Development Of Cancer In Patients Research Articles

Impact of Dyslipidemia on the Risk of Second Cancer in Thyroid Cancer Patients: A Korean National Cohort Study

Studies have shown that radioactive iodine therapy (RAIT) affects the development of second cancer in thyroid cancer patients. The impact of other factors, such as dyslipidemia are not clear. A retrospective analysis of thyroid cancer patients with a 1,251,913 person-year follow-up was conducted using data from the Health Insurance Review and Assessment database in South Korea from January 2008 to December 2018. We investigated factors related to second cancer development using a nested case-control analysis to avoid length bias. The overall risk of developing second cancer was higher in thyroid cancer patients than in the general population [standardized incidence ratio, 3.34; 95% confidence interval (CI) 3.30-3.39]. Second cancer incidence was higher in patients who received RAIT than in those who did not [odds ratio (OR) 1.130; 95% CI 1.094-1.169]. Moreover, the risk of second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.265; 95% CI 1.223-1.309). After adjustment for RAIT, the incidence of a second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.262; 95% CI 1.221-1.306). The risk of second cancer development in patients with thyroid cancer appears to be high. Dyslipidemia may be associated with an increased risk of several types of second cancers.

Nonpalpable breast masses: One-year ultrasound follow-up and morbidity outcomes in Shanghai.

Women with nonpalpable breast masses are at a high risk of developing breast cancer (BC) due to misdiagnosis during the follow-up period.A total of 40,334 women were divided into palpable and nonpalpable breast mass groups. We assessed the risk factors for cancer development in patients with nonpalpable breast masses during a 1-year follow-up period.Of the 1335 patients in the nonpalpable breast mass group, we found 50 patients of BC, of which 35 patients accepted surgery and were confirmed with biopsy at the beginning of the study. The remaining 15 (1.1%) were diagnosed with BC during follow-up, and included 10 in situ and 5 invasive carcinomas. Four of the 10 patients in the in situ subgroup, and 2 out of the 5 in the invasive subgroup were overweight (Body mass index > 24 kg/m2). Nine in situ BC patients had breast-conserving surgery, 1 had a mastectomy. No patient in the in situ group received chemotherapy or radiotherapy. All 5 patients with invasive disease received 6 cycles of chemotherapy. Only 3 (20%) of the 15 patients with BC had a positive family history. We found 131 BC cases, including BC detected during screening (81) and follow-up (50). The incidence of BC was 240.2 per 100,000 inhabitants.Patients with nonpalpable breast masses require regular follow-up as they have a high risk of cancer occurrence. Regular follow-up can lead to early diagnosis and effective treatment of these early-stage BC patients.

Study of the dynamics of Ceritinib in complex with common variants of anaplastic lymphoma kinase

ABSTRACT Anaplastic lymphoma kinase, a transmembrane receptor tyrosine kinase belongs to the insulin receptor superfamily. Genetic aberrations including mutation, amplification, and gene fusion have led to its involvement in the development of cancer in patients and have also been approved for targeted therapy by Food and Drug Administration. Mutations in its kinase domain have resulted in resistance to targeted therapy. In the present study, using molecular dynamics simulations we explore the mechanism of resistance of the ALK inhibitor-Ceritinib with Phenylalanine variant at position 1174 while comparing it with the wild type and other reported mutants. We observed that binding of Ceritinib to the Phenylalanine 1174 mutant results in elevated fluctuations in residues which are component of the adenosine triphosphate binding pocket. Residues of P loop, β3 strand and αC Helix undergo anti correlated motions with respect to the αD, αE helix, component amino acids of β6-β7 strands and their interconnecting loop. This anti-correlated motion of the residues around the binding pocket results in the elevated deviations of the bound Ceritinib. Molecular mechanics-generalized born surface area free energy of binding analysis reveals comparatively weak binding of the Ceritinib to this variant compared to other forms of ALK kinase studied.

Development of Cancer in Patients With Heart Failure: How Systemic Inflammation Can Lay the Groundwork.

In the last decade, cardiologists and oncologists have provided clinical and experimental evidence that cancer, and not only chemotherapeutic agents, can cause detrimental effects on heart structure and function, a consequence that has serious clinical implications for patient management. In parallel, the intriguing idea that heart failure (HF) may be an oncogenic condition has also received growing attention. A number of epidemiological and clinical studies have reported that patients with HF have a higher risk of developing cancer. Chronic low-grade systemic inflammation has been proposed as a major pathophysiological process linking the failing heart to the multi-step process of carcinogenesis. According to this view, pro-inflammatory mediators secreted by the damaged heart generate a favorable milieu that promotes tumor development and accelerates malignant transformation. HF-associated inflammation synergizes with tumor-associated inflammation, so that over time it is no longer possible to distinguish the effects of one or the other. Experimental studies have just begun to search for the molecular effectors of this process, with the ultimate goal that of identifying mechanisms suitable for anti-cancer target therapy to reduce the risk of incident cancer in patients already affected by HF. In this review we critically discuss strengths and limitations of clinical and experimental studies that support a causal relationship between HF and cancer, and focus on HF-associated inflammation, cardiokines and their endocrine functions linking one and the other disease.

Study of the Association Between Antihyperglycemic Therapy and Cancer in Patients with Type 2 Diabetes Mellitus

The objective of the research was to investigate the features and association of antihyperglycemic therapy and cancer in patients with type 2 diabetes mellitus.
 Materials and Methods. The study included the analysis of medical records of patients with type 2 diabetes mellitus who were diagnosed with cancer during 2012-2016. The obtained results were processed by statistical methods using the software packages Microsoft Excel and Statistika-12. The significance of differences between the frequency of using different treatment schemes was assessed by the Pearson’s test (χ²). To determine the risk of predicted events, the odds ratio, the 95% confidence interval, the positive and negative prognostic values were calculated.
 Results. There were diagnosed 533 cases of cancer in patients with type 2 diabetes mellitus. The most common scheme of antihyperglycemic therapy prior to the detection of malignant diseases was a combination of metformin and sulfonylurea derivatives (35.65%), as well as monotherapy with sulfonylurea derivatives (17.26%) and metformin (11.28%). Prior to diagnosing cancer in 396 (74.30%) patients, antihyperglycemic therapyalong with sulfonylurea derivatives and insulin was used. Among obese patients 68.82% used sulfonylureas and insulin as part of antidiabetic therapy before diagnosis of cancer. The connection between insulin therapy and the risk of cancer development in patients with type 2 diabetes mellitus was proved (the odds ratio=2.35; the 95% confidence interval (1.91 - 2.91); p<0.001).
 Conclusions. Prior to the detection of cancer in patients with type 2 diabetes mellitus, the combination therapy with metformin and sulfonylurea derivatives was most often used. The association between insulin therapy and the development of cancer in patients with type 2 diabetes mellitus was revealed. Cancer screening is advisable for patients with type 2 diabetes mellitus and obesity, who receive as a therapy sulfonylurea derivates and/or insulin.

Risk of Cancers in Patients with Pediatric Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

We performed a systematic review and meta-analysis to evaluate the risk of the development of cancers in patients with pediatric-onset inflammatory bowel disease (IBD). A computerized literature search was performed. The primary outcome was the pooled incidence of cancer in studies reporting the risk as a standardized incidence ratio. The secondary outcomes were the pooled incidence rates of all cancers and site-specific cancers including colorectal cancer and hematologic cancers. Sixty-six studies reporting outcomes in 38 092 patients were included. The pooled standardized incidence ratio for cancer was 2.39 (P<.0001, 95% CI 2.00-2.86) in IBD. The pooled incidence rates for cancer in patients with Crohn's disease (CD) and ulcerative colitis (UC) were 0.014 (95% CI 0.0087-0.021) and 0.031 (95% CI 0.018-0.052), respectively. The pooled incidence rate of colorectal cancer in CD and UC were 0.0075 (95% CI 0.0049-0.011) and 0.020 (95% CI 0.012-0.034), respectively. The pooled rates of hematologic cancers in CD and UC were 0.0061 (95% CI 0.0040-0.0090) and 0.0045 (95% CI 0.0026-0.0079), respectively. Cumulative meta-analyses showed a decreasing trend in the incidence of these cancers in both CD and UC. Patients with pediatric-onset IBD had an increased risk of cancer development compared with the general population, however, incidence appeared to be decreasing in recent years.

Helicobacter pylori-related precancerous lesions in Turkey: a retrospective endoscopic surveillance study

AimTo assess the relationship between Helicobacter pylori (H. pylori) infection and atrophic gastritis (AG) and intestinal metaplasia (IM) development and to assess the rate of dysplasia or gastric cancer development in patients with AG and/or IM.MethodsThis retrospective endoscopic follow-up study enrolled 2214 patients. The patients were followed for at least five years between 2007 and 2017 at the Department of Endoscopy at Antalya Ataturk Government Hospital. The results of third-year and five-year surveillance biopsy were assessed.ResultsThe mean follow-up time was 7.77 ± 2.78 years. H. pylori was histologically assessed in 1417 (64.6%) patients. Of 198 patients with severe H. pylori infection, 32 (16%) and 139 (70.3%) developed extensive AG and extensive IM, respectively. There was a significant relationship between H. pylori density and AG and IM degrees. High grade dysplasia, early gastric cancer, and advanced gastric cancer were diagnosed in 73 patients with median age 58.2 (28-80) years, and the incidence rate was 3.29% (73/2214). The annual incidence of gastric neoplastic lesions was 0.46% in total, 0.08% for early GC, and 0.02% for advanced gastric cancer.ConclusionsH. pylori infection has an important role in the development of AG and IM. H. pylori density is directly related to atrophy and metaplasia degree.

Cancer development in patients with COPD: a retrospective analysis of the National Health Insurance Service-National Sample Cohort in Korea

BackgroundCOPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove the hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients.MethodsThis study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 16,757 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. This cohort enrolled six arms consisting of never-smokers without COPD (N = 313,553), former smokers without COPD (N = 41,359), smokers without COPD (N = 112,627), never-smokers with COPD (N = 7789), former smokers with COPD (N = 1085), and smokers with COPD (N = 2677).ResultsIncident rate of lung cancer per 100,000 person-year was higher according to smoking and COPD (216 in non-COPD and 757 in COPD among never-smokers, 271 in non-COPD and 1266 in COPD among former smokers, 394 in non-COPD and 1560 in COPD among smokers, p < 0.01). Old age, male sex, lower BMI, low exercise level, history of diabetes mellitus, smoking, and COPD were independent factors associated with the development of lung cancer (p < 0.01). Multi-variable analyses showed that COPD, regardless of smoking status, contributed to the development of lung cancer, and colorectal cancer and liver cancer among other major cancers (p < 0.01).ConclusionOur data suggested that COPD was an independent risk factor for the development of lung cancer, and colorectal cancer and liver cancer among other major cancers in the Korean population, regardless of smoking status.

Cancer development and mortality differences in patients with glomerulonephritis after renal biopsy: a single center retrospective cohort study

BackgroundThe association between glomerulonephritis (GN) and cancer has been well known for decades. However, studies evaluating long-term de novo cancer development in patients with GN are limited. This study aimed to evaluate the incidence of cancer development among patients with renal biopsy-proven GN during post-biopsy follow-up and the differences in outcomes according to cancer occurrence.MethodsWe conducted a retrospective cohort study of adult patients who underwent renal biopsy at Seoul National Bundang Hospital between 2003 and 2017. After excluding 778 patients with age < 18 years, cancer diagnosis before or within 6 months after renal biopsy, immunosuppressant therapy before renal biopsy, or pathologic diagnoses other than GN, 822 patients were included in the analysis. Data on baseline clinical characteristics, renal biopsy results, and types and doses of immunosuppressant agents were collected from electronic medical records. The incidence of cancer was censored on the date when the first cancer was diagnosed. We evaluated rates of mortality and end-stage renal disease (ESRD) development during follow-up.ResultsDuring a mean follow-up period of 58.9 ± 44.5 months, 45 subjects (5.5%) developed de novo cancer. A comparison of clinical characteristics between subjects who did and did not develop cancer revealed that cancer patients were older and had higher comorbidities and immunosuppressant use. Overall, patients with GN had an elevated standardized incidence ratio (SIR) of 7.16 (95% confidence interval (CI): 5.22–9.61) relative to the age- and sex-matched general population. In particular, the SIR was significantly higher in GNs such as membranous nephropathy (MN), IgA nephropathy, lupus nephritis, and focal segmental glomerulosclerosis. Multivariable Cox proportional hazard model revealed that patients with MN had an increased risk of cancer development, with a hazard ratio of 2.30 [95% CI: 1.06–4.98]. Patients with MN who developed cancer had a significantly higher risk of mortality (hazard ratio: 6.59; 95% CI: 1.22–35.56, P = 0.03) than those without cancer, but there was a non-significant difference in ESRD development. Conclusions: Patients with GN without concurrent cancer, particularly those with MN, have significantly higher risks of cancer development and subsequent mortality and should remain aware of the potential development of malignancy during follow-up.

Indeno[1,2,3-cd]pyrene and picene mediate actions via estrogen receptor α signaling pathway in in vitro cell systems, altering gene expression

Currently, the environmental impact of ubiquitous plastic debris triggered quite some public attention. However, the global impact of microplastic on human health is by and large either unknown or neglected. By looking at the underlying biochemical mechanisms leading to the global health threat microplastic was discovered to carry persistent organic pollutants, such as polycyclic aromatic hydrocarbons (PAH), to marine life. The effect of microplastic-ingestion in the human body remains unfortunately somewhat elusive as of yet. For this reason, we screened for compounds binding to the human estrogen receptor α (ERα) and identified the PAH compounds indeno[1,2,3-cd]pyrene (Indpy) and picene (Pice) with a high binding affinity. We applied next generation sequencing to analyze the differentially expressed genes in MCF-7 cells after treatment with Indpy and Pice. We found 8 upregulated genes: ABCC5, CCNG2, CYP1A1, DDIT4, IER3, RUNX2, STC2, and SLC7A5 and 14 downregulated genes: ADORA1, CEBPB, CELSR2, CTSD, CXCL12, KRT19, PGR, PKIB, RARA, RET, SEMA3B, SIAH2, TFAP2C, and XBP1 induced by both ligands and associated with ESR1-regulation. The altered gene expression may influence cell proliferation and metastasis, favoring cancer development with a poor response to therapy. In addition, we confirmed the binding of Indpy and Pice to ERα using molecular docking and microscale thermophoresis. ERα activation was measured with ESR1-overexpressing HEK293 (HEK-ESR1) cells and confirmed for Indpy. In conclusion, we showed an ESR1-mediated influence of the PAH compounds Indpy and Pice on the gene expression pattern of MCF-7 cells, possibly also promoting breast cancer development in patients.

Figures of the Heart Failure Association (HFA): Dr. Rudolf de Boer, HFA Board Member (2014-2020), Chair of the Basic Science Section (2016-2018), coordinator of the Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio-oncology.

Figures of the Heart Failure Association (HFA): Dr. Rudolf de Boer, HFA Board Member (2014-2020), Chair of the Basic Science Section (2016-2018), coordinator of the Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio-oncology.

Reverse Cardio-Oncology: Cancer Development in Patients With Cardiovascular Disease.

Reverse Cardio-Oncology: Cancer Development in Patients With Cardiovascular Disease.

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.

Side-branch intraductal papillary mucinous neoplasms of the pancreas: outcome of MR imaging surveillance over a 10 years follow-up

PurposeTo evaluate the outcome of a MR imaging procotol in assessing the evolution of individuals with branch duct - intraductal papillary mucinous neoplasms (BD-IPMN) without worrisome features (WF) and/or high risk stigmata (HRS) at the time of the diagnosis in a follow-up period of at least 10 years. Material and methodsA retrospective revision of a prospectively collected radiological database including a total number of 600 patients who were investigated and diagnosed with “presumed” diagnosis of BD-IPMN at MRI/MRCP at our Department since 2008 was performed. Inclusion criteria were: 1) absence of worrisome features and/or high-risk stigmata at the time of diagnosis (baseline); 2) a radiological follow-up with abdominal MRI/MRCP of at least 10 years. Changes in cysts size, development of WF, HRS and pancreatic cancer, and any other modification during the follow-up were retrospectively analysed by two observers in consensus. ResultsSixty-nine patients fulfilled all the inclusion criteria. During surveillance, the cysts remained dimensionally unchanged or slightly reduced in size in 26.2% and 4.3% of cases respectively, whereas cyst enlargement was demonstrated in 69.5% of cases. Median annual growth rate was of 0.97 ± 0.87 mm/yr (range 0.13-5.0). WF and HRS developed in 10/69 (14.5%) and 3/69 (4.3%) cases, respectively. The incidence of pancreatic cancer in patients with BD-IPMN was 2.9%. ConclusionOur data confirm the low risk of pancreatic cancer development in patients with BD-IPMN, thus justifying an imaging follow-up. Worrisome features and high-risk stigmata were promptly identified during the follow-up, supporting the utility of our surveillance MR imaging protocol.

Anti-tumour necrosis factor-α therapy and recurrent or new primary cancers in patients with inflammatory bowel disease, rheumatoid arthritis, or psoriasis and previous cancer in Denmark: a nationwide, population-based cohort study

Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy. In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration. Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11). Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications. None.

Study of risk factors for development of urinary bladder cancer in patients in Urmia; a single-center study by logit regression approach

Introduction: Urinary bladder cancer is the most common genitourinary system malignancy in humans. Objectives: Due to the high prevalence of urinary bladder cancer, having enough knowledge about urinary bladder cancer risk factors can assist in prevention and early recognition of this malignancy. Patients and Methods: In this study case-control, 109 individuals with urinary bladder tumor (as a case group) and 200 individuals without any neoplastic history aged &gt;40 years (as a control group) were included (2016-2017). The data were collected using patients’ files, their pathology reports and also a checklist. The data were analyzed using SPSS version 20, and logistic regression test was applied to investigate the binary outcome. A P value less than 0.05 was considered significant. Results: The results showed, a significant relationship between smoking (P&lt;0.001), having high risk occupation (P&lt;0.001), low water intake (P&lt;0.001) and pickle consumption (P&lt;0.001) with urinary bladder cancer. Conclusion: Smoking is a strong risk factor for urinary bladder cancer. Our study showed smoking and other occupational carcinogens are the main causes of urinary bladder cancers. Thus preventing and controlling these risk factors are important for health schedules.

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population.

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

Visit-to-Visit Hemoglobin A1c Variability Is Associated With Later Cancer Development in Patients With Diabetes Mellitus.

Recent studies have shown that patients with diabetes mellitus have a higher risk of tumorigenesis. However, the effect of glycemic variability on tumorigenesis among diabetic patients has not been well investigated. Hence, we performed a retrospective cohort study to analyze the effect of visit-to-visit hemoglobin A1c (HbA1c) variability and later onset of malignancies. This study included 2640 patients with diabetes mellitus 50 years or older. To analyze visit-to-visit glycemic activity, we calculated intrapersonal SD of all recorded HbA1c and used SD-HbA1c as a measure of glycemic variability. Because the number of individual visits varied, we divided SD-HbA1c by visit times in order to adjust for the potential influence of visit time difference between individuals. Patients were divided into quartiles according to their HbA1c variability, and Cox regression models were used to evaluate the association between glycemic variability and later onset of tumorigenesis. Three hundred thirty patients (12.5%) developed malignancy during follow-up. The median follow-up period was 1511 days (4.1 years; interquartile range, 2487.5 days). Relative to the group with the lowest glycemic variability (first quartile), the groups with higher glycemic variability showed a dose-dependent association with tumorigenesis. The odds ratios for the second, third, and fourth quartiles were 1.20 (95% confidence interval, 0.88-1.65), 1.43 (1.02-2.00), and 2.19 (1.52-3.17), respectively. The mean HbA1c and diabetes mellitus duration periods were not significantly associated with tumorigenesis. This result was consistent when limiting the number of covariates. These results demonstrated that visit-to-visit HbA1c variability is a potential risk factor for later tumorigenesis. The association may be mediated by oxidative stress or hormone variability. Routine cancer screening may be suggested for diabetic patients with unstable glycemic control.

Abstract 1728: Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis

Abstract Aim: p53 is a tumor suppressor and its dysfunction promotes carcinogenesis of several organs including the liver. Meanwhile, p53 is reported to be overactivated in non-tumorous liver tissues of patients with chronic liver diseases, presumably due to several stressful stimuli to hepatocytes, including viral infection, ethanol exposure, fat accumulation. The aim of this study is to clarify the impact of p53 overactivation on hepatocarcinogenesis. Methods: To induce hepatocyte-specific overactivation of p53 in liver cancer models, hepatic Mdm2, a negative regulator of p53, was genetically ablated in diethylnitrosoamine (DEN)-treated mice (Alb-CreMdm2fl/fl) and liver-specific constitutive-active Kras-mutant knock-in mice (Alb-CreKrasLSL-G12DMdm2fl/fl called as KrasG12DΔMdm2 mice). To analyze the significance of p53, hepatic p53 was deleted in Mdm2-wild KrasG12D mice (Alb-CreKrasLSL-G12DMdm2+/+p53fl/fl) and KrasG12DΔMdm2 mice (Alb-CreKrasLSL-G12DMdm2fl/flp53fl/fl). Results: Mdm2 deletion significantly elevated serum ALT levels and increased tumor penetrance in both DEN-treated mice and Kras-mutant mice, suggesting that p53 overactivation accelerated hepatocarcinogenesis. KrasG12DΔMdm2 mice upregulated hepatic expressions of pro-apoptotic molecules (p16, p21, Bax, Noxa), number of TUNEL positive hepatocytes and serum caspase-3/7 levels, indicating accelerated hepatocyte apoptosis. They also increased the number of β-galactosidase positive hepatocytes and upregulated hepatic inflammatory cytokines (Tnf, Ccl2, Il-1β), suggesting senescence-associated secretory phenotype (SASP). Expressions of hepatic progenitor cell (HPC) markers (Afp, Epcam, Ck7, Ck19, Cd90, Cd133, Dlk1) were up-regulated in their liver. HPC marker staining suggested that liver tumors in KrasG12DΔMdm2 mice may originate from HPCs. All the phenotypes including accelerated hepatocyte apoptosis, SASP and emergence of HPCs in KrasG12DΔMdm2 mice were significantly alleviated by p53 deletion. Most importantly, deletion of p53 significantly decelerated hepatocarcinogenesis in those mice, indicating that p53 overactivation was responsible for the accelerated hepatocarcinogenesis. In sharp contrast, p53 deletion significantly accelerated hepatocarcinogenesis in Mdm2-wild Kras-mutant mice, confirming the tumor suppressive role of normal level of p53 in the liver. Conclusion: Whereas p53 deletion accelerated hepatocarcinogenesis, p53 overactivation induced liver injury and activation of HPCs, leading to the acceleration of hepatocarcinogenesis. p53 overactivation in hepatocytes might be associated with liver cancer development in patients with chronic liver diseases. Citation Format: Yuki Makino. Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1728.

Trifluoperazine as an alternative strategy for the inhibition of tumor growth of colorectal cancer.

The development of cancer in patients with schizophrenia is affected by genetic and environmental factors and antipsychotic medication. Several studies found that schizophrenia was associated with decreased risk of some cancers, and the neuroleptic medication might help to reduce the risk of colorectal cancer (CRC). Phenothiazine drugs including trifluoperazine (TFP) are widely used antipsychotic drugs and showed some antitumor effects, we here investigated the potential application of TFP in the treatment of colon cancer. A series doses of TFP were treated to the colon cancer cell line HCT116 and the inhibitory concentration (IC50 ) of TFP for HCT116 was determined by cell counting kit-8. The results indicated that the treatment of TFP impaired the cell vitality of HCT116 in a dose- and time-dependent manner. Meanwhile, the Edu assay demonstrated that the proliferation was also inhibited by TFP, which was accompanied with the induction of apoptosis and autophagy. The expression of CCNE1, CDK4, and antiapoptosis factor BCL-2 was downregulated but the proapoptosis factor BAX was upregulated. The autophagy inhibitor chloroquine could significantly reverse the TFP-induced apoptosis. Moreover, the ability of migration and invasion of HCT116 was found to be suppressed by TFP, which was associated with the inhibition of epithelial-mesenchymal transition (EMT). The function of TFP in vivo was further confirmed. The results showed that the administration of TFP remarkably abrogated the tumor growth with decreased tumor volume and proliferation index Ki-67 level in tumor tissues. The EMT phenotype was also confirmed to be inhibited by TFP in vivo, suggesting the promising antitumor effects of TFP in CRC.