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Journal For Immunotherapy of Cancer May 2024The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been...
BACKGROUND
The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of PTC immune remodeling and exploration of novel treatment targets.
METHODS
This study conducted a single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured from 14 patients diagnosed with adjacent tissues, non-progressive PTC or progressive PTC. Key findings were authenticated through spatial transcriptomics RNA sequencing, immunohistochemistry, multiplex immunohistochemistry, and an independent bulk RNA-seq data set containing 502 samples.
RESULTS
A total of 151,238 individual cells derived from 18 adjacent tissues, non-progressive PTC and progressive PTC specimens underwent scRNA-seq analysis. We found that progressive PTC exhibits the following characteristics: a significant decrease in overall immune cells, enhanced immune evasion of tumor cells, and disrupted antigen presentation function. Moreover, we identified a subpopulation of lysosomal associated membrane protein 3 (LAMP3) dendritic cells (DCs) exhibiting heightened infiltration in progressive PTC and associated with advanced T stage and poor prognosis of PTC. LAMP3 DCs promote CD8 T cells exhaustion (mediated by NECTIN2-TIGIT) and increase infiltration abundance of regulatory T cells (mediated by chemokine (C-C motif) ligand 17 (CCL17)-chemokine (C-C motif) receptor 4 (CCR4)) establishing an immune-suppressive microenvironment. Ultimately, we unveiled that progressive PTC tumor cells facilitate the retention of LAMP3 DCs within the tumor microenvironment through NECTIN3-NECTIN2 interactions, thereby rendering tumor cells more susceptible to immune evasion.
CONCLUSION
Our findings expound valuable insights into the role of the interaction between LAMP3 DCs and T-cell subpopulations and offer new and effective ideas and strategies for immunotherapy in patients with progressive PTC.
Topics: Humans; Dendritic Cells; Thyroid Cancer, Papillary; Lysosomal-Associated Membrane Protein 3; Thyroid Neoplasms; Male; Female; Tumor Microenvironment; Middle Aged; Tumor Escape; T-Lymphocyte Subsets; Neoplasm Proteins
PubMed: 38816233
DOI: 10.1136/jitc-2024-008983 -
Life Science Alliance Aug 2024In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 is...
In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 is associated with neurodegenerative diseases including Parkinson's, cardiovascular diseases and cancer, making Drp1 a pivotal biomarker for monitoring mitochondrial status and potential pathophysiological conditions. Here, we developed nanobodies (Nbs) as versatile binding molecules for proteomics, advanced microscopy and live cell imaging of Drp1. To specifically enrich endogenous Drp1 with interacting proteins for proteomics, we functionalized high-affinity Nbs into advanced capture matrices. Furthermore, we detected Drp1 by bivalent Nbs combined with site-directed fluorophore labelling in super-resolution STORM microscopy. For real-time imaging of Drp1, we intracellularly expressed fluorescently labelled Nbs, so-called chromobodies (Cbs). To improve the signal-to-noise ratio, we further converted Cbs into a "turnover-accelerated" format. With these imaging probes, we visualized the dynamics of endogenous Drp1 upon compound-induced mitochondrial fission in living cells. Considering the wide range of research applications, the presented Nb toolset will open up new possibilities for advanced functional studies of Drp1 in disease-relevant models.
Topics: Dynamins; Mitochondrial Dynamics; Humans; Single-Domain Antibodies; Mitochondria; Proteomics; Animals; Protein Binding; HeLa Cells; Mitochondrial Proteins
PubMed: 38816213
DOI: 10.26508/lsa.202402608 -
American Society of Clinical Oncology... Jun 2024Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods... (Review)
Review
Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods available within the country's existing health care system. Although cancer survival rates have markedly led in the past few decades, any improvement in the 5-year survival of gynecologic cancers has been modest, as in the case of ovarian and cervical cancers, or has declined, as in the case of endometrial cancer. The lack of effective screening options contributes to many women presenting with advanced-stage disease and the need for radical approaches to treatment. Although treatment for early-stage disease can lead to a cure, advanced-stage disease is fraught with a high potential for morbidity and mortality, and recent clinical trials have aimed to assess the noninferiority of minimally invasive options versus aggressive surgical approaches. Of particular interest is fertility-sparing treatments for endometrial and cervical cancers, which have recently been on the rise among younger women. Balancing morbidity with the risk of mortality, and loss of fertility and quality of life requires a targeted patient-centered approach to treatment. This is an ongoing area of intense research and sometimes may challenge current treatment paradigms. In this two-part review, we present an overview of current approaches to gynecologic cancer treatment and the need to de-escalate radical surgical approaches and preserve fertility. We also review the intricacies of ovarian and advanced endometrial cancer treatment, exploring the nuances in surgical debulking timing and its impact on outcomes.
Topics: Humans; Female; Genital Neoplasms, Female; Quality of Life; Gynecologic Surgical Procedures; Neoplasm Staging
PubMed: 38815208
DOI: 10.1200/EDBK_438550 -
American Society of Clinical Oncology... Jun 2024Early palliative care, palliative care integrated with oncology care early in the course of illness, has myriad benefits for patients and their caregivers, including... (Review)
Review
Early palliative care, palliative care integrated with oncology care early in the course of illness, has myriad benefits for patients and their caregivers, including improved quality of life, reduced physical and psychological symptom burden, enhanced prognostic awareness, and reduced health care utilization at the end of life. Although ASCO and others recommend early palliative care for all patients with advanced cancer, widespread implementation of early palliative care has not been realized because of barriers such as insufficient reimbursement and a palliative care workforce shortage. Investigators have recently tested several implementation strategies to overcome these barriers, including triggers for palliative care consultations, telehealth delivery, navigator-delivered interventions, and primary palliative care interventions. More research is needed to identify mechanisms to distribute palliative care optimally and equitably. Simultaneously, the transformation of the oncology treatment landscape has led to shifts in the supportive care needs of patients and caregivers, who may experience longer, uncertain trajectories of cancer. Now, palliative care also plays a clear role in the care of patients with hematologic malignancies and may be beneficial for patients undergoing phase I clinical trials and their caregivers. Further research and clinical guidance regarding how to balance the risks and benefits of opioid therapy and safely manage cancer-related pain across this wide range of settings are urgently needed. The strengths of early palliative care in supporting patients' and caregivers' coping and centering decisions on their goals and values remain valuable in the care of patients receiving cutting-edge personalized cancer care.
Topics: Humans; Palliative Care; Neoplasms; Precision Medicine; Quality of Life
PubMed: 38815187
DOI: 10.1200/EDBK_100038 -
The Oncologist May 2024In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and...
BACKGROUND
In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported.
MATERIALS AND METHODS
Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated.
RESULTS
The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95).
CONCLUSION
The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer.
CLINICALTRIALS.GOV ID
NCT03189719.
PubMed: 38815152
DOI: 10.1093/oncolo/oyae087 -
PLoS Biology May 2024Glioblastoma, the most aggressive and prevalent form of primary brain tumor, is characterized by rapid growth, diffuse infiltration, and resistance to therapies.... (Review)
Review
Glioblastoma, the most aggressive and prevalent form of primary brain tumor, is characterized by rapid growth, diffuse infiltration, and resistance to therapies. Intrinsic heterogeneity and cellular plasticity contribute to its rapid progression under therapy; therefore, there is a need to fully understand these tumors at a single-cell level. Over the past decade, single-cell transcriptomics has enabled the molecular characterization of individual cells within glioblastomas, providing previously unattainable insights into the genetic and molecular features that drive tumorigenesis, disease progression, and therapy resistance. However, despite advances in single-cell technologies, challenges such as high costs, complex data analysis and interpretation, and difficulties in translating findings into clinical practice persist. As single-cell technologies are developed further, more insights into the cellular and molecular heterogeneity of glioblastomas are expected, which will help guide the development of personalized and effective therapies, thereby improving prognosis and quality of life for patients.
Topics: Humans; Glioblastoma; Single-Cell Analysis; Brain Neoplasms; Transcriptome; Animals
PubMed: 38814900
DOI: 10.1371/journal.pbio.3002640 -
JAMA Network Open May 2024Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with...
IMPORTANCE
Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems.
OBJECTIVE
To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain).
DESIGN, SETTING, AND PARTICIPANTS
In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023.
MAIN OUTCOMES AND MEASURES
Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed.
RESULTS
The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab.
CONCLUSIONS AND RELEVANCE
In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Lung Neoplasms; Antibodies, Monoclonal; Brazil; Spain; Quality-Adjusted Life Years; Male; Singapore; Female; United States; Middle Aged; Neoplasm Staging; Aged; Antineoplastic Agents, Immunological; Markov Chains; Cost-Effectiveness Analysis
PubMed: 38814640
DOI: 10.1001/jamanetworkopen.2024.13938 -
Biomolecules & Biomedicine May 2024The effectiveness of removing lymph nodes before initial treatment in patients with locally advanced cervical cancer is still debated. This article presents a... (Meta-Analysis)
Meta-Analysis
The effectiveness of removing lymph nodes before initial treatment in patients with locally advanced cervical cancer is still debated. This article presents a meta-analysis that systematically evaluates the impact of this approach on oncological outcomes. A systematic literature search of PubMed, Embase, Science Direct, and the Cochrane Database of Systematic Reviews (up to December 2023) was performed to obtain relevant studies. The findings were combined using fixed-effects models to address potential differences. Combined risk ratios (HR) and 95% confidence intervals (CI) were calculated. Egger's test was used to assess publication bias. Out of 1025 screened articles, four studies (involving 838 women) met the inclusion criteria. The results showed that lymph node dissection before initial treatment did not affect overall survival (OS) in patients with locally advanced cervical cancer compared to concurrent radiotherapy (HR = 1.11, 95% CI = 0.91-1.36, P = 0.30). It also did not increase the incidence of postoperative complications or cause delays in radiotherapy. In particular, removing larger lymph nodes (>2cm) aided in defining the radiation field and decreasing radiotherapy-related complications. The surgical technique also had some impact on postoperative complications. In summary, in order to obtain the best therapeutic outcomes, personalized plans should be developed for each patient, accounting for their individual circumstances to achieve precise treatment and enhance their quality of life.
PubMed: 38814195
DOI: 10.17305/bb.2024.10591 -
CA: a Cancer Journal For Clinicians May 2024Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead,... (Review)
Review
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
PubMed: 38814103
DOI: 10.3322/caac.21844 -
Turkish Journal of Medical Sciences 2023It wasaimed herein to investigate coronavirus disease (COVID-19) in cancer patients and compare hematological and solid organ cancer patients in terms of the course and...
BACKGROUND/AIM
It wasaimed herein to investigate coronavirus disease (COVID-19) in cancer patients and compare hematological and solid organ cancer patients in terms of the course and outcome of this disease.
MATERIALS AND METHODS
Data from cancer patients with laboratory-confirmed COVID-19 infection were analyzed retrospectively. Risk factors for poor prognosis and the effect of vaccination on the clinical outcomes of the patients were evaluated.
RESULTS
A total of 403 cancer patients who were diagnosed with COVID-19 between March 1st, 2021, and November 30th, 2022, were included, of whom 329 (81.6%) had solid and 74 (18.4%) had hematological cancers. Hospitalization and intensive care unit (ICU) admission rates were significantly higher in the hematological cancer patients compared to the solid organ cancer patients (73.0% vs. 35.9%, p< 0.001 and 25.7% vs. 14.0%, p= 0.013, respectively). The COVID-19related case fatality rate (CFR) was defined as 15.4%, and it was higher in the hematologicalcancer patientsthan inthe solid organ cancer patients (23.0% vs. 13.7%, p= 0.045) and was higher in patients with metastatic/advanced disease compared to the other cancer stages (p< 0.001). In the solid organ cancergroup, hospitalization, ICU admission, and the COVID-19 CFR were higher in patients with respiratory and genitourinary cancers (p< 0.001). A total of 288 (71.8%) patients had receivedCOVID-19 vaccination; 164 (56.94%) had≤2 doses and 124 (43.06%) had≥3 doses. The hospitalization rate was higher in patients with ≤2 doses of vaccine compared to those with ≥3 doses (48.2% vs. 29.8%,p= 0.002). Patients with COVID-19related death had higher levels of leucocyte, neutrophil, D-dimer, troponin, C-reactive protein (CRP), procalcitonin, and ferritin and lower levels of lymphocyte than the survivors. In the logistic regression analysis,the risk of COVID-19related mortality was higher in the hematological cancer patients(OR:1.726), those who were male (OR:1.757), and with the Pre-Delta/Delta variants (OR:1.817).
CONCLUSION
This study revealed that there is an increased risk of COVID-19-related serious events (hospitalization, ICU admission, or death) in patients with hematological cancerscompared with those who have solid organ cancers. It wasalso shown that receiving ≥3 doses of COVID-19 vaccine is more protective against severe illness and the need for hospitalization than ≤2 doses.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Neoplasms; Retrospective Studies; COVID-19 Vaccines; Aged; Hospitalization; Risk Factors; SARS-CoV-2; Intensive Care Units; Adult; Vaccination; Prognosis
PubMed: 38813483
DOI: 10.55730/1300-0144.5744