胰腺癌与糖尿病关联的探讨

背景与目的:在十九世纪早期,人们即认识到胰腺癌与糖尿病(DM)的关系,但至今两者的因果关系仍有争论,本文探讨两者的关联,从而提高胰腺癌早期诊断水平。方法:对2003年12月-2005年2月收住我院的胰腺癌合并DM患者及非合并DM患者共83例进行回顾性分析,并将其中13例以DM为首发症状或DM病情加重胰腺癌患者与另外20例病程匹配的2型糖尿病(T2DM)进行年龄、体重指数、DM家族史及实验室指标的比较。结果:①83例胰腺癌中,35例(42.17%)合并DM,其中24(68.57%)例DM病程小于2年(其中14(40%)例与胰腺癌同时发现),8(22.86%)例DM病程大于2年,3例DM病程不详。胰腺癌合并DM患者高血压的患病率高于非DM患者(45.71%vs25%,P<0.05)。②胰腺癌合并DM患者腹痛(χ2=5.332,P<0.01)、纳差(χ2=3.867,P<0.01)的发生率低于非DM患者。③胰腺癌合并DM患者直接胆红素(DB)(χ2=23.46,P<0.01)升高发生率较低。④两组患者在肿瘤的部位、转移、手术情况和生存期差异无统计学意义。⑤13例以DM为首发症状或DM病情加重胰腺癌患者与20例T2DM进行比较,胰腺癌患者发病年龄较大(68.93±10.62vs55.6±11.14岁,P<0.01)且体型更消瘦(BMI21.51±1.98vs23.87±3.04kg/m2,P<0.01)。结论:胰腺癌为进展较快的肿瘤,即使合并DM,也不影响胰腺癌临床表现及预后。对于高龄且消瘦初发DM患者及血糖短期恶化DM患者,要警惕胰腺癌的发生。     

New-onset type 2 diabetes,elevated HbA1c,anti-diabetic medications,and risk of pancreatic cancer

Background:

Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels.

Methods:

A nested case–control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders.

Results:

Among 1 574 768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (⩾4 mmol mol⁻¹ compared with <0 mmol mol⁻¹) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72–2.72 and OR, 5.06, 95% CI 1.52–16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55–56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85–2.52), compared with no use of any anti-diabetic medications.

Conclusions:

New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin.     

2型糖尿病与肝癌关系的探讨

我国是肝癌的高发病区.有研究表明,2型糖尿病与肝癌的发生发展有关.本文拟从2型糖尿病对肝癌的发生影响、可能的机制、药物治疗的影响及预后几方面对两者的关系进行综述.     

Type 2 diabetes mellitus and survival in pancreatic adenocarcinoma

BACKGROUND:

Recent evidence has identified pre‐existing type 2 diabetes mellitus (T2DM) as a risk factor for the development of PAC, but relatively little is known about its effects on survival. Our aim was to determine the effect of varying durations of pre‐existing T2DM on survival in patients with PAC.

METHODS:

We conducted a retrospective cohort study using The Health Improvement Network (THIN), a primary care electronic medical record database from the UK (2003‐2010). The study cohort included all subjects with a diagnostic code for PAC. Subjects with a diagnostic code for T2DM before their PAC diagnosis were classified as exposed; otherwise, subjects were classified as unexposed. The primary outcome was overall survival. The analysis was performed using univariate and multivariable Cox proportional‐hazards models. Additional analysis was performed to assess the effect of increasing duration of pre‐existing T2DM [i.e., <90 days, 90 days to <1 year, 1 to <3 years, 3 to 5 years, >5 years] on survival.

RESULTS:

The study included 3,147 patients with PAC, with 745 patients having pre‐existing T2DM and 2,402 patients without pre‐existing T2DM. In the primary multivariate analysis, there was no difference in survival between those exposed and those unexposed to pre‐existing T2DM (HR 1.02 [0.93, 1.12], p = 0.620). In the secondary analysis, only those patients with T2DM > 5 years duration had a significantly increased mortality (HR 1.16 [1.00, 1.33], p < 0.05).

CONCLUSIONS:

Long‐term pre‐existing T2DM is associated with increased mortality in patients diagnosed with PAC. Cancer 2013. © 2012 American Cancer Society.     

Progress on diagnostic and prognostic markers of pancreatic cancer

Pancreatic cancer is a malignant disease characterized by low survival and high recurrence rate, whose patients are mostly at the stage of locally advanced or metastatic disease when first diagnosed. Early diagnosis is particularly important because prognostic/predictive markers help guide optimal individualized treatment regimens. So far, CA19-9 is the only biomarker for pancreatic cancer approved by the FDA, but its effectiveness is limited by low sensitivity and specificity. With recent advances in genomics, proteomics, metabolomics, and other analytical and sequencing technologies, the rapid acquisition and screening of biomarkers is now possible. Liquid biopsy also occupies a significant place due to its unique advantages. In this review, we systematically describe and evaluate the available biomarkers that have the greatest potential as vital tools in diagnosing and treating pancreatic cancer.     

Reduction of miR-29c enhances pancreatic cancer cell migration and stem cell-like phenotype

The hallmarks of pancreatic cancer are limitless replicative potential as well as tissue invasion and metastasis, leading to an extremely aggressive disease with shockingly high lethality. However, the molecular mechanisms underlying these characteristics remain largely unclear. Herein, we report the results of a differential miRNA expression screen that compared pancreatic cancer tissues and normal pancreatic tissues, where the pancreatic cancer tissues had highly downregulated miR-29c with relative Wnt cascade hyperactivation. MiR-29c directly suppressed the following Wnt upstream regulators: frequently rearranged in advanced T-cell lymphomas 2 (FRAT2), low-density lipoprotein receptor–related protein 6 (LRP6), Frizzled-4 (FZD4) and Frizzled-5 (FZD5). Furthermore, transforming growth factor-β (TGF-β) inhibited miR-29c expression, leading to Wnt activation. Significantly, our results were consistent with an important correlation between miR-29c levels and TGF-β hyperactivation and the activated Wnt cascade in human pancreatic cancer specimens. These findings reveal a novel mechanism for Wnt hyperactivation in pancreatic cancer and may suggest a new target for clinical intervention in pancreatic cancer.     

Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10-year follow-up of population-based cohort

Background:

Type 2 diabetes mellitus, gastric and hepatobiliary comorbidities, and cancer share common risk factors: for example, tobacco, obesity, physical inactivity, high calorie intake, and metabolic disorders. Prior studies find type 2 diabetes and gastric and hepatobiliary comorbidities heightening risk of pancreatic cancer. Yet joint association of type 2 diabetes mellitus and gastric and hepatobiliary comorbidities on pancreatic cancer risk has not been assessed.

Methods:

This study rates independent/joint effects of type 2 diabetes as well as gastric and hepatobiliary comorbidity on pancreatic cancer risk for a retrospective population-based cohort of 166 850 type 2 diabetics identified in 1997–1998 and followed for 10–11 years, comparing their cancer incidence with that of 166 850 non-diabetics matched for age, gender, and locale. Time-dependent Cox''s proportional hazards model evaluted joint association of type 2 diabetes and chronic conditions on pancreatic cancer risk.

Results:

A total of 1178 subjects were newly diagnosed with pancreatic cancer during follow-up, with incidence rates of 0.49 per 1000 person-years in type 2 diabetes and 0.26 per 1000 person-years in the non-diabetics. We observed greater magnitude of hazard ratios (HRs) of pancreatic cancer for patients with type 2 diabetes along with acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer compared with patients without type 2 diabetes or counterpart comorbidity (HR: 1.36, 95% confidence interval (CI): 1.19–1.56; 1.74, 1.23–2.45; 9.18, 7.44–11.33; and 2.31, 1.98–2.70, respectively). Main effects of type 2 diabetes were all statistically with narrow 95% CI and remained similar across risk stratification with various comorbidities: range 1.59–1.80.

Conclusions:

Our study demonstrates that pre-existing type 2 diabetes, acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer independently or jointly predict subsequent pancreatic cancer risk. Clinicians must recognise burden of these gastric and hepatobiliary comorbidities and keep clinically vigilant for their diagnosis.     

2型糖尿病合并胃癌患者血清IGF-1、IGFBP-3的变化

目的:研究2型糖尿病（diabetes mellitus,DM）合并胃癌（gastric cancer,GC）患者血清胰岛素样生长因子-1（insulin-like growth factor-1,IGF-1）、胰岛素样生长因子结合蛋白-3(insulin-like growth factor binding protein-3,IGFBP-3)的变化。方法:选择2型DM患者30例（DM组）、2型DM合并GC患者48例（DM并GC组）为研究对象,ELISA 法测定血清IGF-1、 IGFBP-3水平;同时测定空腹血糖、空腹胰岛素、血脂水平。 结果:DM并GC组的IGF-1、IGF-1/IGFBP-3比值高于DM组（P<0.05）,IGFBP-3在两组之间无统计学差异（P>0.05）。IGF-1、IGF-1/IGFBP-3比值与空腹胰岛素水平呈正相关（r=0.598,0.626,P=0.000）,IGF-1/IGFBP-3比值是DM并GC患者淋巴结转移的危险因素（OR=2.142,P=0.001）。结论:IGF-1可能参与2型DM合并GC的发生及淋巴结转移。     

Familial pancreatic cancer

Familial pancreatic cancer (FPC) includes those kindreds that contain at least two first-degree relatives with pancreatic ductal adenocarcinoma. At least 12 known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the foremost being BRCA2 and CDKN2A. Research into the identification of mutations in known cancer predisposition genes and through next-generation sequencing has revealed extensive heterogeneity. The development of genetic panel testing has enabled genetic risk assessment and predisposition testing to be routinely offered. Precision oncology has opened the possibility of “incidental” germline mutations that may have implications for family members. However, in both cases, evidence-based recommendations for managing patients and at-risk family members in light of genetic status remain emergent, with current practice based on expert opinion.     

Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy

Preclinical data suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors may promote metastatic progression of preexisting cancer via nuclear factor erythroid 2-related factor 2 (NRF2) activation. We aimed to investigate the association between different glucose-lowering treatments, including DPP-4 inhibitors and metformin, both with potential NRF2 modulating effects, and new-onset metastatic cancer among type 2 diabetes patients with comorbid incident cancer. This population-based cohort study included 223,530 diabetic patients newly diagnosed with primary cancer during 2009–2011 in Korea. The patients were categorized into five study cohorts in accordance with treatment modalities during the follow-up until the end of 2016: no-antidiabetic drugs (no-AD), metformin, DPP-4 inhibitors, metformin+DPP-4 inhibitors, and insulin treatment. After propensity score (PS) matching in a 1:1 ratio against the no-AD group, 18,805 patients in metformin, 1,865 in DPP-4 inhibitors, 31,074 in metformin+DPP-4 inhibitors, and 1,895 patients in insulin groups were identified for cohort entry and analyzed against the corresponding number of no-AD patients in each PS-matched comparison pair. Metastatic risk was lower with metformin plus or minus DPP-4 inhibitors (HR 0.84, 95% CI 0.79–0.90 and 0.87, 0.80–0.95, respectively), not significantly associated with DPP-4 inhibitors (0.99, 0.77–1.29) except after thyroid cancer (3.89, 1.01–9.64), and higher with insulin therapy (1.81, 1.46–2.24) compared to no-AD use for all cancers combined. In conclusion, DPP-4 inhibitor therapy was not associated with significant risk of cancer metastasis relative to no-AD therapy, irrespective of patient age and sex, except after thyroid cancer, while metastatic risk was decreased with metformin treatment among type 2 diabetes patients with preexisting cancer.     

Association between diabetes,diabetes treatment and risk of developing endometrial cancer

Background:

A growing body of evidence suggests that diabetes is a risk factor for endometrial cancer incidence. However, most of these studies used case-control study designs and did not adjust for obesity, an established risk factor for endometrial cancer. In addition, few epidemiological studies have examined the association between diabetes treatment and endometrial cancer risk. The objective of this study was to assess the relationships among diabetes, diabetes treatment and endometrial cancer risk in postmenopausal women participating in the Women''s Health Initiative (WHI).

Methods:

A total of 88 107 postmenopausal women aged 50–79 years who were free of cancer and had no hysterectomy at baseline were followed until date of endometrial cancer diagnosis, death, hysterectomy or loss to follow-up, whichever came first. Endometrial cancers were confirmed by central medical record and pathology report review. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% confidence interval (CI)) for diagnosis of diabetes and metformin treatment as risk factors for endometrial cancer.

Results:

Over a mean of 11 years of follow-up, 1241 endometrial cancers developed. In the primary analysis that focused on prevalent diabetes at enrolment, compared with women without diabetes, women with self-reported diabetes, and the subset of women with treated diabetes, had significantly higher risk of endometrial cancer without adjusting for BMI (HR=1.44, 95% CI: 1.13–1.85 for diabetes, HR=1.57, 95% CI: 1.19–2.07 for treated diabetes). However after adjusting for BMI, the associations between diabetes, diabetes treatment, diabetes duration and the risk of endometrial cancer became non-significant. Elevated risk was noted when considering combining diabetes diagnosed at baseline and during follow-up as time-dependent exposure (HR=1.31, 95% CI: 1.08–1.59) even after adjusting for BMI. No significant association was observed between metformin use and endometrial cancer risk.

Conclusions:

Our results suggest that the relationship observed in previous research between diabetes and endometrial cancer incidence may be largely confounded by body weight, although some modest independent elevated risk remains.     

Postoperative surveillance of pancreatic cancer patients

BackgroundThe aim of this study is to collect the best available evidence for diagnostic modalities, frequency, and duration of surveillance after resection for pancreatic ductal adenocarcinoma (PDAC).MethodsPDAC guidelines published after 2015 were collected. Furthermore, a systematic search of the literature on postoperative surveillance was performed in PubMed and Embase from 2000 to 2019. Articles comparing different diagnostic modalities and frequencies of postoperative surveillance in PDAC patients with regard to survival, quality of life, morbidity and cost-effectiveness were selected.ResultsThe literature search resulted in 570 articles. A total of seven guidelines and twelve original clinical studies were eventually evaluated. PDAC guidelines increasingly recommend a combination of tumor marker testing and computed tomography (CT) imaging every three to six months during the first two years after resection. These guidelines are, however, based on expert opinion and other low-level evidence. Prospective studies comparing different surveillance strategies are lacking. According to recent studies, surveillance with tumor markers and imaging at regular intervals results in the detection of PDAC recurrence before the onset of symptoms and more frequent administration of further therapy, such as chemotherapy or radiotherapy.ConclusionCurrent evidence for recurrence-focused surveillance after PDAC resection is limited and contradictory. Consequently, recommendations on surveillance are conflicting. To define the clinical merit of recurrence-focused surveillance, patients who are most likely to benefit from early detection and treatment of PDAC recurrence need to be identified. To this purpose, well-designed prospective studies are needed, accounting for both economical and psychosocial implications of surveillance.     

Association between serum urea concentrations and the risk of colorectal cancer,particularly in individuals with type 2 diabetes: A cohort study

Dysregulation of the urea cycle (UC) has been detected in colorectal cancer (CRC). However, the impact of the UC's end product, urea, on CRC development remains unclear. We investigated the association between serum urea and CRC risk based on the data of 348 872 participants cancer-free at recruitment from the UK Biobank. Multivariable Cox proportional hazards models were fitted to conduct risk estimates. Stratification analyses based on sex, diet pattern, metabolic factors (including body mass index [BMI], the estimated glomerular filtration rate [eGFR] and type 2 diabetes [T2D]) and genetic profiles (the polygenic risk score [PRS] of CRC) were conducted to find potential modifiers. During an average of 9.0 years of follow-up, we identified 3408 (1.0%) CRC incident cases. Serum urea showed a nonlinear relationship with CRC risk (P-nonlinear: .035). Lower serum urea levels were associated with a higher CRC risk, with a fully-adjusted hazard ratio (HR) of 1.26 (95% confidence interval [CI]: 1.13-1.41) in the first quartile (Q1) of urea, compared to the Q4. This association was largely consistent across subgroups of sex, protein diet, BMI, eGFR and CRC-PRSs (P-interaction >.05); however, it was stronger in the T2D, with an interaction between urea and T2D on both additive (synergy index: 3.32, [95% CI: 1.24-8.88]) and multiplicative scales (P-interaction: .019). Lower serum urea concentrations were associated with an increased risk of CRC, with a more pronounced effect observed in individuals with T2D. Maintaining stable levels of serum urea has important implications for CRC prevention, particularly in individuals with T2D.     

Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies

Pancreatic cancer is the eighth major form of cancer-related death worldwide, causing 227 000 deaths annually. Type-II diabetes is widely considered to be associated with pancreatic cancer, but whether this represents a causal or consequential association is unclear. We conducted a meta-analysis to examine this association. A computer-based literature search from 1966 to 2005 yielded 17 case-control and 19 cohort or nested case-control studies with information on 9220 individuals with pancreatic cancer. The age and sex-adjusted odds ratio (OR) for pancreatic cancer associated with type-II diabetes was obtained from each study. The combined summary odds ratio was 1.82 (95% confidence interval (95% CI) 1.66-1.89), with evidence of heterogeneity across the studies (P=0.002 for case-control and P=0.05 for cohort studies) that was explained, in part, by higher risks being reported by smaller studies and studies that reported before 2000. Individuals in whom diabetes had only recently been diagnosed (< 4 years) had a 50% greater risk of the malignancy compared with individuals who had diabetes for > or =5 years (OR 2.1 vs 1.5; P=0.005). These results support a modest causal association between type-II diabetes and pancreatic cancer.     

Survivin and pancreatic cancer

Pancreatic cancer is estimated to be the fourth most common cancer in men and fifth in women in the world and has poor prognosis. In recent years, more and more effort has been put on the relationship between pancreatic cancer and apoptosis. As a newly discovered inhibitor of apoptosis, survivin has drawn more attention. Strong evidence has shown that survivin is expressed in pancreatic cancer cells on frozen sections. Survivin increases in the development of pancreatic ductal adenocarcinoma and its expression can be a marker in evaluating the prognosis of pancreatic cancer patients. Survivin itself may be a new target in the treatment of pancreatic cancer and a survivin DNA vaccine could generate specific antitumor effects in pancreatic carcinoma models.     

蛙皮素与胰腺癌的相关性研究进展

蛙皮素与肿瘤增殖关系密切,在多种人胰腺癌细胞系及其移植瘤中均发现其高表达,但在人胰腺肿瘤组织中的表达仍存在争议,因此人们对其表达及作用机制进行了广泛研究,并探讨了蛙皮素及其受体拮抗剂与胰腺癌治疗间的关系。多种放射性标记的蛙皮素类似物的出现也使得在蛙皮素受体阳性的胰腺癌中的放射性显像及靶向治疗成为可能。现就蛙皮素及其同类物与胰腺癌的关系作一综述。     

肿瘤相关中性粒细胞与胰腺癌关系的研究进展

胰腺癌是一种起病隐匿、预后不良的消化系统恶性肿瘤,具有早期诊断困难、进展期生存时间短等特点。胰腺癌的肿瘤微环境(Tumor microenvironment, TME)中常常伴有大量免疫细胞的浸润,而肿瘤相关中性粒细胞(Tumor-associated neutrophils, TANs)作为TME的重要组成部分,在肿瘤的进程中起着重要作用。相关研究表明,TANs在胰腺癌的TME中发挥多种作用。本文从TANs与胰腺癌的关系进行综述,为理解胰腺癌发生机制与提出新疗法提供思路。     

Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans

Obesity, type 2 diabetes mellitus (T2DM) and aging are associated with pancreatic cancer risk, but the mechanisms of pancreatic cancer development caused by these factors are not clearly understood. Syrian golden hamsters are susceptible to N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinogenesis. Aging, BOP treatment and/or a high‐fat diet cause severe and scattered fatty infiltration (FI) of the pancreas with abnormal adipokine production and promote pancreatic ductal adenocarcinoma (PDAC) development. The KK‐A^y mouse, a T2DM model, also develops severe and scattered FI of the pancreas. Treatment with BOP induced significantly higher cell proliferation in the pancreatic ducts of KK‐A^y mice, but not in those of ICR and C57BL/6J mice, both of which are characterized by an absence of scattered FI. Thus, we hypothesized that severely scattered FI may be involved in the susceptibility to PDAC development. Indeed, severe pancreatic FI, or fatty pancreas, is observed in humans and is associated with age, body mass index (BMI) and DM, which are risk factors for pancreatic cancer. We analyzed the degree of FI in the non‐cancerous parts of PDAC and non‐PDAC patients who had undergone pancreatoduodenectomy by histopathology and demonstrated that the degree of pancreatic FI in PDAC cases is significantly higher than that in non‐PDAC controls. Moreover, the association with PDAC is positive, even after adjusting for BMI and the prevalence of DM. Accumulating evidence suggests that pancreatic FI is involved in PDAC development in animals and humans, and further investigations to clarify the genetic and environmental factors that cause pancreatic FI are warranted.     

Obesity and pancreatic cancer

BackgroundPancreatic cancer is an invariably fatal malignancy. Cigarette smoking and diabetes are established risk factors, but over the last two decades studies have shown that excess adiposity is an additional independent risk factor with 30–50% of cases thought to be attributed to nutritional factors. The aim of this narrative review is to analyze all the epidemiological evidence on the topic and possible pathophysiology.MethodsWe searched PubMed, Embase, Cochrane Library and Medline, and all available evidence was included. We firstly analyze meta- and pooled analysis. Then we discuss individual studies to identify sources of discrepancies between studies and attempt to delineate pathophysiology.ResultsIt is estimated that obese individuals have a relative risk (RR) ranging between 1.19 and 1.47, when compared with those of normal weight, regardless of diabetes or smoking status. No significant differences were found between gender.ConclusionThere is a measurable increased risk of developing pancreatic cancer in obese individuals, and excess adiposity is related to the condition with a “dose–response” curve.Hyperinsulinemia and possibly hyperestrogenism secondary to a metabolic syndrome, and independently from diabetes status, appear to be the key elements of the pathogenesis in pancreatic cancer secondary to excess body fat. Increased efforts should therefore be made in tackling the epidemic levels of obesity in the Western world countries.