MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T‐ or B‐cell acute lymphoblastic leukemia (T‐ALL or B‐ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave‐one‐out approach and FDR ≤ 0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T‐ and B‐ALL, of which 10 (miR‐708‐5p, miR‐497‐5p, miR‐151a‐5p, miR‐151b, miR‐371b‐5p, miR‐455‐5p, miR‐195‐5p, miR‐1266‐5p, miR‐574‐5p, and miR‐425‐5p) were downregulated and six (miR‐450b‐5p, miR‐450a‐5p, miR‐542‐5p, miR‐424‐5p, miR‐629‐5p, and miR‐29c‐5p) were upregulated in childhood T‐ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B‐cell receptor signaling pathways for induced miRNAs and TGF‐beta signaling, apoptosis, and NF‐kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR‐29c‐5p expression as the best discriminator between childhood T‐ and B‐ALL, which is involved in calcium signaling, critical for B‐cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR‐29c‐5p on acute lymphoblastic leukemia subtypes and on disease prognosis.
PURPOSE A nationwide lockdown was enforced in Brazil starting in March 2020 because of the COVID-19 pandemic when cancer screening activities were reduced. In this study, we evaluated the impact of the COVID-19 pandemic on breast cancer (BC) diagnosis. METHODS We extracted data from the medical records of patients age older than 18 years who were diagnosed with BC and started treatment or follow-up in private oncology institutions in Brazil between 2018 and 2021. The primary objective was to compare the stage distribution during the COVID-19 pandemic (2020-2021) with a historical prepandemic control cohort (2018-2019). Early BC was defined as stage I-II and advanced disease as stage IV. RESULTS We collected data for 11,753 patients with an initial diagnosis of BC, with 6,493 patients in the pandemic (2020-2021) and 5,260 patients in the prepandemic period (2018-2019). We observed a lower prevalence of early-stage BC (63.6% v 68.4%) and a higher prevalence of advanced-stage BC (16.9 v 12.7%), after the onset of the pandemic (both P < .01). This pattern was similar for both estrogen receptor–positive/human epidermal growth factor receptor 2–negative and human epidermal growth factor receptor 2–positive tumors: significantly decreased in the early stage from 69% to 67% and 68% to 58%, respectively, and a considerable increase in advanced-stage disease from 13% to 15% and 13% to 20%, respectively. For triple-negative BC, there was a significantly higher percentage of patients with advanced-stage disease during the pandemic (17% v 11%). Overall, age 50 years or older and postmenopausal status were associated with a greater risk of advanced stage at diagnosis during the pandemic period. CONCLUSION We observed a substantial increase in the number of cases of advanced-stage BC in Brazil during the COVID-19 pandemic.
e21126 Background: Circadian rhythms have shown direct impact on toxicity and efficacy of anticancer treatments. Adaptive immune responses related to (or associated with) check point inhibitor (CPI) administration may have lower intensity later in the day. Notably, emerging evidence suggests that the time-of-day administration of different immunotherapies could have survival implications in different tumor types. Methods: We extracted de-identified data from curated the Real-World database of the Oncoclínicas Group, including 21 community-oncology practices in Brazil with EHR information on time-of-day administration of CPI in patients with advanced NSCLC. Only patients treated with single-agent CPIs with palliative intent (Nivolumab, Pembrolizumab or Atezolizumab) from Jan 2018 through Dec 2021 were analyzed. The primary endpoint was a comparative analysis of the median Time to Treatment Discontinuation (TTD) of CPI stratified according to time-of-day administration using a propensity-score (PS) matching model. On the basis of previous reports, we selected the cutoff of 20% of CPI doses administered after 4:00 pm as the late-day subgroup. Variables included in PS matching were: age (< 60, 60+); line of therapy (1st, 2ndor beyond); gender (male, female), and CPI agent (Pembrolizumab vs. others). Results: From a total of 1,603 patients with advanced NSCLC treated at Oncoclínicas during the study period, 508 received CPI as per inclusion criteria. Median age was 73 years (36-94), 66% were male, 63% received CPI in the 1stline setting, 50% with Pembrolizumab. Overall, 219 CPI infusions (15%) occurred after 4:00 pm and 9% of the patients (n = 43) qualified as late-day infusion subgroup (more than 20% of infusions after 4pm). Median TTD was 4.9 months (CI 95%, 2.83-13.5) in these patients. In the PS matched population with early-day infusions (2:1, n = 86), median TTD was 14 months (CI 95%, 8.87-23.4). Overall, with 73 events in 129 patients, we found a significantly increased risk of treatment discontinuation in the late-day subgroup (HR 1.61, CI95% 1.0-2.6, p = 0.05). With only 33 death events and median follow-up of 11 months, median overall survival was not reached in late-day or early-day subgroups (HR 1.25, CI95% 0.6-2.6, p = 0.5). Conclusions: This preliminary and exploratory real-world data analysis suggests that the time-of-day administration of CPI in patients with advanced NSCLC could have a meaningful impact on patient outcomes, in line with studies conducted in melanoma. This simple and inexpensive intervention merits further exploration in prospective controlled clinical trials.
The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after contacting with its ligands (PD-L1 and PD-L2) exerts an inhibitory effect on the cellular immune response, maintaining the balance between activation, tolerance, and immune cell-dependent lesion. We evaluated 295 patients exhibiting or not HPV infection, stratified according to the location (injured and adjacent non-injured areas) and severity of the lesion (benign, pre-malignant lesions). Additionally, we investigated the role of the promoter region PDCD1 -606G>A polymorphism (rs36084323) on the studied variables. PD-1 and PDCD1 expression were evaluated by immunohistochemistry and qPCR, respectively, and the PDCD1 polymorphism was evaluated by nucleotide sequencing. Irrespective of the severity of the lesion, PD-1 levels were increased compared to adjacent uninjured areas. Additionally, in cervical intraepithelial neoplasia (CIN) I, the presence of HPV was associated with increased (P = 0.0649), whereas in CIN III was associated with decreased (P = 0.0148) PD-1 levels, compared to the uninjured area in absence of HPV infection. The PDCD1 -606A allele was rare in our population (8.7%) and was not associated with the risk for development of HPV infection, cytological and histological features, and aneuploidy. In contrast, irrespective of the severity of the lesion, patients exhibiting the mutant PDCD1 -606A allele at single or double doses exhibited increased protein and gene expression when compared to the PDCD1 -606GG wild type genotype. Besides, the presence of HPV was associated with the decrease in PDCD1 expression and PD-1 levels in carriers of the -606 A allele presenting severe lesions, suggesting that other mediators induced during the HPV infection progression may play an additional role. This study showed that increased PD-1 levels are influenced by the -606G>A nucleotide variation, particularly in low-grade lesions, in which the A allele favors increased PDCD1 expression, contributing to HPV immune system evasion, and in the high-grade lesion, by decreasing tissue PD-1 levels.
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