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We prospectively recorded clinical and laboratory parameters from patients with metastatic non-small cell lung cancer (NSCLC) treated with 2nd line PD-1/PD-L1 inhibitors in order to address their effect on treatment outcomes. Clinicopathological information (age, performance status, smoking, body mass index, histology, organs with metastases), use and duration of proton pump inhibitors, steroids and antibiotics (ATB) and laboratory values [neutrophil/lymphocyte ratio, LDH, albumin] were prospectively collected. Steroid administration was defined as the use of > 10 mg prednisone equivalent for [greater than or equal to] 10 days. Prolonged ATB administration was defined as ATB [greater than or equal to] 14 days 30 days before or within the first 3 months of treatment. JADBio, a machine learning pipeline was applied for further multivariate analysis. Data from 66 pts with non-oncogenic driven metastatic NSCLC were analyzed; 15.2% experienced partial response (PR), 34.8% stable disease (SD) and 50% progressive disease (PD). Median overall survival (OS) was 6.77 months. ATB administration did not affect patient OS [HR = 1.35 (CI: 0.761-2.406, p = 0.304)], however, prolonged ATBs [HR = 2.95 (CI: 1.62-5.36, p = 0.0001)] and the presence of bone metastases [HR = 1.89 (CI: 1.02-3.51, p = 0.049)] independently predicted for shorter survival. Prolonged ATB administration, bone metastases, liver metastases and BMI < 25 kg/m.sup.2 were selected by JADbio as the important features that were associated with increased probability of developing disease progression as response to treatment. The resulting algorithm that was created was able to predict the probability of disease stabilization (PR or SD) in a single individual with an AUC = 0.806 [95% CI:0.714-0.889]. Our results demonstrate an adverse effect of prolonged ATBs on response and survival and underscore their importance along with the presence of bone metastases, liver metastases and low BMI in the individual prediction of outcomes in patients treated with immunotherapy.

Background In primary breast cancer metastases frequently arise from a state of dormancy that may persist for extended periods of time. We investigated the efficacy of plasma micro-RNA (miR)-21, miR-23b, miR-190, miR-200b and miR-200c, related to dormancy and metastasis, to predict the outcome of patients with early breast cancer. Methods miRNAs were evaluated by RT-qPCR in plasma obtained before adjuvant chemotherapy. miRNA expression, classified as high or low according to median values, correlated with relapse and survival. Receiver operating characteristic (ROC) curves were constructed to determine miRNA sensitivity and specificity. Results miR-21 ( p  < 0.001), miR-23b ( p  = 0.028) and miR-200c ( p  < 0.001) expression were higher and miR-190 was lower ( p  = 0.013) in relapsed ( n  = 49), compared to non-relapsed patients ( n  = 84). Interestingly, miR-190 was lower ( p  = 0.0032) in patients with early relapse (at < 3 years; n  = 23) compared to those without early relapse ( n  = 110). On the other hand, miR-21 and miR-200c were higher ( p  = 0.015 and p  < 0.001, respectively) in patients with late relapse (relapse at ≥ 5 years; n  = 20) as compared to non-relapsed patients. High miR-200c was associated with shorter disease-free survival (DFS) ( p  = 0.005) and high miR-21 with both shorter DFS and overall survival (OS) ( p  < 0.001 and p  = 0.033, respectively) compared to low expression. ROC curve analysis revealed that miR-21, miR-23b, miR-190 and miR-200c discriminated relapsed from non-relapsed patients. A combination of of miR-21, miR-23b and miR-190 showed higher sensitivity and specificity in ROC analyses compared to each miRNA alone; accuracy was further improved by adding lymph node infiltration and tumor grade to the panel of three miRs (AUC 0.873). Furthermore, the combination of miR-200c, lymph node infiltration, tumor grade and estrogen receptor predicted late relapse (AUC 0.890). Conclusions Circulating miRNAs are differentially expressed among relapsed and non-relapsed patients with early breast cancer and predict recurrence many years before its clinical detection. Our results suggest that miRNAs represent potential circulating biomarkers in early breast cancer.

[This corrects the article DOI: 10.1371/journal.pone.0252537.].[This corrects the article DOI: 10.1371/journal.pone.0252537.].

Background In the realm of HER2-positive (HER2+) metastatic breast cancer (MBC), the advent of targeted therapies, notably trastuzumab and pertuzumab, represents a substantial advancement in enhancing patient outcomes. However, the intricacies of treatment escalate when patients encounter progression or resistance during first-line (1L) therapy. The togetHER study aimed to elucidate real-world insights into the profile, management strategies, and outcomes for HER2+ MBC patients initiating second-line treatment (2LT) in Greece, predating recent international guideline changes incorporating trastuzumab deruxtecan and tucatinib in the second line and beyond lines of treatments. Methods Data from adult female patients with HER2+ MBC who had initiated 2LT between 01-Jan-2015 and 31-Dec-2018 in 18 oncology departments across Greece were retrospectively abstracted through medical chart review. Results The eligible population comprised 122 patients, 68.0% of whom presented with recurrent MBC. Among the latter, 26.5% were tested for HER2 both in early and metastatic settings with 27.3% of them changing HER2 status from negative to positive. Retesting of HER2 expression following 2LT initiation was recorded in 8 cases. At 2LT initiation, patients’ median age was 57.0 years and 63.6% were hormone receptor-positive. The most common metastatic sites were bone (56.6%), lung (44.3%), liver (41.0%), and brain (29.5%). Anti-HER2 agent usage in 1L and 2L stood at 91.8% and 92.6%, respectively, with rates slightly diminishing in third (3L) (85.9%) and fourth line (4L) (82.4%). Endocrine therapy administration was generally low across treatment lines (12.3%, 9.9%, and 5.9%, in 2L, 3L, and 4L respectively), while chemotherapy use increased from 30.3% in 2L to 47.9% and 47.1% to 3L and 4L, correspondingly. Median progression-free survival (PFS) for 2L, 3L, and 4L was 7.7 [95% confidence interval (CI) 6.0–14.4], 6.4 (95% CI 5.4–7.1), and 5.6 (95% CI 2.6–9.0) months, respectively, while median overall survival was 25.0 (95% CI 20.5–34.4) months. Conclusions Although the 2LT pattern in Greece generally aligned with guidelines, persistently poor treatment outcomes underscore a significant unmet medical need for these patients.

The early diagnosis of lung cancer improves the probability of successful treatment. However, patients and physicians face several difficulties that can considerably delay the diagnostic process. A mixed-methods study that would follow the patient’s journey throughout the diagnostic process could alleviate these difficulties. This study aimed to (a) track the patients’ journey from the onset of symptoms until diagnosis and, (b) explore the patients’ perspective of the journey until diagnosis, on the largest island of Greece. A convergent mixed-methods study was conducted with 94 patients with lung cancer. Patients completed a self-report questionnaire and were interviewed about their symptoms and journey through the healthcare system before their diagnosis. Our findings revealed several problems and delays in the diagnostic process. Both quantitative and qualitative data showed that patients did not recognize their symptoms and sought medical advice in time because they overlooked or attributed their symptoms to ‘simpler’/‘more common’ causes. Furthermore, most patients were diagnosed 1–3 months after their first visit to a physician for their symptoms. Qualitative data analysis revealed three broad categories of problems that delayed diagnosis: (1) physician missteps, (2) administrative problems, and (3) the effect of the Covid-19 pandemic. This study found that major issues and delays prolong the diagnostic process for lung cancer. Therefore, optimization of diagnostic processes at each level of healthcare and interspecialty cooperation programs are needed. Furthermore, population-based interventions and patient education can help lung cancer patients be diagnosed early and improve their quality of life and disease outcomes.

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC.

To evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC). Patients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin. A total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03). The above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents. Clinical trial.gov NCT00694252.

Background/Objectives: Alterations in DNA damage repair mechanisms can impair the therapeutic effectiveness of cisplatin. MicroRNAs (miRNAs), key regulators of DNA damage repair processes, have been proposed as promising biomarkers for predicting the response to platinum-based chemotherapy (CT) in non-small cell lung cancer (NSCLC). In this study, by using a bioinformatics approach, we identified six miRNAs, which were differentially expressed (DE) between NSCLC patients characterized as responders and non-responders to platinum-based CT. We further validated the differential expression of the selected miRNAs on tumor and matched normal tissues from patients with resected NSCLC. Methods: Two miRNA microarray expression datasets were retrieved from the Gene Expression Omnibus (GEO) repository, comprising a total of 69 NSCLC patients (N = 69) treated with CT and annotated data from their response to treatment. Differential expression analysis was performed using the Linear Models for Microarray Analysis (Limma) package in R to identify DE miRNAs between responders (N = 33) and non-responders (N = 36). Quantitative real-time PCR (qRT-PCR) was used to assess miRNA expression levels in clinical tissue samples (N = 20). Results: Analysis with the Limma package revealed 112 DE miRNAs between responders and non-responders. A random-effects meta-analysis further identified 24 miRNAs that were consistently up- or downregulated in at least two studies. Survival analysis using the Kaplan–Meier plotter (KM plotter) indicated that 22 of these miRNAs showed significant associations with prognosis in NSCLC. Functional and pathway enrichment analysis revealed that several of the identified miRNAs were linked to key pathways implicated in DNA damage repair, including the p53, Hippo, PI3K and TGF-β signaling pathways. We finally distinguished a six-miRNA signature consisting of miR-26a, miR-29c, miR-34a, miR-30e-5p, miR-30e-3p and miR-497, which were downregulated in non-responders and are involved in at least three DNA damage repair pathways. Comparative expression analysis on tumor and matched normal tissues from surgically treated NSCLC patients confirmed their differential expression in clinical samples. Conclusions: In summary, we identified a signature of six miRNAs that are suppressed in NSCLC and may serve as a predictor of cisplatin response in NSCLC.

Novel therapies have significantly improved survival for non-metastatic non-small cell lung cancer (NSCLC), however recurrence remains a challenge. Current treatment and surveillance strategies rely on imaging and clinical assessments with limited sensitivity in early detection of disease progression. Liquid biopsy-mediated detection of minimal residual disease (MRD) allows monitoring of tumor activity at the molecular level before clinical and radiologic progression. Here, we review the current evidence for MRD in the adaptive management and surveillance of non-metastatic NSCLC, focusing on the missing links that prevent its widespread clinical adoption.