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ACS Nano Sep 2023Tumor immunotherapy has shown considerable therapeutic potential in the past few years, but the clinical response rate of immunotherapy is less than 20%. Encountering...
Tumor immunotherapy has shown considerable therapeutic potential in the past few years, but the clinical response rate of immunotherapy is less than 20%. Encountering the high heterogeneity of tumors, it will be a general trend to apply combined therapy for cancer treatment. Photodynamic therapy (PDT) transiently kills tumor cells by producing reactive oxygen species (ROS), while residual tumor cells are prone to metastasis, leading to tumor recurrence. In combination with tumor immunotherapy, it is hoped to awaken the host immune system and eradicate residual tumor cells. Herein, cancer cell membrane-coated nanoparticles as a platform to combine PDT, TLR7 agonist, and tumor antigen for the enhancement of tumor therapeutic efficacy are designed. The final biomimetic nanoparticles (CCMV/LTNPs) can specifically kill tumor cells through PDT, while strong host antitumor immune responses are elicited to eliminate residue tumor cells under the help of immune adjuvant and tumor antigen from the cancer cell membrane. In summary, a photoimmunotherapy strategy is designed that synergistically enhances the tumor therapeutic effects by killing tumor cells through PDT and activating host antitumor immune responses through the co-delivery of adjuvant and tumor antigen, which may offer a promising strategy for clinical immunotherapy in the future.
Topics: Humans; Toll-Like Receptor 7; Photosensitizing Agents; Neoplasm, Residual; Immunotherapy; Adjuvants, Immunologic; Cell Membrane; Nanoparticles; Antigens, Neoplasm
PubMed: 37606341
DOI: 10.1021/acsnano.3c02724 -
Cancer Research Feb 2024Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using...
UNLABELLED
Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment.
SIGNIFICANCE
In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools.
Topics: Humans; Female; Circulating Tumor DNA; Neoplasm, Residual; Neoplasm Recurrence, Local; Ovarian Neoplasms; High-Throughput Nucleotide Sequencing; Biomarkers, Tumor; Mutation
PubMed: 38038965
DOI: 10.1158/0008-5472.CAN-23-1429 -
Advanced Materials (Deerfield Beach,... Sep 2023Missed or residual tumor burden results in high risk for bladder cancer relapse. However, existing fluorescent probes cannot meet the clinical needs because of...
Missed or residual tumor burden results in high risk for bladder cancer relapse. However, existing fluorescent probes cannot meet the clinical needs because of inevitable photobleaching properties. Performance can be improved by maintaining intensive and sustained fluorescence signals via resistance to intraoperative saline flushing and intrinsic fluorescent decay, providing surgeons with sufficiently clear and high-contrast surgical fields, avoiding residual tumors or missed diagnosis. This study designs and synthesizes a photostable cascade-activatable peptide, a target reaction-induced aggregation peptide (TRAP) system, which can construct polypeptide-based nanofibers in situ on the cell membrane to achieve long-term and stable imaging of bladder cancer. The probe has two parts: a target peptide (TP) targets CD44v6 to recognize bladder cancer cells, and a reaction-induced aggregation peptide (RAP) is introduced, which effectively reacts with the TP via a click reaction to enhance the hydrophobicity of the whole molecule, assembling into nanofibers and further nanonetworks. Accordingly, probe retention on the cell membrane is prolonged, and photostability is significantly improved. Finally, the TRAP system is successfully employed in the high-performance identification of human bladder cancer in ex vivo bladder tumor tissues. This cascade-activatable peptide molecular probe based on the TRAP system enables efficient and stable imaging of bladder cancer.
Topics: Humans; Neoplasm Recurrence, Local; Peptides; Urinary Bladder Neoplasms; Nanofibers; Cell Membrane
PubMed: 37172955
DOI: 10.1002/adma.202210732 -
ACS Nano Dec 2023Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to...
Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to have a serious impact on tumor recurrence and metastasis postresection. Implantation of an hydrogel system postresection has shown to be an effective treatment with great clinical potential. Herein, an injectable zwitterionic hydrogel system was developed for local drug delivery with enhanced immune activation and prevention of tumor recurrence. Driven by electrostatic interactions, poly(sulfobetaine methacrylate) (PSBMA) self-assembles into a hydrogel in saline, achieving low protein adsorption and tunable biodegradability. The chemotherapy drug doxorubicin (DOX) was loaded into copper peroxide nanoparticles (CuO/DOX), which were coated with macrophage membranes to form tumor-targeting nanoparticles (M/CuO/DOX). Next, M/CuO/DOX and the stimulator of interferon genes (STING) agonist 2',3'-cGAMP were coloaded into PSBMA hydrogel (Gel@M/CuO/DOX/STING). The hydrophilic STING agonist was first released by diffusion from hydrogel to activate the STING pathway and upregulate interferon (IFN) signaling related genes, remodeling the immunosuppressive TME. Then, M/CuO/DOX targeted the residual tumor cells, combining with DOX-induced DNA damage, immunogenic tumor cell death, and copper death. Hence, this work combines chemodynamic therapy with STING pathway activation in TME, encouraging residual tumor cell death, promoting the maturation of dendritic cells, enhancing tumor-specific CD8 T cell infiltration, and preventing postoperative recurrence and metastasis.
Topics: Humans; Hydrogels; Neoplasm Recurrence, Local; Copper; Neoplasm, Residual; Tumor Microenvironment; Doxorubicin; Nanoparticles; Interferons; Cell Line, Tumor
PubMed: 37883579
DOI: 10.1021/acsnano.3c05898 -
Journal of Clinical Oncology : Official... Aug 2023The majority of patients with advanced nonseminomatous germ-cell tumor are cured with combination chemotherapy and surgical resection of residual disease when...
PURPOSE
The majority of patients with advanced nonseminomatous germ-cell tumor are cured with combination chemotherapy and surgical resection of residual disease when appropriate. In patients with both retroperitoneal (RP) and non-RP postchemotherapy residual disease, management of the non-RP disease is typically guided by pathologic findings at the time of RP resection. There are limited data to help guide management decisions in patients with non-RP postchemotherapy residual disease alone.
MATERIALS AND METHODS
The prospectively maintained Indiana University testicular cancer database was queried for patients with metastatic nonseminomatous germ-cell tumor treated between 1990 and 2021 who had residual non-RP disease in the absence of residual RP disease after completing either first-line or salvage chemotherapy.
RESULTS
One hundred twenty-nine patients met eligibility and were included in this analysis. Seventy-five patients had teratoma in the primary tumor site, while 54 did not. Of those with teratoma in the primary, 55% had at least one postchemotherapy non-RP surgical specimen with teratomatous elements compared with 17% of those without teratoma in the primary ( < .001). Of those without teratoma in the primary site, 56% had at least one postchemotherapy non-RP surgical specimen with active germ-cell tumor compared with 31% of those with teratoma in the primary ( = .0046).
CONCLUSION
The presence of teratoma in the primary tumor site is associated with a higher rate of teratoma in postchemotherapy residual non-RP disease. Patients without teratoma in the primary tumor should still be considered for resection of residual postchemotherapy disease that could harbor teratoma or active germ-cell tumor.
Topics: Male; Humans; Testicular Neoplasms; Treatment Outcome; Lymph Node Excision; Neoplasms, Germ Cell and Embryonal; Teratoma; Neoplasm, Residual
PubMed: 36758196
DOI: 10.1200/JCO.22.02205 -
European Radiology Dec 2023Contrast enhancement by MRI done early after cryoablation for renal malignancies may suggest residual tumor (RT). However, we have observed MRI enhancement within 48 h...
OBJECTIVES
Contrast enhancement by MRI done early after cryoablation for renal malignancies may suggest residual tumor (RT). However, we have observed MRI enhancement within 48 h of cryoablation in patients who had no contrast enhancement 6 weeks later. Our purpose was to identify features of 48-h contrast enhancement in patients without RT.
METHODS
This single-center retrospective study included consecutive patients who underwent percutaneous cryoablation of renal malignancies in 2013-2020, exhibited cryoablation-zone MRI contrast enhancement 48 h later, and had available 6-week MRI scans. Persistent or growing CE at 6 weeks vs. 48 h was classified as RT. A washout index was calculated for each 48-h MRI, and its performance for predicting RT was assessed by receiver operating characteristic curve analysis.
RESULTS
We included 60 patients with 72 cryoablation procedures and 83 cryoablation zones exhibiting 48-h contrast enhancement; mean age was 66 ± 17 years. Clear-cell renal cell carcinoma accounted for 95% of tumors. Of the 83 48-h enhancement zones, RT was observed in eight while 75 were benign. The 48-h enhancement was consistently visible at the arterial phase. Washout was significantly associated with RT (p < 0.001) and gradually increasing contrast enhancement with benignity (p < 0.009). A washout index below - 1.1 predicted RT with 88% sensitivity and 84% specificity.
CONCLUSION
MRI contrast enhancement 48 h after cryoablation of renal malignancies was usually benign. Washout was associated with residual tumor, with a washout index value below - 1.1 exhibiting good performance in predicting residual tumor. These findings may help to guide decisions about repeat cryoablation.
CLINICAL RELEVANCE STATEMENT
Magnetic resonance imaging contrast enhancement 48 h after cryoablation of renal malignancies rarely indicates residual tumor, which is characterized by washout with a washout index lower than - 1.1.
KEY POINTS
• Contrast enhancement at the arterial phase of magnetic resonance imaging done 48 h after cryoablation of a renal malignancy is usually benign. • Residual tumor manifesting as contrast enhancement at the arterial phase is characterized by subsequent marked washout. • A washout index below - 1.1 has 88% sensitivity and 84% specificity for residual tumor.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Renal Cell; Cryosurgery; Retrospective Studies; Neoplasm, Residual; Kidney Neoplasms; Magnetic Resonance Imaging; Contrast Media
PubMed: 37405502
DOI: 10.1007/s00330-023-09814-7 -
Current Opinion in Oncology May 2024Despite the remarkable advances in the treatment of germ cell tumors (GCT), several challenges remain. This review aims to highlight some of these challenges and provide... (Review)
Review
PURPOSE OF REVIEW
Despite the remarkable advances in the treatment of germ cell tumors (GCT), several challenges remain. This review aims to highlight some of these challenges and provide guidance on how to navigate through them.
RECENT FINDINGS
Patients with International Germ Cell Cancer Collaborative Group poor risk disease have worse prognosis and investigating novel therapeutic interventions are warranted in this population. Patients with brain metastases require a multidisciplinary approach by a group of clinicians experienced in the management of germ cell tumors. Patients with platinum refractory disease have poor prognosis and development of novel treatment options is urgently needed. Conventional tumor markers including alpha fetoprotein and human chorionic gonadotropin remain standard. Development of novel biomarkers to detect minimal residual disease or teratoma is needed.
SUMMARY
Management of patients with GCT requires a multidisciplinary approach. Patients should preferably be evaluated at tertiary care centers with expertise in the management of this disease.
Topics: Humans; Neoplasms, Germ Cell and Embryonal; Teratoma; Biomarkers, Tumor; Brain Neoplasms; Neoplasm, Residual
PubMed: 38573206
DOI: 10.1097/CCO.0000000000001026 -
Journal of Hematology & Oncology Aug 2023About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for...
BACKGROUND
About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells.
METHODS
This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1-5: single dose of 0.5 mg/m, 1.5 mg/m, 5 mg/m, 15 mg/m, 45 mg/m; cohort 6: 15 mg/m on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow.
RESULTS
Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses.
CONCLUSIONS
FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254).
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Immunoglobulin Fc Fragments; Neoplasm, Residual; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3
PubMed: 37587502
DOI: 10.1186/s13045-023-01490-w -
International Journal of Molecular... Sep 2023Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any...
Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many cases, these cells are occult and are not visible to the surgeon. Analysis of circulating tumour DNA in the blood (ctDNA) may offer a sensitive method to predict the presence of occult (non-visible) residual disease after surgery and may help predict disease recurrence. We assessed 48 women diagnosed with serous ovarian cancer (47 high-grade and 1 low-grade) for visible residual disease and for ctDNA. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. We sequenced DNA samples for 59 breast and ovarian cancer driver genes. The plasma sample was collected after surgery and before initiating chemotherapy. We compared survival in women with no residual disease, with and without a positive plasma ctDNA test. We found tumour-specific variants (TSVs) in cancer cells from 47 patients, and these variants were sought in ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Thirty-one patients (65.9%) had no visible residual disease; of these, 24 (77.4%) patients had detectable ctDNA. Of the patients with no visible residual disease, those patients with detectable ctDNA had higher mortality (20 of 27 died) than those without detectable ctDNA (3 of 7 died) (HR 2.32; 95% CI: 0.67-8.05), although this difference was not statistically significant ( 0.18). ctDNA in post-surgical serum samples may predict the presence of microscopic residual disease and may be a predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings.
Topics: Humans; Female; Neoplasm, Residual; Neoplasm Recurrence, Local; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Oncogenes; Cystadenocarcinoma, Serous; Cell-Free Nucleic Acids
PubMed: 37762691
DOI: 10.3390/ijms241814388 -
Scientific Reports Jul 2023Patients with acute myeloid leukemia (AML) and nucleophosmin 1 gene mutations (NPM1) show a favorable prognosis with chemotherapy (CT) in the absence of negative...
Patients with acute myeloid leukemia (AML) and nucleophosmin 1 gene mutations (NPM1) show a favorable prognosis with chemotherapy (CT) in the absence of negative prognostic genetic abnormalities. Between 2008 and 2021 64 patients with NPM1AML received alloHSCT because of additional adverse prognostic factors (1st line), inadequate response to or relapse during or after CT (2nd line). To expand the evidence in alloTX in NPM1 AML, clinical and molecular data were retrospectively analyzed with respect to pre-transplant strategies and outcome. Patients with minimal residual disease negative (MRD-) CR at transplant had better 2-y-PFS and 2-y-OS (77% and 88%) than patients with minimal residual disease positive (MRD+) CR (41% and 71%) or patients with active disease (AD) at transplant (20% and 52%). The 2nd line patients with relapse after completing CT responded well to high dose cytarabine based salvage chemotherapy (salvage CT) in contrast to patients relapsing while still on CT (90% vs 20%, P = 0.0170). 2-y-PFS and 2-y-OS was 86% in patients who achieved a 2nd MRD- CR pre alloHSCT. Outcome in NPM1AML depends on disease burden at alloHSCT. Time and type of relapse in relation to CT are predictive for response to salvage CT.
Topics: Humans; Nuclear Proteins; Nucleophosmin; Neoplasm, Residual; Retrospective Studies; Mutation; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Prognosis; Recurrence
PubMed: 37402862
DOI: 10.1038/s41598-023-38037-5