Incidence Of Tumors Research Articles

Comparison of the latest cancer statistics, cancer epidemic trends and determinants between China and the United States

Objective: To provide supports for the cancer prevention and control strategies in China by comparing the disease burden, epidemic trends, 5-year relative survival rate and major determinants of common cancers between China and the United States. Methods: A descriptive secondary analysis was conducted using data extracted from the GLOBOCAN database, the Surveillance, Epidemiology, and End Results database, Global Burden of disease 2019 database, and previous studies. The main indicators included the cases of malignant tumors in different sites, the cases of deaths, the age-standardized incidence (world standard incidence) and mortality (world standard mortality), the 5-year relative survival rate, and population attributable fraction (PAF). Results: In 2022, an estimated 4.825 million new cases and 2.574 million deaths of malignant neoplasms in China. The world standard incidence rate (201.6/100 000) in China was lower than that in the United States (367.0/100 000), and the world standard mortality rate (96.5/100 000) was higher than that in the United States (82.3/100 000). Lung cancer ranked first in the disease burden of malignant tumors in China, the new cases and deaths accounted for 22.0% and 28.5% of all malignant tumors, respectively. The top three malignant tumors in China were breast cancer (11.5%), prostate cancer (9.7%) and lung cancer (9.5%), which were also among the top five causes of death. However, the second to fifth leading causes of death from malignant tumors in China were digestive system tumors (liver cancer 12.3%, stomach cancer 10.1%, colorectal cancer 9.3%, and esophageal cancer 7.3%). From 2000 to 2018, the world standard incidence of malignant tumors showed an increasing trend and the world standard mortality of malignant tumors showed a decreasing trend in China, while the world standard incidence and mortality of malignant tumors in the United States showed a significant decreasing trend after 2000. The incidence of breast cancer, colorectal cancer and thyroid cancer increased rapidly in China, while the incidence and mortality of stomach cancer, liver cancer and esophageal cancer decreased, but they still had a heavy disease burden. From 2003 to 2015, the overall 5-year relative survival rate of malignant tumors increased from 30.9% to 40.5% in China. However, with the exception of esophageal cancer, the 5-year relative survival rates of other major malignant tumors were lower than those in the United States. In 2019, the PAF of malignant tumors death attributable to potential modifiable risk factors was 48.3% in China, which was similar to the United States (49.8%). Of these, smoking was the most important attributable risk factor, and the PAF was more than 30% both in China and the United States. In addition, about 18.8% of malignant tumors were caused by preventable chronic infections, such as hepatitis B virus and Helicobacter pylori, while less than 4% of malignant tumors in the United States were caused by infection. Conclusions: China has made great progress in the prevention and treatment of malignant tumors, but it still faces a serious disease burden. The cancer spectrum is changing from developing countries to developed countries. We should pay attention to modifiable factors, take comprehensive measures, and prevent cancer scientifically.

Can the use of antithrombotic drugs be a predictive factor in the early diagnosis of bladder cancer?: A single-center analysis.

Hematuria is the most common symptom of bladder cancer (BCa). It is well-known that the frequency of hematuria increases with the use of antithrombotic drugs (ATDs). We designed our study with the hypothesis that patients using antithrombotic drugs who present with the complaint of hematuria and are subsequently diagnosed with BCa may receive an earlier diagnosis, leading to lower tumor grades and stages. Data of 441 consecutive patients who presented to our urology outpatient clinic with macroscopic hematuria between 2020 and 2023 were retrospectively evaluated. A total of 88 patients (21.4%) with a primary diagnosis of BCa were included in our study. Patients were divided into 2 groups: those using ATDs during the episode of macroscopic hematuria (group 1) and those not using ATDs (group 2). Univariate and multivariate binary logistic regression analysis was performed to identify risk factors that could predict tumor grade. The incidence of multiple tumors (>1) was significantly lower in patients using ATDs (P = .033). The number of patients with tumor size larger than 3 cm was significantly higher in the group not using ATDs (P = .005). The rates of pathological T1 stage in the group using ATDs were significantly lower than those in the nonuser group (P = .038). According to the results of the multivariate model, the effect of pathology stage and ATD use on predicting tumor grade was significant (P = .002 and P < .001, respectively). The probability of having a high-grade tumor in patients with pathology stage T1 was 5.32 times higher than in patients with pathology stage TA. The probability of having a high-grade tumor in patients not using ATDs was 7.73 times higher than in those using ATDs. The effect of pathology stage and ATD use on predicting tumor grade was found to be significant. The probability of having a high-grade tumor was higher in patients not using ATDs compared to those using ATDs. In light of these results, we can state that the use of ATDs is a positive predictive factor in the early diagnosis of BCa, bringing along the chance of early diagnosis and treatment.

Abstract A011: Bladder cancerization is linked to epithelial basalization and is reversed by EGF inhibition

Abstract Introduction: Epithelial changes can extend beyond the boundaries of an incipient tumor, leading to cancer recurrence even after effective excision of the primary tumor. This ‘field cancerization’ and consequent high recurrence rate is especially pronounced in bladder cancer. The purpose of this study is to characterize the urothelium in the context of ‘field cancerization’ in a mouse model of bladder cancer as well as in patients with bladder cancer and to determine if reversal of the field effect will prevent tumor formation. Results: We investigated field cancerization by single cell transcriptomics (scRNA-Seq) in a murine (male FVB mice) bladder carcinogenesis model using N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and found that prior to overt tumor formation urothelial cells throughout the entire bladder take on a strongly basal phenotype, characterized by reduced expression of differentiation markers (i.e. Upk1a, Upk2, and Upk3a) and increased expression of basal markers (i.e. Krt14, Krt6a, Krt5). Using monocle, we applied single cells from a BBN treated mouse bladder library to a pseudotime trajectory generated from a control mouse bladder library in order to unbiasedly characterize urothelial differentiation in the non-tumor urothelium of BBN treated mouse bladders. scRNA-Seq analysis of non-tumor urothelium from bladder cancer patients revealed a similar ‘basalization’ among non-tumor urothelial cells. In order to apply our single cell findings to bulk RNA-seq data, we developed a basal index from differentially expressed genes in basal clusters versus non-basal clusters from healthy control human urothelium single cell libraries, and we applied this basal index to non-tumor bladder samples from the The Cancer Genome Atlas (TCGA). We found that among a small subset of patients with paired tumor and non-tumor urothelium in the bladder TCGA dataset, the basal index, when applied to the non-tumor urothelium, was prognostic of survival. Finally, we found that basalization in BBN treated mice could be reversed pharmacologically by epidermal growth factor (EGF) pathway antagonism using erlotinib and trametinib and that over a 4-month time course this reversal dramatically decreased tumor incidence and improved survival, suggesting a new, more effective approach using mechanism-based cancer drugs for the prevention of bladder cancer recurrence in patients. Conclusions: The non-tumor urothelium in BBN treated mouse bladders, prior to overt tumor formation, demonstrates a basal phenotype which we characterize with scRNA-Seq and pseudotime analysis. Similarly, in patients with bladder cancer we observe that the non-tumor urothelium also takes on a basal phenotype. This ‘basalization’ of the non-tumor urothelium may potentially be prognostic, and pharmacologic reversal of the basal phenotype in the non-tumor urothelium using EGF pathway inhibitors prevents tumors in BBN treated mice. Citation Format: Aaron M. Kershner, Kris B. Prado, Bernhard M. Kiss, Karim Mrouj, Lolita Penland, Wan-Jin Lu, Jiyun Choi, Edward Diaz, Rovin Lachmansingh, Bertha Chen, Chia-Sui Kao, Joseph C. Liao, Philip A. Beachy. Bladder cancerization is linked to epithelial basalization and is reversed by EGF inhibition [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A011.

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in patients with metastatic neuroendocrine tumors

The incidence of gastroenteropancreatic neuroendocrine tumors has been rising and these tumors are usually only diagnosed at a metastatic stage. Present first line treatments include somatostatin analogs, targeted therapies and peptide receptor radionuclide therapy. The Lutetium-177 [177Lu] based radiotracer [177Lu]Lu-DOTATATE has only been approved as first-line treatment of metastatic midgut NETs however its efficacy as a third line or above treatment in patients with non ileal primaries has not been tested. In our study, we identified 25 patients with histologically confirmed well-differentiated metastatic neuroendocrine tumors and administered [177Lu]Lu-DOTATATE as a second line, third line and fourth line treatment. Our study demonstrated a notable response in patients with non-ileal primaries and heavily pretreated disease, warranting further studies for additional cycles of treatment.

Trends of cervical tumours amongst women from perspectives of demographic, socioeconomic and geographic indicators: retrospective ecological study in Czechia

IntroductionFor many infectious diseases, women are at higher risk and have a more severe disease course than men for many reasons, including biological differences, social inequalities, and restrictive cultural norms. The study focuses on infections with human papillomaviruses (HPV) in the form of cervical cancer as a gender-specific disease. The main goal is to evaluate cervical tumour incidence trends in the Czech female population in the HPV vaccination period 2012–2020 in relation to selected demographic, socioeconomic, and geographic indicators.MethodsThis is a retrospective ecological study. Data from publicly available databases about the incidence and mortality of cervical tumours (C53 Malignant neoplasm of cervix uteri, D06 Carcinoma in situ of cervix uteri according to ICD 10) and HPV vaccination rate were analysed and compared with demographic, socioeconomic and territorial data. Associations were searched using correlation analysis.ResultsThere was a decreasing trend in the incidence of cervical cancer in the observed period. Regarding cervical tumours (C53, D06) and malignant neoplasm of cervix uteri incidence (C53), the decrease was approximately 11 and 20%, respectively. Differences between regions were observed in incidences and vaccination rates. Based on correlation analysis, indicators connected with urban/rural aspects, such as a share of urban population and population density, were statistically significant. The indicators related to higher cervical cancer incidence are the high unemployment rate of women, the high number of divorces, the high number of abortions, the high share of the urban population, the high number of students, and the high number of women with only primary education. On the other hand, the indicators related to lower cervical cancer incidence are the high gross domestic product (GDP), the high average gross monthly wage per employee, the high employment rate of women, the higher average age of mothers at birth, and the high number of women with tertiary education.ConclusionResults underline the problem of economically disadvantaged regions and families. Increasing vaccination rates, promoting regular screening for cervical cancer, and supporting awareness in the population, especially in regions with higher incidence rates, should be priorities for public health efforts.

Progress in research on the role of fluoride in immune damage

Excessive fluoride intake from residential environments may affect multiple tissues and organs; however, the specific pathogenic mechanisms are unclear. Researchers have recently focused on the damaging effects of fluoride on the immune system. Damage to immune function seriously affects the quality of life of fluoride-exposed populations and increases the incidence of infections and malignant tumors. Probing the mechanism of damage to immune function caused by fluoride helps identify effective drugs and methods to prevent and treat fluorosis and improve people’s living standards in fluorosis-affected areas. Here, the recent literature on the effects of fluoride on the immune system is reviewed, and research on fluoride damage to the immune system is summarized in terms of three perspectives: immune organs, immune cells, and immune-active substances. We reviewed that excessive fluoride can damage immune organs, lead to immune cells dysfunction and interfere with the expression of immune-active substances. This review aimed to provide a potential direction for future fluorosis research from the perspective of fluoride-induced immune function impairment. In order to seek the key regulatory indicators of fluoride on immune homeostasis in the future.

Rate of Benign and Malignant Secondary Tumors Associated With Nevus Sebaceous: A Systematic Review and Meta-Analysis.

Nevus sebaceous (NS) is a rare congenital skin lesion affecting approximately 0.3% of all newborns. Although benign, NS lesions can harbor malignant secondary tumors. The published rate of development of these malignant tumors varies. This meta-analysis aimed to identify the rate of malignant and benign secondary neoplasms occurring in NS. A literature search was conducted using PubMed, Embase, and Web of Science from inception to April 2023. Eligible studies reported incidence or risk of secondary neoplasms in patients with NS. Two independent reviewers screened studies, extracted data, and assessed the quality of included studies. The primary outcome was the pooled incidence of secondary neoplasms. Studies with sample sizes greater than 50 patients were eligible for meta-analysis using the random-effects model. Twenty-eight studies were identified, 22 of which were eligible for meta-analysis. The overall rate of secondary neoplasms was 12.8% (95% confidence interval [Cl], 9.2%-17.6%). The rates of development of malignant and benign tumors were 2.4% (95% CI, 1.4%-4.1%) and 10.3% (95% CI, 7.5%-13.9%), respectively. The rate of development of basal cell carcinoma was 1.7% (95% CI, 0.9%-3.2%), whereas the rate of the development of syringocystadenoma papilliferum was 3.6% (95% CI, 2.5%-5.3%) and that if trichoblastoma was 2.6% (95% CI, 1.7%-3.8%). Although the rate of development of malignant tumors within a primary NS lesion is low, it is not negligible. Prophylactic early excision remains a viable approach to prevent secondary malignant neoplasms, address cosmetic and functional complications, and preempt the need for complex reconstruction in the future. We propose that resection of NS lesions in childhood remains a reasonable first-line option in the appropriate patient keeping in mind that it may leave an undesirable scar.

Effect of aspirin combination/clopidogrel combination on high-sensitivity C-reactive protein and P-selectin levels in patients with acute coronary syndrome

Purpose: To investigate the effect of combining aspirin with clopidogrel on high-sensitivity C-reactive protein (hs-CRP) and P-selectin in patients with acute coronary syndrome (ACS). Methods: The medical records of 198 ACS patients treated at Zhaotong Traditional Chinese Medicine Hospital, Zhaotong, China between January 2022 and January 2023 were analyzed retrospectively. Control group (88 patients) received aspirin (300 mg once, and subsequently a maintenance dose of 100 mg daily for 6 months), while the study group (118 patients) received the same dose of aspirin and clopidogrel (150 mg once, and a maintenance dose of 75 mg daily for 6 months). Levels of P-selectin, interleukin-6 (IL-6), hs-CRP, IL-8, tumor necrosis factor-α (TNF-α), efficacy, and incidence of adverse reactions in both groups were determined. Results: There was no significant difference in P-selectin and hs-CRP levels between the two groups before treatment (p &gt; 0.05). However, P-selectin and hs-CRP levels in the study group decreased significantly compared to control group (p &lt; 0.0001). Similarly, there was no significant difference in IL-8, IL-6 and TNF-α levels between the two groups before treatment (p &gt; 0.05). However, IL-8, IL-6, and TNF-α reduced significantly after treatment (p &lt; 0.0001), with more significantly lower levels observed in the study group (p &lt; 0.001). There was no significant difference in the incidence of adverse reactions between the two groups. Conclusion: Aspirin combined with clopidogrel significantly lowers P- selectin, and hs-CRP, IL-8, IL-6, and TNF-α levels without worsening adverse reactions. A more comprehensive analysis of the combined use of aspirin with clopidogrel including all the associated mechanisms in the treatment of ACS is necessary.

Occurrence of Residual Breast Tumors and Efficacy of MRI in their Detection after Vacuum-assisted Excisional Biopsy.

Residual breast tumors may remain after vacuum-assisted excisional biopsy (VAEB). To determine the incidence of residual breast tumors in patients after VAEB and the efficacy of magnetic resonance imaging (MRI) in detecting these tumors. This retrospective analysis examined patients who received VAEB before a diagnosis of breast cancer (BC) at our hospital from 2015 to 2019. The incidence of residual tumors after VAEB was determined by MRI and pathological examination. The diagnostic value of MRI in detecting residual tumors was determined for all patients and different subgroups. Logistic regression analysis was used to identify factors associated with residual tumors. We examined 147 patients and obtained pathological samples from 146 patients, including 103 (70.5%) with residual tumors and 43 (29.5%) without residual tumors. The MRI examinations demonstrated the complete tumor resection rate was 48.9%. Compared to the pathological results, MRI had a positive predictive value of 77.8%, negative predictive value of 48.8%, specificity of 65.6%, and sensitivity of 60.7%. Further analysis indicated that MRI had moderate accuracies for patients with stage pT-1 (71.9%), stage pTNM-IA (73.1%), and luminal B subtype (78.3%). Binary logistic regression analysis showed that the risk of tumor residue correlated with the pathological stage. Tumor residue is common after VAEB, and MRI has limited accuracy in detecting these residual tumors. However, for small breast tumors and luminal B subtype BC, MRI had higher accuracy in the detection of residual tumors. The risk of tumor residue is closely associated with the pathological stage.

Predictors of Precancerous Diseases of the Cervix

Introduction. The incidence of malignant neoplasms in the population has increased by 1.66 times over the past 15 years, and the incidence of cancer of the cervix and body of the uterus, placenta — by 1.3 times.Materials and methods. 2 groups were formed by the continuous sampling method: 30 women with a diagnosis of cervical intraepithelial neoplasia (CIN) and 30 women without a diagnosis of CIN, who made up the control group. Statistical analysis was carried out using the StatTech 3.1.7 program (Stattech LLC, Russia).Results. Risk factors for precancerous diseases of the cervix include the presence of a history of cardiovascular diseases(p = 0.043), surgical interventions (p = 0.039), sexually transmitted infections (p = 0.023), a large number of pregnancies (regardless of the outcome) (p = 0.013), the presence of abortions (p = 0.04), a large number of sexual partners during life (p = 0.022).Discussion. Frequent change of sexual partners, and as a consequence — a high risk of STIs are also well-known risk factors for cancer and precancerous cervix, in these conditions HPV passes from free to episomal form faster and starts the process of transformation of cervical epithelial cells.Conclusion. The features of the anamnesis of women with precancerous diseases of the cervix are high parity and the presence of abortions, STIs, cardiovascular diseases and surgical interventions in the anamnesis, a large number of sexual partners in life, low adherence to the use of combined oral contraceptives (COCs).

Impact of environmental pollutants on pediatric brain tumor incidence in New Jersey

ObjectiveThe relationship between environmental contaminants and brain tumor incidence in adults has been thoroughly explored but research into how these contaminants affect pediatric brain tumor (PBT) incidence has not been explored. Children, typically having more limited geographical movement and thus more consistent environmental contaminant exposure, might offer more reliable insights into which environmental contaminants affect the incidence of brain tumors. The present study is the first to focus on exploring whether a possible association exists between the incidence of PBTs and exposure to environmental pollutants in New Jersey (NJ). MethodsLinear regressions were run between PBT incidence and the concentration of air quality pollutants such as Ozone (O3), Particulate Matter 2.5 (PM2.5), Particulate Matter 10 (PM10), and Carbon Monoxide (CO). Similarly, linear regressions were run between PBT incidence and Elevated Blood Lead Levels (BLL). ResultsThe study observed a significant positive relationship between O3 and PBT incidence (β = 0.34, p = 0.028). However, the relationship between PBT incidence, and environmental pollutants such as CO (β = 0.0047, p = 0.098), PM2.5 (β = −0.2624, p = 0.74), and PM10 (β = −0.7353, p = 0.073) were found to be nonsignificant. For elevated BLL, nonsignificant relationships with PBT incidence were observed at 10–14 µg/dL (β = −39.38, p = 0.30), 15–19 µg/dL (β = −67.00, p = 0.21), and 20–44 µg/dL (β = −201.98, p = 0.12). ConclusionsThe results indicate a possible impact of O3 on the incidence of PBTs in NJ. In contrast to the significant links found in prior studies of adult brain tumors, the associations between PBT occurrence and particulate matter were not significant. These findings highlight the importance of further investigating how environmental factors, especially O3, relate to PBTs.

A systematic review on performance characteristics of FNA of renal lesions: It is time for a standardized classification system.

The incidence of renal tumors has steadily increased over the past decade. In this study, the authors performed a systematic review and analysis of the literature on renal fine-needle aspiration (FNA) to determine its performance and explore whether a standardized classification system can be used for reporting renal FNA cytology. A systematic search of published articles on renal FNA was conducted. The data on FNA and histologic diagnosis were extracted and categorized, and the risk of malignancy was calculated. Different scenarios were used to estimate FNA performance statistics. Of the 3766 potentially relevant studies, 23 met the inclusion criteria of the study. The 2231 FNA cases included were re-categorized according to the classification system, rendering 142 (6.36%) nondiagnostic, 270 (12.1%) nonneoplastic, 271 (12.14%) benign neoplasm, 65 (2.91%) renal neoplasm with unknown malignant potential, oncocytic type, 25 (1.12%) atypia of undetermined significance, 60 (2.68%) suspicious for malignancy, and 1398 (62.66%) malignant FNA diagnoses. The risk of malignancy in these cases was 65.4%, 18.1%, 16.6%, 16.9%, 60%, 73.3%, and 96.9%, respectively. According to the classification system, the study indicated that the accuracy of renal FNA was between 91% and 95%, the sensitivity was 90.9%-96.7%, and the specificity was 82%-92% in different scenarios. There is a need for a standardized reporting in renal cytology that will improve the sensitivity and accuracy of renal cytology, reduce the rate of indeterminate diagnoses, and alter the management strategies of renal lesions. Based on the available literature, a new reporting system is proposed, including categories with an associated risk of malignancy.

Primary omental smooth muscle tumor in an adult male: a diagnostic dilemma for leiomyoma: a case report

BackgroundThe greater omentum comprises peritoneal, adipose, vascular, and lymphoid tissues. Most omental malignancies are metastatic tumors, and the incidence of primary tumors is rare. We report on a prior omental smooth muscle tumor case in an adult male patient.Case presentationA 54-year-old Japanese male patient with no relevant medical history was diagnosed with an abdominal mass during a routine medical checkup. Subsequent contrast-enhanced computed tomography revealed a mass of approximately 3 cm in size in the greater omentum, and a laparotomy was performed. A 27 × 25 × 20 mm raised lesion was found in the omentum. Microscopically, spindle cells were observed and arranged in whorls and fascicles. Individual tumor cells had short spindle-shaped nuclei with slightly increased chromatin and were characterized by a slightly eosinophilic, spindle-shaped cytoplasm. The mitotic count was less than 1 per 50 high-power fields. The tumor cells showed positive immunoreactivity for α smooth muscle actin, HHF35, and desmin on immunohistochemical examination. The Ki-67 labeling index using the average method was 1.76% (261/14806). No immunoreactivity was observed for any of the other tested markers. We considered leiomyoma owing to a lack of malignant findings. However, primary omental leiomyoma has rarely been reported, and it can be difficult to completely rule out the malignant potential of smooth muscle tumors in soft tissues. Our patient was decisively diagnosed with a primary omental smooth muscle tumor considering leiomyoma. Consequently, the patient did not undergo additional adjuvant therapy and was followed up. The patient was satisfied with treatment and showed neither recurrence nor metastasis at the 13-month postoperative follow-up.Discussion and conclusionWe encountered a primary smooth muscle tumor of the greater omentum with no histological findings suggestive of malignancy in an adult male patient. However, omental smooth muscle tumors are extremely difficult to define as benign, requiring careful diagnosis. Further case reports with long-term follow-up and case series are required to determine whether a true omental benign smooth muscle tumor (leiomyoma) exists. In addition, proper interpretation of the Ki-67 labeling index should be established. This case study is a foundation for future research.

Construction of a prognostic model for autophagy in Wilm's tumor.

Wilm's tumor (WT) is one of the most common childhood urological tumors, ranking second in the incidence of pediatric abdominal tumors. The development of WT is associated with various factors, and the correlation with autophagy is currently unclear. To develop a new prognostic model of autophagy-related genes (ATG) for WT. Using the Therapeutically applicable research to generate effective treatments (TARGET) database to screen for differentially expressed ATGs in WT and normal tissues. ATGs were screened for prognostic relevance to WT using one-way and multifactorial Cox regression analyses and prognostic models were constructed. The risk score was calculated according to the model, and the predictive ability of the constructed model was analyzed using the ROC (receiver operating characteristic) curve to verify the significance of the model for the prognosis of WT. Sixty-eight differentially expressed ATGs were identified by univariate Cox regression analysis, and two critical prognostic ATGs (CXCR4 and ERBB2) were identified by multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups according to the differential expression of these two ATGs. Kaplan-Meier (KM) curves showed a significant difference in survival time between the two groups. The critical prognostic ATGs were combined with race, age, and stage in a multifactorial regression analysis, and the final prognostic model was produced as a line graph. The prognostic model of autophagy-related genes composed of the CXCR4 gene and ERBB2 gene has a specific predictive value for the prognosis of WT, and the present study provides a clear basis for future research on biomarkers and therapeutic targets.

Effect of Clonal Hematopoiesis Mutations and Canakinumab Treatment on Incidence of Solid Tumors in the CANTOS Randomized Clinical Trial.

Clonal hematopoiesis (CH) is more common in older persons and has been associated with an increased risk of hematological cancers and cardiovascular diseases. The most common CH mutations occur in the DNMT3A and TET2 genes and result in increased pro-inflammatory signaling. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS, NCT01327846) evaluated the neutralizing anti-IL-1β antibody canakinumab in 10,061 randomized patients with a history of myocardial infarction and persistent inflammation; DNA samples were available from 3,923 patients for targeted genomic sequencing. We examined the incidence of non-hematological malignancy by treatment assignment and CH mutations and estimated the cumulative incidence of malignancy events during trial follow-up. Patients with TET2 mutations treated with canakinumab had the lowest incidence of non-hematological malignancy across cancer types. The cumulative incidence of at least one reported malignancy was lower for patients with TET2 mutations treated with canakinumab vs those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL-1β blockade cooperating with CH mutations to modify the disease course.

Persistent gene expression and DNA methylation alterations linked to carcinogenic effects of dichloroacetic acid.

Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver tumor incidence in B6C3F1 mice after continuous or early life exposures significantly over background level. Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), 3.5 g/L DCA continuously in drinking water ("Direct" group), or DCA for 10-, 32-, or 57-weeks followed by deionized water until sample collection ("Stop" groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) in 78-week liver samples for control, Direct, 10-week Stop DCA exposed mice. Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure was withdrawn. We observed a similar pattern with DNA methylation alterations where we noted attenuated differentially methylated regions (DMRs) in the 10-week Stop DCA exposure groups compared to the Direct group at 78-weeks. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns correlated to early gene pathway perturbations, such as cellular signaling, regulation and metabolism, suggesting persistence in the epigenome and possible regulatory effects. Liver metabolic reprogramming effects of DCA interacted with normal age mechanisms, increasing tumor burden with both continuous and prior DCA exposure in the male B6C3F1 rodent model.

Abstract PO5-02-03: Does the recommendation of adjuvant CDK4/6 inhibitors implicate more ovarian suppression in premenopausal patients? A real-world study of a public and a private Argentinean institution

Abstract Introduction The recently published NATALEE trial has reported an increase of invasive disease free survival with the addition of ribociclib to hormone therapy during 3 years. Given the fact that aromatase inhibitors are required as the endocrine therapy backbone, premenopausal patients require ovarian function suppression (OFS) during CDKi treatment In the era of CDKi in the adjuvant setting, we hypothesize that the recommendation of GnRh analogs administration in addition to aromatase inhibitors will increase for premenopausal patients, given the inclusion criteria of this pivotal trial. For this reason, we explored in a retrospective cohort of a public and a private Argentinean institution to define whether the application of these criteria would imply an increase of the recommendation of OFS as part of the adjuvant endocrine treatment. Methods This was a multicentric retrospective cohort comprising premenopausal patients with early breast cancer diagnosis. Descriptive statistics were used to summarize data. The criteria for defining ribociclib recommendations were based on the phase III NATALEE clinical trial. Univariate analysis, including t and chi-square tests were used to determine differences between the populations that received and did not receive OFS, and between both participating institutions. p&amp;lt; 0,05 was considered to evaluate statistical significance. Results 191 premenopausal patients were incorporated in our analysis, and 48 (25.1%) received OFS. In this subgroup, mean age was lower (38.1 vs 44.2 years; p&amp;lt; 0.001) and the incidence of T3 (23.9 vs 6.5%; p=0.002), node-positive tumors (57.4 vs 28.9%; p=0.005), and prior chemotherapy treatment (75.5 vs 58.8%; p&amp;lt; 0.001) was higher. Among the 143 patients that did not receive OFS, 121 (84.6%) would have fulfilled clinical trial criteria for receiving ribociclib. No differences were observed according to the treating institution: 80.3 vs 87.8%; (p=0.22). The patient subgroup that would have met NATALEE criteria and did not receive OFS, had median age of 44.19 (SD 4.18), and had prior chemotherapy in 63.8% of the cases. Considering these characteristics, we observed that chemotherapy-induced amenorrhea and local institutional guidelines were the main explanations to understand why these moderate and high-risk patients did not receive OFS. Conclusion We observed that in premenopausal patients, the application of NATALEE criteria would result in an increase of the recommendation of GnRh analogues in around 80% of patients that had not received OFS in a retrospective cohort. This scenario may result in new challenges in treatment adherence and quality of life. In addition, this information is of special importance to carefully analyze the financial toxicity of a modern adjuvant approach that will be applied in a high proportion of eBC patients, especially in low and middle-income countries. Citation Format: Vanesa Lopez, Dana Narvaez, Jorge Nadal, Federico Waisberg, Adrian Nervo, Victoria Costanzo, Claudio Paletta, Fernando E. Petracci, Sergio Rivero, Alexis Ostinelli, Matías Chacón, Andrea Aguilar, Alejandro Kuzminin, Ageles Nico, Evelina Rovera, Naima Kassis, Maria Zapata Camaño, Carolina Almada, Maria Savignano, Gustavo Roganovich, Maria Eugenia Azar, Valeria Caceres. Does the recommendation of adjuvant CDK4/6 inhibitors implicate more ovarian suppression in premenopausal patients? A real-world study of a public and a private Argentinean institution [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-03.

Abstract PO4-11-08: Risk of second malignancies in breast cancer patients. A population-based retrospective cohort study between 2010-2020

Abstract Introduction: Breast cancer survivors live longer due to early detection programs and therapeutic advances. Staging and molecular classification are important for prognosis and treatment. At the same time these patients are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decade with early detection and prevention programs of other tumors lacking. This study aims to identify, characterize and associate breast cancers with second primary malignancies based on different variables. Methods: We identified 3487 females with a first primary breast cancer between 2010 and 2020 in medical records at University Hospital of A Coruña in Spain. Over a median follow-up of 8 years, one hundred patients (2,9%) develop second cancer. According National Cancer Institute, second primary tumor (SPT) was defined as an invasive primary cancer after a first primary cancer. In our case a breast carcinoma. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast carcinoma) which were diagnosed at least 12 months after primary breast tumor. We analyzed breast cancer subtype, family history and pathogenic genetic variants, tobacco use and second primary tumor type. Results: Several clinical characteristics were evaluated, including breast cancer stage, histological type and subtype. The incidence of breast cancer and SPT was increased with age with peaks in the 60’s and 70’s, respectively. Only 13% had SPT between 40-49 years. Approximately 10 women a year, in our study, developed second cancer. 52% of SPT patients had cancer family history. Pathogenic variant study was carried in 25% of women with SPT, 46% of them no mutation were found, but in 17% was detected a germline BRCA1 deleterious variant. Other pathogenic variants were founded: 4% in BRCA2, and 33% in others genes (CHEK2, MSH2, MSH6, PMS2, CDH1, FANC1 y SMAD4) Regards tobacco use, active smokers were 13% and 12% of women had been smoking years ago. Of these 13 active smokers, 10 develop lung cancer (77%) an 5 of former smokers (42%). Luminal subtype was the most common breast cancer (33% Luminal A, 34% Luminal B Her2 negative, 10% Luminal B Her2 positive, 4% Her2-enriched, 10% Triple negative and 3% carcinoma in situ with estrogen and progesterone expression) and stage I and II were most frequent (80%). The most usual second primary neoplasms were lung, colorectal and pancreatic carcinoma (21%, 17% and 7% respectively), and only 2% contralateral breast cancer, with an average of approximately 4 years between breast cancer and the SPT. In 11% of patients were found more than 2 tumors. At the time of the analysis, 73% of these patients are free of disease. In SPT study population few recurrences were described, 2 relapses of breast cancer and 9 of SPT. The median between breast cancer diagnosis and the SPT diagnosis was 54 months [0,7 – 129]. The median to relapse of breast cancer was 73 months [68 – 77]. The median between SPT diagnosis and relapse was 39,25 months [1 - 134]. STP recurrences were observed in colorectal and lung cancer, mainly. Data on recurrences and mutations were not significative. Conclusion: In our breast cancer population the incidence of second primary tumors is around 3% over a 10 – year period. The diagnosis of the SPT arises several years after breast cancer and generally has a worse prognosis. Elevated risks of second cancer among breast cancer survivors treated in recent decade suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed. It is mandatory make an effort and focusing in recommendations and advise about tobacco consumption, healthy lifestyle and adherence to Pap test and stool test in survivors. Citation Format: Guadalupe Rama, Maria-Eva Perez-Lopez, Silvia Antolin Novoa, Cristina Reboredo, Beatriz Alonso, Sofia Silva Diaz, Begoña Graña, Lourdes Calvo, Tomas Garcia-Caballero. Risk of second malignancies in breast cancer patients. A population-based retrospective cohort study between 2010-2020 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-08.

Potential utility of l-carnitine for preventing liver tumors derived from metabolic dysfunction-associated steatohepatitis.

Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully. l-carnitine (2g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated. Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway. Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC.

Mode of action analysis for fluxapyroxad-induced rat liver tumour formation: evidence for activation of the constitutive androstane receptor and assessment of human relevance

The fungicide fluxapyroxad (BAS 700F) has been shown to significantly increase the incidence of liver tumours in male Wistar rats at dietary levels of 1500 and 3000 ppm and in female rats at a dietary level of 3000 ppm via a non-genotoxic mechanism. In order to elucidate the mode of action (MOA) for fluxapyroxad-induced rat liver tumour formation a series of in vivo and in vitro investigative studies were undertaken. The treatment of male and female Wistar rats with diets containing 0 (control), 50, 250, 1500 and 3000 ppm fluxapyroxad for 1, 3, 7 and 14 days resulted in a dose-dependent increases in relative weight at 1500 and 3000 ppm from day 3 onwards in both sexes, with an increase in relative liver weight being also observed in male rats given 250 ppm fluxapyroxad for 14 days. Examination of liver sections revealed a centrilobular hepatocyte hypertrophy in some fluxapyroxad treated male and female rats. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 1500 and 3000 ppm fluxapyroxad for 3 and 7 days and in female rats given 50-3000 ppm fluxapyroxad for 7 days and 250-3000 ppm fluxapyroxad for 3 and 14 days; the maximal increases in RDS in both sexes being observed after 7 days treatment. The treatment of male and female Wistar rats with 250-3000 ppm fluxapyroxad for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content and CYP2B subfamily-dependent enzyme activities. Male Wistar rat hepatocytes were treated with control medium and medium containing 1-100μM fluxapyroxad or 500μM sodium phenobarbital (NaPB) for 4 days. Treatment with fluxapyroxad and NaPB increased CYP2B and CYP3A enzyme activities and mRNA levels but had little effect on markers of CYP1A and CYP4A subfamily enzymes and of the peroxisomal fatty acid β-oxidation cycle. Hepatocyte RDS was significantly increased by treatment with fluxapyroxad, NaPB and 25ng/ml epidermal growth factor (EGF). The treatment of hepatocytes from two male human donors with 1-100μM fluxapyroxad or 500μM NaPB for 4 days resulted in some increases in CYP2B and CYP3A enzyme activities and CYP mRNA levels but had no effect on hepatocyte RDS, whereas treatment with EGF resulted in significant increase in RDS in both human hepatocyte preparations. Hepatocytes from male Sprague-Dawley wild type (WT) and constitutive androstane receptor (CAR) knockout (CAR KO) rats were treated with control medium and medium containing 1-16μM fluxapyroxad or 500μM NaPB for 4 days. While both fluxapyroxad and NaPB increased CYP2B enzyme activities and mRNA levels in WT hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both fluxapyroxad and NaPB only increased RDS in WT and not in CAR KO rat hepatocytes, whereas treatment with EGF increased RDS in both WT and CAR KO rat hepatocytes. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that fluxapyroxad is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for fluxapyroxad-induced rat liver tumour formation has been established. Based on the lack of effect of fluxapyroxad on RDS in human hepatocytes, it is considered that the MOA for fluxapyroxad-induced liver tumour formation is qualitatively not plausible for humans.