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Journal of Ovarian Research Jun 2024Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC....
PURPOSE
Ovarian cancer (OC) is characterized by a high recurrence rate, and homologous recombination deficiency (HRD) is an important biomarker in the clinical management of OC. We investigated the differences in clinical genomic profiles between the primary and platinum-sensitive recurrent OC (PSROC), focusing on HRD status.
MATERIALS AND METHODS
A total of 40 formalin-fixed paraffin-embedded (FFPE) tissues of primary tumors and their first platinum-sensitive recurrence from 20 OC patients were collected, and comprehensive genomic profiling (CGP) analysis of FoundationOneCDx (F1CDx) was applied to explore the genetic (dis)similarities of the primary and recurrent tumors.
RESULTS
By comparing between paired samples, we found that genomic loss of heterozygosity (gLOH) score had a high intra-patient correlation (r = 0.79) and that short variants (including TP53, BRCA1/2 and NOTCH1 mutations), tumor mutational burden (TMB) and microsatellite stability status remained stable. The frequency of (likely) pathological BRCA1/2 mutations was 30% (12/40) in all samples positively correlated with gLOH scores, but the proportion of gLOH-high status (score > 16%) was 50% (10/20) and 55% (11/20) in the primary and recurrent samples, respectively. An additional 20% (4/20) of patients needed attention, a quarter of which carried the pathological BRCA1 mutation but had a gLOH-low status (gLOH < 16%), and three-quarters had different gLOH status in primary-recurrent pairs. Furthermore, we observed the PSROC samples had higher gLOH scores (16.1 ± 9.24 vs. 19.4 ± 11.1, p = 0.007), more CNVs (36.1% vs. 15.1% of discordant genomic alternations), and significant enrichment of altered genes in TGF-beta signaling and Hippo signaling pathways (p < 0.05 for all) than their paired primaries. Lastly, mutational signature and oncodrive gene analyses showed that the computed mutational signature similarity in the primary and recurrent tumors were best matched the COSMI 3 signature (Aetiology of HRD) and had consistent candidate cancer driver genes of MSH2, NOTCH1 and MSH6.
CONCLUSION
The high genetic concordance of the short variants remains stable along OC recurrence. However, the results reveal significantly higher gLOH scores in the recurrent setting than in paired primaries, supporting further clinically instantaneity HRD assay strategy.
Topics: Humans; Female; Ovarian Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Genomics; Aged; Mutation; Loss of Heterozygosity; Adult; Biomarkers, Tumor; Gene Expression Profiling
PubMed: 38937827
DOI: 10.1186/s13048-024-01455-8 -
In Vivo (Athens, Greece) 2024Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)....
BACKGROUND
Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy.
PATIENTS AND METHODS
In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival.
RESULTS
The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%).
CONCLUSION
The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.
Topics: Humans; Male; Female; Middle Aged; Aged; Salvage Therapy; Head and Neck Neoplasms; Drug Resistance, Neoplasm; Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Adult; Ifosfamide; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Platinum; Neoplasm Metastasis; Aged, 80 and over; Treatment Outcome
PubMed: 38936932
DOI: 10.21873/invivo.13644 -
In Vivo (Athens, Greece) 2024In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles...
BACKGROUND/AIM
In recent years, switch maintenance after platinum-based chemotherapy has been a standard of care. However, the appropriate number of systemic chemotherapy cycles against advanced-stage urothelial carcinoma (UC) remains unclear. This study assessed the survival outcomes of first-line platinum-based chemotherapy according to treatment cycles in patients with metastatic disease.
PATIENTS AND METHODS
We retrospectively evaluated patients with metastatic bladder and upper urinary tract cancer who received platinum-based combination therapy. Overall survival (OS) was evaluated using the Kaplan-Meier method and the log-rank test.
RESULTS
Of 179 patients, 47 (26.3%) were women, and 73 (40.8%) had upper urinary tract cancer. Furthermore, 47 (26.3%) who were not eligible for cisplatin received carboplatin. The median number of treatment cycles was 3 (range=1-14 cycles). The rates of progressive disease within two cycles, from two to four cycles, and from four to six cycles were 18.4%, 19.2%, and 30.6%, respectively. The median OS of patients with 2, 3, 4, 5-6, and ≥7 treatment cycles were 8.6, 14.3, 21.3, 24.4, and 26.1 months, respectively. The OS did not significantly differ between patients receiving four treatment cycles and those receiving ≥5 treatment cycles. In patients with disease control (complete or partial response or stable disease) receiving ≥4 treatment cycles, there was no significant difference in terms of OS between patients receiving four cycles and those receiving six cycles.
CONCLUSION
Four cycles of first-line platinum-based chemotherapy can be effective in patients with metastatic UC.
Topics: Humans; Female; Male; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged, 80 and over; Adult; Neoplasm Metastasis; Treatment Outcome; Platinum; Retrospective Studies; Carcinoma, Transitional Cell; Urologic Neoplasms; Carboplatin; Kaplan-Meier Estimate; Neoplasm Staging; Urinary Bladder Neoplasms; Cisplatin
PubMed: 38936900
DOI: 10.21873/invivo.13648 -
Gynecologic Oncology Jun 2024Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study...
OBJECTIVE
Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer.
METHODS
The human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with BNZ-111, and cell proliferation, apoptosis, and cell cycle were assessed.
RESULTS
It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating β-3 tubulin expression to suppress microtubule dynamics.
CONCLUSION
BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology.
PubMed: 38936282
DOI: 10.1016/j.ygyno.2024.06.011 -
European Journal of Medicinal Chemistry Jun 2024Metal ions carry out a wide variety of functions, including acid-base/redox catalysis, structural functions, signaling, and electron transport. Understanding the... (Review)
Review
Metal ions carry out a wide variety of functions, including acid-base/redox catalysis, structural functions, signaling, and electron transport. Understanding the interactions of transition metal complexes with biomacromolecules is essential for biology, medicinal chemistry, and the production of synthetic metalloenzymes. After the coincidental discovery of cisplatin, importance of the metal complexes in biochemistry became a top priority for inquiry. In this review, a decade update on various synthetic strategies to first row transition metal complex and their interaction with DNA through non-covalent binding are explored. Moreover, this effort provides an excellent analysis on the efficacy of theoretical and practical approaches to the systematic generation of new non-platinum based metallodrugs for anti-cancer therapeutics.
PubMed: 38936150
DOI: 10.1016/j.ejmech.2024.116603 -
Food Chemistry Jun 2024Paper chip as a representative microfluidic device has been mushroomed for rapid identification of contaminants in agro-food. However, the sensitivity and accuracy have...
Paper chip as a representative microfluidic device has been mushroomed for rapid identification of contaminants in agro-food. However, the sensitivity and accuracy have still been challenged by inevitable background noise or interference in food matrix. Herein, we designed and fabricated a dual-mode paper chip (DPC) by assembling a patterned paper electrode with a platinum nanoparticles-treated colorimetric region through a flow channel. Dual-mode outputs were guided by an aptamer-gated UiO-66-NH metal-organic frameworks (MOFs). UiO-66-NH loaded with 3, 3', 5, 5'-tetramethylbenzidine (TMB) was controlled by a switch comprised of CdS quantum dots-aptamer. Aflatoxin B1 (AFB1, a kind of carcinogenic mycotoxin) target came and induced TMB release, triggering colorimetric and ECL signals on DPC, ultra-high sensitivity with a detection limit of 7.8 fg/mL was realized. The practicability of the DPC was also confirmed by spiking AFB1 in real corn samples. This portable paper-based device provides an ideal rapid detection platform tailored for diverse food contaminants analysis.
PubMed: 38936131
DOI: 10.1016/j.foodchem.2024.140182 -
Nano Letters Jun 2024Developing ultrasensitive lateral flow immunoassays (LFIAs) has garnered significant attention in the field of point-of-care testing. In this study, a trimetallic...
Developing ultrasensitive lateral flow immunoassays (LFIAs) has garnered significant attention in the field of point-of-care testing. In this study, a trimetallic dendritic nanozyme (Pd@Pt-Ru) was synthesized through Ru deposition on a Pd@Pt core and utilized to enhancing the sensitivity of LFIAs. Pd@Pt-Ru exhibited a value of 5.23 mM for detecting HO, which indicates an HO affinity comparable with that of horseradish peroxidase. The Ru surface layer reduces the activation energy barrier, which increases the maximum reaction rate. As a proof of concept, the proposed Pd@Pt-Ru nanozyme was incorporated into LFIAs (A-Pd@Pt-Ru-LFIAs) for detecting human chorionic gonadotropin (hCG). Compared with conventional gold nanoparticle (AuNP)-LFIAs, A-Pd@Pt-Ru-LFIAs demonstrated 250-fold increased sensitivity, thereby enabling a visible detection limit as low as 0.1 IU/L. True positive and negative rates both reached 100%, which renders the proposed Pd@Pt-Ru nanozyme suitable for detecting hCG in clinical samples.
PubMed: 38935481
DOI: 10.1021/acs.nanolett.4c01568 -
The Cochrane Database of Systematic... Jun 2024This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of secondary CRS and chemotherapy in...
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of secondary CRS and chemotherapy in comparison to chemotherapy alone for women with platinum-sensitive recurrent epithelial ovarian cancer.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Neoplasm Recurrence, Local; Cytoreduction Surgical Procedures; Systematic Reviews as Topic; Randomized Controlled Trials as Topic; Combined Modality Therapy; Antineoplastic Agents
PubMed: 38934360
DOI: 10.1002/14651858.CD015297 -
Heliyon Jun 2024Modeling of proton exchange membrane (PEM) fuel cells is attracting more attention as fuel cell technology continues to develop. In this study, we considered a hybrid...
Using a three-dimensional computational fluid dynamics model and an agglomerate model to investigate the effect of varying agglomerate parameters and output voltages on proton exchange membrane fuel cell performance.
Modeling of proton exchange membrane (PEM) fuel cells is attracting more attention as fuel cell technology continues to develop. In this study, we considered a hybrid model that combines an agglomerate model based on the agglomeration of catalyst particles and the coverage-dependent kinetic equation of platinum oxide for ORR, and another 3D numerical model of a PEM fuel cell based on computational fluid dynamics (CFD). The obtained results from our developed models were validated with experimental results from literature. In fact, we investigated the effects of changing the agglomerate radius , the ionomer volume fraction within the agglomerate the effective agglomerate surface area , the distribution of the gases and the temperature on the cell performances. The results revealed that the cell performances are strongly influenced by changing and for medium and high current densities: The activation loss increases with increasing and decreasing . Also, increases with decreasing and increasing . In addition, the PEM fuel cell's power output is significantly enhanced when is decreased and is increased, the optimal power being obtained for values of and = 0.6. The numerical results also showed that decreasing the output voltage from 0.95V to 0.35V can accelerate the electrochemical reaction process.
PubMed: 38933966
DOI: 10.1016/j.heliyon.2024.e32277 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves... (Review)
Review
BACKGROUND
Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi).
MATERIALS AND METHODS
This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov.
RESULTS
The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients.
CONCLUSIONS
PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.
PubMed: 38931448
DOI: 10.3390/ph17060778