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Journal of Clinical Oncology : Official... Feb 2024Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study...
PURPOSE
Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease.
METHODS
This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS.
RESULTS
With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% 51%, = .03; 82% 15%, < .001; and 82% 24%, < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS.
CONCLUSION
Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.
Topics: Female; Humans; Circulating Tumor DNA; Uterine Cervical Neoplasms; Human Papillomavirus Viruses; Prospective Studies; Papillomavirus Infections; Pilot Projects; Neoplasm Recurrence, Local; Biomarkers, Tumor
PubMed: 37972346
DOI: 10.1200/JCO.23.00954 -
Materials Today. Bio Oct 2023Residual tumor recurrence after surgical resection of hepatocellular carcinoma (HCC) remains a considerable challenge that imperils the prognosis of patients. Notably,...
Residual tumor recurrence after surgical resection of hepatocellular carcinoma (HCC) remains a considerable challenge that imperils the prognosis of patients. Notably, intraoperative bleeding and postoperative infection are potential risk factors for tumor recurrence. However, the biomaterial strategy for the above problems has rarely been reported. Herein, a series of cryogels (coded as SQ-n) based on sodium alginate (SA) and quaternized chitosan (QC) were synthesized and selected for optimal ratios. The assays showed that SQ-50 possessed superior hemostasis, excellent antibacterial property, and great cytocompatibility. Subsequently, SQAP was constructed by loading black phosphorus nanosheets (BPNSs) and anlotinib hydrochloride (AL3818) based on SQ-50. Physicochemical experiments confirmed that near-infrared (NIR)-assisted SQAP could control the release of AL3818 in photothermal response, significantly inhibiting the proliferation and survival of HUVECs and H22 cells. Furthermore, studies indicated that the NIR-assisted SQAP prevented local recurrence of ectopic HCC after surgical resection, achieved through the synergistic effect of mPTT and molecular targeted therapy. Thus, the multifunctional SQAP provides a "one-stop" synergistic strategy for HCC postoperative recurrence, showing great potential for clinical application.
PubMed: 37564266
DOI: 10.1016/j.mtbio.2023.100746 -
Frontiers in Genetics 2023Minimal residual disease (MRD) refers to a very small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor and... (Review)
Review
Minimal residual disease (MRD) refers to a very small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor and the possibility of clinical progress. Circulating tumor DNA (ctDNA) is a DNA fragment actively secreted by tumor cells or released into the circulatory system during the process of apoptosis or necrosis of tumor cells, which emerging as a non-invasive biomarker to dynamically monitor the therapeutic effect and prediction of recurrence. The feasibility of ctDNA as MRD detection and the revolution in ctDNA-based liquid biopsies provides a potential method for cancer monitoring. In this review, we summarized the main methods of ctDNA detection (PCR-based Sequencing and Next-Generation Sequencing) and their advantages and disadvantages. Additionally, we reviewed the significance of ctDNA analysis to guide the adjuvant therapy and predict the relapse of lung, breast and colon cancer et al. Finally, there are still many challenges of MRD detection, such as lack of standardization, false-negatives or false-positives results make misleading, and the requirement of validation using large independent cohorts to improve clinical outcomes.
PubMed: 37636270
DOI: 10.3389/fgene.2023.1172108 -
Cancers Jul 2023: The second cytoreductive surgery performed for a patient who has recurrent ovarian cancer remains controversial. Our study analyzes overall survival (OS) and... (Review)
Review
: The second cytoreductive surgery performed for a patient who has recurrent ovarian cancer remains controversial. Our study analyzes overall survival (OS) and disease-free survival (DFS) for cytoreductive surgery in addition to chemotherapy in recurrent ovarian cancer instead of chemotherapy alone. : A meta-analysis was conducted using PubMed and the Cochrane database of systematic reviews to select randomized controlled studies. In total, three randomized studies were used, employing a total of 1249 patients. : The results of our meta-analysis of these randomized controlled trials identified significant differences in OS (HR = 0.83, IC 95% 0.70-0.99, < 0.04) and DFS (HR = 0.63, IC 95% 0.55-0.72, < 0.000001). A subgroup analysis comparing complete cytoreductive surgery and surgery with residual tumor achieved better results for both OS (HR = 0.65, IC 95% 0.49-0.86, = 0.002) and DFS (HR = 0.67, IC 95% 0.53-0.82, = 0.0008), with statistical significance. : A complete secondary cytoreductive surgery (SCS) in recurrent ovarian cancer (ROC) demonstrates an improvement in the OS and DFS, and this benefit is most evident in cases where complete cytoreductive surgery is achieved. The challenge is the correct patient selection for secondary cytoreductive surgery to improve the results of this approach.
PubMed: 37444580
DOI: 10.3390/cancers15133470 -
Journal of Clinical Oncology : Official... May 2024Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of () AML. These patients... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of () AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit.
METHODS
Adults with AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS.
RESULTS
Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; = .575).
CONCLUSION
Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.
Topics: Humans; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Male; Female; Middle Aged; Pyrazines; Adult; Aniline Compounds; Hematopoietic Stem Cell Transplantation; Mutation; Aged; Tandem Repeat Sequences; Young Adult; Neoplasm, Residual; Protein Kinase Inhibitors; Maintenance Chemotherapy; Gene Duplication
PubMed: 38471061
DOI: 10.1200/JCO.23.02474 -
Annals of Oncology : Official Journal... Oct 2023We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative...
BACKGROUND
We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy.
PATIENTS AND METHODS
We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
RESULTS
Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 (range 7.9 × 10-4.9 × 10). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.
CONCLUSIONS
Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.
Topics: Humans; Female; Circulating Tumor DNA; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Neoplasm, Residual; Prospective Studies; Breast Neoplasms; Neoplasm Recurrence, Local
PubMed: 37597579
DOI: 10.1016/j.annonc.2023.08.004 -
Journal of Thoracic Disease Oct 2023Immune checkpoint inhibitors have been increasingly applied for esophageal cancer. The aims of this study were to evaluate the pattern of tumor regression after...
BACKGROUND
Immune checkpoint inhibitors have been increasingly applied for esophageal cancer. The aims of this study were to evaluate the pattern of tumor regression after neoadjuvant chemoimmunotherapy.
METHODS
From January 2020 to December 2021, 138 patients with esophageal squamous cell carcinoma who had esophagectomy after neoadjuvant chemoimmunotherapy were reviewed. Surgical and pathological results were analyzed, and tumor regression pattern was evaluated.
RESULTS
Of the 138 patients, 65 (47.1%) patients had chemotherapy combined with camrelizumab, 48 (34.8%) with pembrolizumab, 13 (9.4%) with tislelizumab, and 12 (8.7%) with sintilimab. Sixty-four patients (46.4%) underwent McKewon procedure, and 74 (53.6%) Ivor-Lewis procedure, respectively. There were 131/138 patients (94.9%) who had R0 resections, and the median number of resected lymph nodes was 28. Pneumonia was the most common complication after surgery (14.5%). Pathological complete regression occurred in 28 patients (20.3%). Regarding to residual tumor, there were 50 patients (36.2%) with residual tumor in the mucosa, 81 (58.7%) in the submucosa, 85 (61.6%) in the muscularis propria, 47 (34.1%) in the adventitia and 71 (51.4%) in the lymph nodes. There were 88 patients with no residual tumor in the mucosa, of whom 60 (68.2%) had residual tumors in other layers or in the lymph nodes.
CONCLUSIONS
In this retrospective study, esophagectomy after neoadjuvant chemoimmunotherapy is safe with acceptable surgical risk. Preferential clearing of tumor cells in mucosa layer is common after immunotherapy, while the rate of complete pathological response is relatively low, indicating surgery is still necessary.
PubMed: 37969295
DOI: 10.21037/jtd-23-882 -
Frontiers in Immunology 2024Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit... (Review)
Review
Despite significant progress in targeted therapy for acute myeloid leukemia (AML), clinical outcomes are disappointing for elderly patients, patients with less fit disease characteristics, and patients with adverse disease risk characteristics. Over the past 10 years, adaptive T-cell immunotherapy has been recognized as a strategy for treating various malignant tumors. However, it has faced significant challenges in AML, primarily because myeloid blasts do not contain unique surface antigens. The preferentially expressed antigen in melanoma (PRAME), a cancer-testis antigen, is abnormally expressed in AML and does not exist in normal hematopoietic cells. Accumulating evidence has demonstrated that PRAME is a useful target for treating AML. This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up, and its use in antigen-specific immunotherapy for AML.
Topics: Male; Humans; Aged; Antigens, Neoplasm; Leukemia, Myeloid, Acute; T-Lymphocytes; Prognosis; Leukocytes
PubMed: 38596687
DOI: 10.3389/fimmu.2024.1378277 -
Cancer Biology & Therapy Dec 2023Molecular residual disease (MRD), detected by circulating tumor DNA (ctDNA) can be involved in the entire process of solid tumor management, including recurrence... (Review)
Review
Molecular residual disease (MRD), detected by circulating tumor DNA (ctDNA) can be involved in the entire process of solid tumor management, including recurrence prediction, efficacy evaluation, and risk stratification. Currently, the detection technologies are divided into two main categories, as follows: tumor-agnostic and tumor informed. Tumor-informed assay obtains mutation information by sequencing tumor tissue samples before blood MRD monitoring, followed by formulation of a personalized MRD panel. Tumor-agnostic assays are carried out using a fixed panel without the mutation information from primary tumor tissue. The choice of testing strategy may depend on the level of evidence from ongoing randomized clinical trials, investigator preference, cost-effectiveness, patient economics, and availability of tumor tissue. The review describes the difference between tumor informed and tumor agnostic detection. In addition, the clinical application of ctDNA MRD in solid tumors was introduced, with emphasis on lung cancer, colorectal cancer, Urinary system cancer, and breast cancer.
Topics: Humans; Female; DNA, Neoplasm; Breast Neoplasms; Circulating Tumor DNA; Lung Neoplasms; Biological Assay; Radiopharmaceuticals
PubMed: 37955635
DOI: 10.1080/15384047.2023.2274123 -
Journal of Clinical Oncology : Official... Dec 2023Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in...
Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.
PURPOSE
Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma.
METHODS
This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters.
RESULTS
We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm ( = .79). Incision-suture times ( < .001) were significantly longer in the iMRI arm (316 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS ( < .001) and OS ( = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors ( = .006).
CONCLUSION
We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
Topics: Humans; Glioblastoma; Aminolevulinic Acid; Brain Neoplasms; Prospective Studies; Neoplasm, Residual; Quality of Life; Magnetic Resonance Imaging
PubMed: 37335962
DOI: 10.1200/JCO.22.01862