration method,the proposed method avoids the need to choose regularization parameters.

Improvement of the minimal residual method for solving nonsymmetric linear systems

In this paper, the minimal residual （MRES） method for solving nonsymmetric equation systems was improved, the recurrence relation was deduced between the approximate solutions of the linear equation system Ax = b, and a more effective method was presented, which can reduce the operational count and the storage.

DETECTION AND ITS CLINICAL VALUE OF MINIMAL RESIDUAL DISEASES IN ACUTE PROMYELOCYTIC LEUKEMIA

Objective: To detect the minimal residual diseases (MRD) in acute promyelocytic leukemia (APL) after complete remission (CR) and to analyze its clinical value in prognosis. Methods: Reverse transcription Polymerase chain reaction (RT/PCR) was used to detect MRD of patients with APL. Results: MRD positive rate in patients with APL was 92.8% (39/42) before treatment and 56.7 (21/37) immediately after the ATRA or chemotherapy-induced CR. Furthermore, MRD positive rate was related to the relapse in APL patients and could be considered as a marker to predict the relapse of patients with APL after CR. The MRD detection could also be applied to direct the consolidation therapy to prevent relapses. Conclusion: RT-PCR is valuable to monitor MRD and can be used as a marker to predict relapses.

Circulating tumor DNA(ctDNA)-based minimal residual disease in non-small cell lung cancer

Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related fatalities,with non-small cell lung cancer(NSCLC)accounting for 85%of all lung cancers.Over the past forty years,patients with NSCLC have had a 5-year survival rate of only 16%,despite improvements in chemotherapy,targeted therapy,and immunotherapy.Circulating tumor DNA(ctDNA)in blood can be used to identify minimal residual disease(MRD),and ctDNA-based MRD has been shown to be of significance in prognostic assessment,recurrence monitoring,risk of recurrence assessment,efficacy monitoring,and therapeutic intervention decisions in NSCLC.The level of MRD can be obtained by monitoring ctDNA to provide guidance for more precise and personalized treatment,the scientific feasibility of which could dramatically modify lung cancer treatment paradigm.In this review,we present a comprehensive review of MRD studies in NSCLC and focus on the application of ctDNA-based MRD in different stages of NSCLC in current clinical practice.

Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease： Analysis from a Single Center of China

Background：The postremission therapics for adult patients generally contain consolidation chemotherapy,allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation （auto-HSCT）.Because of the various results from different centers,the optimal therapy for adult acute lymphoblastic leukemia （ALL） patients is still uncertain.This study aimed to better understand predictive factors and role of auto-HSCT in the postremission thcrapy for adult ALL patients.Methods：The outcomes of 135 adult patients with ALL,who received the first auto-HSCT in Hematopoietic Stem Cell Transplantation Center of Blood Diseases Hospital,Chinese Academy of Medical Sciences from January 1,1994 to February 28,2014,were retrospectively analyzed.Survival curves were estimated using the Kaplan-Meier method and simultaneous effects of multiple covariates were estimated with the Cox model.Results：Overall survival （OS） and disease-free survival （DFS） at 5 years for the whole cohort were 59.1 ± 4.5% and 59.0 ± 4.4%,respectively.The cumulative nonrelapse mortality and relapse rate at 5 years were 4.5 ± 0.03% and 36.6 ± 0.19%.For both OS and DFS,acute T-cell lymphoblastic leukemia,high lactate dehydrogenase （LDH） at diagnosis,blast cell proportion ≥5% on the 15th day of induction therapy,and extramedullary infiltration before HSCT were the poor prognosis factors.In addition,age ≥35 years predicted poor DFS.Only T-ALL and high LDH were the independent undesirable factors associated with OS and DFS in Cox regression model.For 44 patients who had results of pretransplantation minimal residual disease （MRD）,positive MRD （MRD ≥0.01%） indicated poor OS （P =0.044） and DFS （P =0.008）.Furthermore,for the standard risk group,the patients with negative MRD （MRD 〈0.01%） had better results （OS at 18 months was 90.0 ± 9.5%,while for the patients with positive MRD OS was 50.0 ± 35.4%,P =0.003;DFS at 18 months was 90.0 ± 9.5%,while for the positive MRD group DFS was 0%,P 〈 0.001）.Conclusions：This study confirmed that auto-HSCT combined with posttransplantation maintenance chemotherapy could be an option for adult ALL patients and pretransplantation MRD may play a significant role in the direction of therapy for adult ALL patients.

Effect of Yiqi Bushen Granule (益气补肾颗粒) on the Peripheral Natural Killer Cell and γ δ T-cell in the Patients with Minimal Residual Leukemia

Objective： To analyze the changes in peripheral natural killer T-cells （NKT） and gammadelta T-cells （γδT-cell） in patients with minimal residual leukemia （MRL） before and after being treated with Yiqi Bushen Granule （益气补肾颗粒, YBG） in order to determine their significance in prognosis of the disease. Methods： Before and after treatment, the changes in 36 patients （16 males and 20 females） receiving long-term （more than 3 months） YBG therapy were analyzed using multi-parameter flow cytometry, with 34 healthy persons （19 males and 15 females） acting as controls. Results： The absolute value and percentage of NKT cells and γδT-cells were all significantly raised after treatment, for NKT cells, 0.52%±0.39% to 0.83%±0.66% and 7.25±7.77 cell/μL to 12.86±11.99 cell/μL, for γδT-cells, 6.08%±3.03% to 7.24%±2.78% and 83.97±48.09 cell/μL to 110.53±54.12 cell/μL, respectively （P0.05 or P0.01）. Conclusion： YBG could regulate the immune function and elevate the amount of NKT cells and γδT-cells, thus to kill or suppress the residual leukemic cell in the body, which might be one of the mechanisms of YBG in prolonging the disease-free survival in MRL patients.

Coexisting opportunities and challenges:In which scenarios can minimal/measurable residual disease play a role in advanced non-small cell lung cancer?

Curative therapy was not previously available for patients with advanced non-small cell lung cancer(NSCLC);thus,the concept of minimal/measurable(or molecular)residual disease(MRD)was not applicable to these patients.However,advances in targeted and immunotherapy have revolutionized the treatment landscape for patients with advanced NSCLC,with emerging evidence of long-term survival and even the hope of complete remission(CR)by imaging examination.The latest research shows that patients with oligometastatic lung cancer can benefit from local treatment.After removing the lesions,the choice of follow-up therapy and monitoring of the lesions could remain uncertain.MRD plays a role in identifying early-stage NSCLC patients with high risks of recurrence and determining adjuvant therapy after radical treatment.In recent years,evidence has been accumulating regarding the use of circulating cell-free tumor DNA(ctDNA)to assess MRD in solid tumors.This study discussed the possible applications of ctDNA-based MRD monitoring in advanced NSCLC and described the current challenges and unresolved problems in the application of MRD in advanced NSCLC.

Fuzheng Kangbai Granule (扶正抗白冲剂) on Immune Function and Survival Time in Minimal Residual Leukemia Model Mice

To observe the effects of Fuzheng Kangbai Granule (FZKBG) on immune function and survival time in minimal residual leukemia (MRL) model mice and explore its mechanism. Methods: MRL model mice were established by hypodermic inoculation with L7212 cells 1×106 following intraperitoneal injection of cytoxan (CTX) 250 mg/kg 3 days later, and divided into the control group and FZKBG treated group. The changes of T-lymphocyte subsets, including CD3+, CD4+ and CD8+, and the survival time in model mice were observed. Results: Compared with the control, FZKBG could obviously increase both the percentage and absolute value of CD3+ and CD4+ lymphocytes and prolong the survival time of model mice, the prolongation rate being 29.6% - 60.4%. Conclusion: FZKBG could markedly prolong the survival time of MRL mice, and its mechanism might be through elevating the immunologic function and inhibiting the leukemia cells in model mice.

Drug resistance and minimal residual disease in multiple myeloma

Great progress has been made in improving survival in multiple myeloma(MM)patients over the last 30 years.New drugs have been introduced and complete responses are frequently seen.However,the majority of MM patients do experience a relapse at a variable time after treatment,and ultimately the disease becomes drug-resistant following therapies.Recently,minimal residual disease(MRD)detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response.MRD can be considered as a surrogate for both progression-free and overall survival.In this perspective,the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals.The present review gives an overview of drug resistance in MM,i.e.,mutation ofβ5 subunit of the proteasome;upregulation of pumps of efflux;heat shock protein induction for proteasome inhibitors;downregulation of CRBN expression;deregulation of IRF4 expression;mutation of CRBN,IKZF1,and IKZF3 for immunomodulatory drugs and decreased target expression;complement protein increase;sBCMA increase;and BCMA down expression for monoclonal antibodies.Multicolor flow cytometry,or next-generation flow,and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10-5.Sustained MRD negativity is related to prolonged survival,and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

CLINICAL SIGNIFICANCE OF THE DETECTION OF MINIMAL RESIDUAL DISEASE IN CHILDHOOD B-ALL BY FLOW CYTOMETRY

Objective To detect the minimal residual disease in children with B-ALL and to evaluate its clinical significance by flow cytometry. Methods 58 childhood B-ALL cases were enrolled into this study and 33 MRD analyses were performed after remission induction therapy.Four-color combinations of fluorochrome labeled monoclonal antibodies against lymphocyte lineage related phenotypes were used to analyze leukemic cells with flow cytometry.The cells from normal bone marrow were used as controls.The combinations of phenotypes that reflect the antigen expression differences between leukemic and normal bone marrow cells on flow cytometry were considered to be the effective phenotype combinations in the first step screening.The effective phenotype combinations were then used to monitor MRD during the disease course after therapy began. Results 58 cases of childhood B-ALL were screened for MRD effective phenotype combinations.The effective phenotype combinations were identified in 89.7% of B-ALL cases in this study.Four-color phenotype combinations were composed of CD10/CD34/CD19 plus another effective marker such as CD38,CD58,CD66c,CD21.The senstitivity of this method was 0.01%,much higher than that of microscopic inspection.In 8 cases,their bone marrow microscopic inspection results showed no remaining leukemic cells;but with flow cytometry,the percentage of leukemic cells were 5.66%,0.36%,1.43%,0.069%,1.55%,2.7%,0.028% and 0.015%,respectively.In risk stratification,all these MRD positive cases were classified into high risk group for relapse and 1 case showed early relapse within 6 months. Conclusion The application of flow cytometry in MRD measurement can significantly improve the sensitivity of detection of remained leukemic cells in childhood B-ALL,and can provide more accurate information on disease progression as well as the efficacy of therapy,thus facilitate future treatment decisions and follow ups.

Current treatment paradigm and survival outcomes among patients with newly diagnosed multiple myeloma in China:a retrospective multicenter study

Objective:Evidence on the prognostic value of autologous stem cell transplantation(ASCT)and minimal residual disease(MRD)dynamics of patients with newly diagnosed multiple myeloma(NDMM)in China is limited.Our objective in the current study was to understand the current care paradigm and outcomes of these patients.Methods:This longitudinal cohort study used historical data from three top-tier hematologic disease care hospitals that contributed to the National Longitudinal Cohort of Hematological Diseases-Multiple Myeloma.Treatment regimens[proteasome inhibitor(PI)-,immunomodulatory drug(IMiD)-,PI+IMiD-based,and conventional],post-induction response,ASCT and MRD status,and survival outcomes[progression-free survival(PFS)and overall survival(OS)]were evaluated.Results:In total,454 patients with NDMM were included(median age,57 years;59.0%males)with a median follow-up of 58.7 months.The overall response rate was 91.0%,83.9%,90.6%,and 60.9%for PI-,IMiD-,PI+IMiD-based,and conventional regimens,respectively.Patients with ASCT during first-line therapy(26.2%)had a longer PFS and OS than patients who did not receive ASCT[median PFS,42.9 vs.21.2 months,P<0.001;median OS,not reached(NR)vs.65.8 months,P<0.001].The median OS was NR,71.5,and 56.6 months among patients with sustained MRD negativity,loss of MRD negativity,and persistent MRD,respectively(P<0.001).Multivariate analysis revealed that the lactic dehydrogenase level,International Staging System stage,extra-medullary disease,and upfront ASCT were independent factors in predicting OS among NDMM patients.Conclusions:Our study showed that novel agent-based regimens,first-line ASCT,and sustained MRD negativity were associated with a superior outcome for patients with NDMM in China(Identifier:NCT04645199).

The potential role of minimal/molecular residual disease in colorectal cancer: curative surgery, radiotherapy and beyond

Detection of minimal/molecular residual disease(MRD)based on ctDNA assay develops from hematological malignancies to solid tumors.Generally,there are two mainstream assays in MRD testing technology:tumor-informed and tumor-agnostic.For colorectal cancer(CRC),MRD is used not only to monitor recurrence and predict prognosis,but also to help in clinical decision making and assessment of clinical efficacy in the settings of curative surgery,radiotherapy,chemotherapy and surveillance.Accumulated clinical trials are exploring roles of MRD in early or advanced stages of CRC.Here,we give an overview of how MRD is and will be used in CRC.

Two-Parameter Block Triangular Splitting Preconditioner for Block Two-by-Two Linear Systems

This paper proposes a two-parameter block triangular splitting(TPTS)preconditioner for the general block two-by-two linear systems.The eigenvalues of the corresponding preconditioned matrix are proved to cluster around 0 or 1 under mild conditions.The limited numerical results show that the TPTS preconditioner is more efficient than the classic block-diagonal and block-triangular preconditioners when applied to the flexible generalized minimal residual(FGMRES)method.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Squamous cell carcinoma of the oral cavity and circulating tumour cells

Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma(OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells(CTCs) and disseminated tumour cells(DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool todetermine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised.

Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions

Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies.The majority of patients with colon cancer are diagnosed at an early stage(stages I to III),which provides an opportunity for cure.The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients,which is directed at the eradication of minimal residual disease to achieve a cure.Surgery alone is curative for the vast majority of colon cancer patients.Currently,surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement.Adjuvant chemotherapy is recommended for all patients with stage III colon cancer,while the benefit in stage II patients is not unequivocally established despite several large clinical trials.Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques,strategies to limit treatment-related toxicities,precise patient selection for adjuvant therapy,utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology.In this review,we will discuss the current standard treatment,evolving treatment paradigms,and the emerging biomarkers,that will likely help improve patient selection and personalization of therapy leading to superior outcomes.

Expression of interleukin-32 in bone marrow of patients with myeloma and its prognostic significance

BACKGROUND The guiding effect of prognostic stratification in multiple myeloma(MM) for treatment has been increasingly emphasized in recent years. The stratification of risk factors based on the International Staging System(ISS), Durie-Salmon(DS)staging and related indicators is affected by the renal function of patients,resulting in poor performance. This study assesses the relationship between interleukin-32(IL-32) and related risk factors in 67 patients with MM and their clinical outcomes.AIM To investigate the feasibility of IL-32 in evaluating prognosis in patients with MM and the factors influencing prognosis.METHODS This was a pragmatic, prospective observational study of patients with MM at a single center. According to IL-32 level, patients were divided into two groups.The variables under consideration included age, blood β2-microglobulin,albumin, C-reactive protein, serum calcium, serum creatinine, lactate dehydrogenase, M protein type, ISS stage, DS stage, and IL-32 levels and minimal residual disease(MRD) after induction treatment. The main outcomes were progression-free survival(PFS) and overall survival(OS).RESULTS IL-32 was an important factor affecting PFS and OS in patients with MM.Compared with patients with IL-32 levels ≥ 856.4 pg/m L, patients with IL-32 levels < 856.4 pg/m L had longer PFS(P = 0.0387) and OS(P = 0.0379);Univariate analysis showed that IL-32 level and MRD were significantly associated with OS and PFS(P < 0.05). Multivariate analysis showed that IL-32 levels ≥ 856.4 pg/m L and MRD positive were still independent risk factors for OS and PFS(P < 0.05).CONCLUSION IL-32 is valuable for assessing the prognosis of MM patients. IL-32 level combined with MRD may be a useful routine evaluation index for MM patients after treatment.