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International Journal of Molecular... Feb 2024Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells... (Review)
Review
Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells remaining in a patient after treatment, and is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. Patients with a negative MRD tend to have superior disease-free and overall survival rates. Considerable effort has been made to standardize MRD practices. A variety of techniques, including flow cytometry and molecular methods, are used to assess MRD, each with distinct strengths and weaknesses. MRD is recognized not only as a predictive biomarker, but also as a prognostic tool and marker of treatment efficacy. Expected advances in MRD assessment encompass molecular techniques such as NGS and digital PCR, as well as optimization strategies such as unsupervised flow cytometry analysis and leukemic stem cell monitoring. At present, there is no perfect method for measuring MRD, and significant advances are expected in the future to fully integrate MRD assessment into the management of AML patients.
Topics: Humans; Neoplasm, Residual; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence; Flow Cytometry
PubMed: 38396825
DOI: 10.3390/ijms25042150 -
Endocrinology and Metabolism (Seoul,... Dec 2023Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all... (Review)
Review
Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all pituitary tumors and representing the most common type of macroPitNETs. NfPitNETs are usually benign tumors with no evidence of hormone oversecretion except for hyperprolactinemia secondary to pituitary stalk compression. Due to this, they do not typically present with clinical syndromes like acromegaly, Cushing's disease or hyperthyroidism and instead are identified incidentally on imaging or from symptoms of mass effects (headache, vision changes, apoplexy). With the lack of effective medical interventions, first-line treatment is transsphenoidal surgical resection, however, nfPitNETs often have supra- or parasellar extension, and total resection of the tumor is often not possible, resulting in residual tumor regrowth or reoccurrence. While functional PitNETs can be easily followed for recurrence using hormonal biomarkers, there is no similar parameter to predict recurrence in nfPitNETs, hence delaying early recognition and timely management. Therefore, there is a need to identify prognostic biomarkers that can be used for patient surveillance and as therapeutic targets. This review focuses on summarizing the current evidence on nfPitNETs, with a special focus on potential new biomarkers and therapeutics.
Topics: Humans; Pituitary Neoplasms; Neuroendocrine Tumors; Adenoma; Acromegaly; Biomarkers
PubMed: 37964483
DOI: 10.3803/EnM.2023.1838 -
Cancer Medicine Aug 2023Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising...
BACKGROUND
Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection.
METHODS
Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced.
RESULTS
The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression.
CONCLUSION
Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Neoplasm Recurrence, Local; Gastrointestinal Neoplasms; Carcinoma
PubMed: 37602656
DOI: 10.1002/cam4.6286 -
Drug Resistance Updates : Reviews and... May 2024Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of... (Review)
Review
Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.
Topics: Humans; Hematologic Neoplasms; Immunotherapy, Adoptive; Tumor Microenvironment; Molecular Targeted Therapy; Drug Resistance, Neoplasm; Combined Modality Therapy; Receptors, Chimeric Antigen; Antineoplastic Agents; Animals
PubMed: 38569225
DOI: 10.1016/j.drup.2024.101082 -
Cancers Jul 2023Implementation of population-based colorectal cancer screening programs has led to increases in the incidence of pT1 colorectal cancer. These incipient invasive cancers... (Review)
Review
Implementation of population-based colorectal cancer screening programs has led to increases in the incidence of pT1 colorectal cancer. These incipient invasive cancers have a very good prognosis and can be treated locally, but more than half of these cases are treated with surgery due to the presence of histological high-risk criteria. These high-risk criteria are suboptimal, with no consensus among clinical guidelines, heterogeneity in definitions and assessment, and poor concordance in evaluation, and recent evidence suggests that some of these criteria considered high risk might not necessarily affect individual prognosis. Current criteria classify most patients as high risk with an indication for additional surgery, but only 2-10.5% have lymph node metastasis, and the residual tumor is present in less than 20%, leading to overtreatment. Patients with pT1 colorectal cancer have excellent disease-free survival, and recent evidence indicates that the type of treatment, whether endoscopic or surgical, does not significantly impact prognosis. As a result, the protective role of surgery is questionable. Moreover, surgery is a more aggressive treatment option, with the potential for higher morbidity and mortality rates. This article presents a comprehensive review of recent evidence on the clinical management of pT1 colorectal cancer. The review analyzes the limitations of histological evaluation, the prognostic implications of histological risk status and the treatment performed, the adverse effects associated with both endoscopic and surgical treatments, and new advances in endoscopic treatment.
PubMed: 37444621
DOI: 10.3390/cancers15133511 -
Endocrine Jan 2024Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater...
PURPOSE
Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater agreement, especially postoperatively. Automated tumor segmentation and volumetry by use of deep learning techniques may provide more objective and quick volumetry.
METHODS
We developed an automated volumetry pipeline for pituitary adenoma. Preoperative and three-month postoperative T1-weighted, contrast-enhanced magnetic resonance imaging (MRI) with manual segmentations were used for model training. After adequate preprocessing, an ensemble of convolutional neural networks (CNNs) was trained and validated for preoperative and postoperative automated segmentation of tumor tissue. Generalization was evaluated on a separate holdout set.
RESULTS
In total, 193 image sets were used for training and 20 were held out for validation. At validation using the holdout set, our models (preoperative / postoperative) demonstrated a median Dice score of 0.71 (0.27) / 0 (0), a mean Jaccard score of 0.53 ± 0.21/0.030 ± 0.085 and a mean 95 percentile Hausdorff distance of 3.89 ± 1.96./12.199 ± 6.684. Pearson's correlation coefficient for volume correlation was 0.85 / 0.22 and -0.14 for extent of resection. Gross total resection was detected with a sensitivity of 66.67% and specificity of 36.36%.
CONCLUSIONS
Our volumetry pipeline demonstrated its ability to accurately segment pituitary adenomas. This is highly valuable for lesion detection and evaluation of progression of pituitary incidentalomas. Postoperatively, however, objective and precise detection of residual tumor remains less successful. Larger datasets, more diverse data, and more elaborate modeling could potentially improve performance.
Topics: Humans; Pituitary Neoplasms; Magnetic Resonance Imaging; Adenoma; Neoplasm, Residual; Image Processing, Computer-Assisted
PubMed: 37749388
DOI: 10.1007/s12020-023-03529-x -
Blood Cancer Discovery Sep 2023The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics...
UNLABELLED
The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus
SIGNIFICANCE
This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.
Topics: Humans; Receptors, Chimeric Antigen; Prognosis; Multiple Myeloma; Immunotherapy, Adoptive; Neoplasm, Residual; Neoplasms, Plasma Cell
PubMed: 37486974
DOI: 10.1158/2643-3230.BCD-23-0044 -
Journal of Neuro-oncology Sep 2023To report the long-term outcomes in adult patients with grade 2 IDH-mutant astrocytoma treated with temozolomide (TMZ)-based chemoradiation.
PURPOSE
To report the long-term outcomes in adult patients with grade 2 IDH-mutant astrocytoma treated with temozolomide (TMZ)-based chemoradiation.
METHODS
One hundred and three patients with histologically proven grade 2 astrocytoma received radiation therapy (RT), 50.4-54 Gy in 1.8 Gy fractions, and adjuvant TMZ up to 12 cycles. Fifty-two patients received RT at the time of tumor progression and 51 in the early postoperative period for the presence of at least one high-risk feature (age > 40 years, preoperative tumor size > 5 cm, large postoperative residual tumor, tumor crossing the midline, or presence of neurological symptoms). Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis.
RESULTS
With a median follow-up time of 9.0 years (range, 1.3-15 years), median PFS and OS times were 9 years (95%CI, 6.6-10.3) and 11.8 years (95%CI, 9.3-13.4), respectively. Median PFS was 10.6 years in the early treatment group and 6 years in delayed treatment group (hazard ratio (HR) 0.30; 95%CI 0.16-0.59; p = 0.0005); however, OS was not significantly different between groups (12.8 vs. 10.4 years; HR 0.64; 95%CI 0.33-1.25; p = 0.23). Extent of resection, KPS, and small residual disease were associated with OS, with postoperative tumor ≤ 1 cc that emerged as the strongest independent predictor (HR: 0.27; 95%CI 0.08-0.87; p = 0.01).
CONCLUSIONS
TMZ-based chemoradiation is associated with survival benefit in patients with grade 2 IDH-mutant astrocytoma. For this group of patients, chemoradiation can be deferred until time of progression in younger patients receiving extensive resection, while early treatment should be recommended in high-risk patients.
Topics: Humans; Adult; Temozolomide; Antineoplastic Agents, Alkylating; Dacarbazine; Brain Neoplasms; Astrocytoma; Treatment Outcome
PubMed: 37665475
DOI: 10.1007/s11060-023-04418-z -
Medicine Nov 2023Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. NDUFAL42 is an important mitochondrial respiratory chain subunit that plays a critical role...
Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. NDUFAL42 is an important mitochondrial respiratory chain subunit that plays a critical role in cellular energy metabolism. However, the role of NDUFA4L2 in CRC remains unclear. Therefore, we used the data obtained from The Cancer Genome Atlas (TCGA) database to prove the relationship between NDUFA4L2 and CRC. The expression levels of NDUFA4L2 in CRC tissues were analyzed by immunohistochemical staining of NDUFA4L2 from the HPA database. Wilcoxon rank sum test, Chi-square test, Fisher exact test and logistic regression were used to evaluate relationships between clinical-pathologic features and NDUFA4L2 expression. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of NDUFA4L2 using area under curve (AUC) score. Kaplan-Meier method and Cox regression analysis were used to evaluate factors contributing to prognosis. Gene oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to predict the function of differentially expressed genes associated with NDUFA4L2. Gene set enrichment analysis (GSEA) was used to predict canonical pathways associated with NDUFA4L2.Immune infiltration analysis was performed to identify the significantly involved functions of NDUFA4L2. Protein-protein interaction (PPI) networks were established and 20 hub genes identified with Cytoscape software. Increased NDUFA4L2 expression in CRC was associated with T stage (P = .019), N stage (P < .001), Pathologic stage (P = .020), Residual tumor (P = .023), Perineural invasion (P = .039), Lymphatic invasion (P = .007), Histological type(P < .001), PFI event (P = .007) and DSS event (P = .004).ROC curve suggested the significant diagnostic and prognostic ability of NDUFA4L2 (AUC = 0.878). High NDUFA4L2 expression predicted a poorer Overall-survival (P = .021), poorer progression-free interval (P = .001), and poorer Disease Specific Survival (P = .002). GO, KEGG, GSEA and immune infiltration analysis showed that NDUFA4L2 expression was correlated with regulating the function of DNA and some types of immune infiltrating cells. NDUFA4L2 expression was significantly correlated with poor survival and immune infiltrations in CRC, and it may be a promising prognostic biomarker in CRC.
Topics: Humans; Biomarkers; Area Under Curve; Computational Biology; Databases, Factual; Colorectal Neoplasms; Prognosis
PubMed: 37933010
DOI: 10.1097/MD.0000000000035893 -
Annals of Hematology Nov 2023Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response...
Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.
PubMed: 37679605
DOI: 10.1007/s00277-023-05427-8