3.0T磁共振多序列成像对鉴别胰头癌与胰头肿块型慢性胰腺炎的应用价值

目的：探讨磁共振多序列成像对鉴别胰头癌与胰头肿块型慢性胰腺炎的临床价值及意义。方法：对已确诊的16例胰头癌患者和5例胰头肿块型慢性胰腺炎患者的磁共振多序列成像MR进行回顾性分析。主要征象包括：①肿块信号及形态学特点;②胰管及胆管扩张情况;③动态增强的特征;④胰周及大血管受累情况;⑤邻近器官受累与淋巴结肿大情况。检查方法包括：平扫T1WI＋FST2WI＋FS,MRCP,3D—VIBE动态增强扫描。结果：1）肿块形态信号异常：胰头癌与胰头肿块型胰头慢性胰腺炎的信号有较多重叠,在TlwI上均表现为相对低信号,T2WI表现为不均匀稍高、相等或低信号。2）胰管与胆管的异常：胰头癌表现为胰管扩张至肿块处突然截断12例,胆总管突然截断10例,“双管征”10例。胰头肿块型慢性胰腺炎胰管扩张3例,2例为串珠样扩张,扩张的胰管可贯通病灶区,胆总管5例均扩张,远端呈短锥形狭窄3例,鼠尾样狭窄2例。3）3D—VIBE强化特征分析结果：随着时间的延长胰头癌强化程度和强化百分率较胰头肿块型慢性胰腺炎明显减低。4）胰周大血管受累情况：胰头癌肿块与血管分界不清者8例,部分包绕血管6例完全包绕血管6例;胰头肿块型慢性胰腺炎1例与血管分界不清,1例部分被包绕。5）邻近器官受累与淋巴结肿大情况：胰头癌有7例淋巴结肿大主要分布在胰周及腹主动脉旁,胰头肿块型慢性胰腺炎,未见明显肿大淋巴结,有四例肾周筋膜增厚,两例肾前筋膜增厚。结论：磁共振多序列成像的联合使用及征象分析,有助于鉴别胰头癌与胰头肿块型慢性胰腺炎。     

自身免疫性胰腺炎的胰腺外表现

自身免疫性胰腺炎(autoimmune pancreatitis,AIP)是一种特殊类型的胰腺炎,其发病机制与自身免疫密切相关。2010年公布的诊断标准主要从血清学、影像学、组织学、胰腺外器官受累和激素治疗反应五方面将其分为1型和2型。近年来越来越多的资料显示多种胰腺外表现与AIP相关,如泪腺和唾液腺病变,硬化性胆管炎,间质性肺炎,肺门、纵膈淋巴结肿大,腹膜后纤维化,肾小管间质性肾炎等。胰腺外病变与AIP有相同的病理表现:器官内可见大量的Ig G4阳性浆细胞浸润,对激素治疗反应良好。本文主要对AIP的胰腺外表现作一综述。     

Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases

Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers. Resequencing studies of protein kinase coding regions have emphasized the importance of sequence and structure determinants of cancer-causing kinase mutations in understanding of the mutation-dependent activation process. We have developed an integrated bioinformatics resource, which consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence, structure and functional data. The integration of diverse data types provided a convenient framework for kinome-wide study of sequence-based and structure-based signatures of cancer mutations. The database-driven analysis has revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalytic core. We have also found that structurally conserved mutational hotspots can be shared by multiple kinase genes and are often enriched by cancer driver mutations with high oncogenic activity. Structural modeling and energetic analysis of the mutational hotspots have suggested a common molecular mechanism of kinase activation by cancer mutations, and have allowed to reconcile the experimental data. According to a proposed mechanism, structural effect of kinase mutations with a high oncogenic potential may manifest in a significant destabilization of the autoinhibited kinase form, which is likely to drive tumorigenesis at some level. Structure-based functional annotation and prediction of cancer mutation effects in protein kinases can facilitate an understanding of the mutation-dependent activation process and inform experimental studies exploring molecular pathology of tumorigenesis.     

Perineural Mast Cells Are Specifically Enriched in Pancreatic Neuritis and Neuropathic Pain in Pancreatic Cancer and Chronic Pancreatitis

Background

Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown.

Methods

Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients.

Results

In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients.

Conclusion

Pancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.     

Identification of Gene-Expression Signatures and Protein Markers for Breast Cancer Grading and Staging

The grade of a cancer is a measure of the cancer''s malignancy level, and the stage of a cancer refers to the size and the extent that the cancer has spread. Here we present a computational method for prediction of gene signatures and blood/urine protein markers for breast cancer grades and stages based on RNA-seq data, which are retrieved from the TCGA breast cancer dataset and cover 111 pairs of disease and matching adjacent noncancerous tissues with pathologists-assigned stages and grades. By applying a differential expression and an SVM-based classification approach, we found that 324 and 227 genes in cancer have their expression levels consistently up-regulated vs. their matching controls in a grade- and stage-dependent manner, respectively. By using these genes, we predicted a 9-gene panel as a gene signature for distinguishing poorly differentiated from moderately and well differentiated breast cancers, and a 19-gene panel as a gene signature for discriminating between the moderately and well differentiated breast cancers. Similarly, a 30-gene panel and a 21-gene panel are predicted as gene signatures for distinguishing advanced stage (stages III-IV) from early stage (stages I-II) cancer samples and for distinguishing stage II from stage I samples, respectively. We expect these gene panels can be used as gene-expression signatures for cancer grade and stage classification. In addition, of the 324 grade-dependent genes, 188 and 66 encode proteins that are predicted to be blood-secretory and urine-excretory, respectively; and of the 227 stage-dependent genes, 123 and 51 encode proteins predicted to be blood-secretory and urine-excretory, respectively. We anticipate that some combinations of these blood and urine proteins could serve as markers for monitoring breast cancer at specific grades and stages through blood and urine tests.     

Pancreatic Incidentaloma: Differentiating Nonfunctioning Pancreatic Neuroendocrine Tumors from Intrapancreatic Accessory Spleen

Objective: To improve the preoperative assessment of pancreatic incidentalomas (PIs) by analysis of 1 index case and characterization of the published features of intrapancreatic accessory spleen (IPAS) compared to pancreatic neuroendocrine tumor (PNET).Methods: A search of the literature using the online database MEDLINE.Results: In all, 46 cases of IPAS have been described to date: 17 were “presumed” as IPAS based on technetium-99m (Tc-99m) scanning, fine-needle aspiration (FNA) stain for CD8, or contrast-enhanced sonography; 29 were misdiagnosed as PNET and underwent surgery. The pancreatic lesions were 1) mostly solitary; 2) solid on imaging; 3) well defined; 4) located predominantly at the pancreatic tail; 5) not exceeding 3 cm in the largest diameter; 5) all detected in adults (22–81 years); 6) not related to sex. In subjects referred for surgery, standard imaging studies/imaging protocols did not differentiate between IPAS and PNET. FNA was performed in 5/46 cases, all of which were false-positive for PNET. Immunohistochemical staining for T-cells on FNA material and specific imaging features (characteristic arciform splenic enhancement pattern on dynamic computed tomography [CT]; nuclear scintigraphies with radioisotope specifically trapped by splenic tissue [Tc-99m]) or contrast-enhanced sonography offered valuable clues. Still, distal pancreatectomy and splenectomy was carried out in 72%, and the rest had distal pancreatectomies.Conclusion: IPAS should be considered before surgery in patients with PIs. A new practical algorithm is presented for better preoperative evaluation of such lesions; it combines the recognition of early indicators and sequential consideration of cytologic and imaging features to decrease the hazards of unnecessary major surgery.Abbreviations:CT = computed tomographyEUS = endoscopic ultrasoundFNA = fine-needle aspirationHDRBC = heat-damaged red blood cellsIPAS = intrapancreatic accessory spleenMRI = magnetic resonance tomographyNF-PNET = nonfunctioning pancreatic neuroendocrine tumorPET = positron emission tomographyPNET = pancreatic neuroendocrine tumorPI = pancreatic incidentalomasSPIO = superparamagnetic iron oxideTc-99m = technetium-99m     

Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers

Prostate cancer (PCa) is one amongst the most common cancersin western men. Incidence rate ofPCa is on the rise worldwide. The present study deals with theserum lipidome profiling of patients diagnosed with PCa to identify potential new biomarkers. We employed ESI-MS/MS and GC-MS for identification of significantly altered lipids in cancer patient’s serum compared to controls. Lipidomic data revealed 24 lipids are significantly altered in cancer patinet’s serum (n = 18) compared to normal (n = 18) with no history of PCa. By using hierarchical clustering and principal component analysis (PCA) we could clearly separate cancer patients from control group. Correlation and partition analysis along with Formal Concept Analysis (FCA) have identified that PC (39:6) and FA (22:3) could classify samples with higher certainty. Both the lipids, PC (39:6) and FA (22:3) could influence the cataloging of patients with 100% sensitivity (all 18 control samples are classified correctly) and 77.7% specificity (of 18 tumor samples 4 samples are misclassified) with p-value of 1.612×10⁻⁶ in Fischer’s exact test. Further, we performed GC-MS to denote fatty acids altered in PCa patients and found that alpha-linolenic acid (ALA) levels are altered in PCa. We also performed an in vitro proliferation assay to determine the effect of ALA in survival of classical human PCa cell lines LNCaP and PC3. We hereby report that the altered lipids PC (39:6) and FA (22:3) offer a new set of biomarkers in addition to the existing diagnostic tests that could significantly improve sensitivity and specificity in PCa diagnosis.     

Serum CRP Protein as a Differential Marker in Cancer

The objective of this study was to measure the serum concentrations of C-reactive protein (CRP) in cancer patients and compare with those of immune disease patients and healthy individuals for discriminatory analysis. For this purpose, automatic systems for special protein analysis (Type: Drcon Diognostica Tarbox) was used to measure serum CRP concentrations in 276 cancer patients (Group A), 110 immune disease patients (Group B), 161 phlogistic patients (Group C), and 125 age-matched healthy individuals (Group D). Our data show that serum CRP concentrations in Group A were significantly higher than those in Groups B and D, whereas CRP concentrations in Group B were higher than those in Group D. The differences of serum CRP concentrations between Groups A and B as well as between Groups B and D were significant (P?<?0.01). We, therefore, concluded that the measurement of serum CRP concentrations was a fast and accurate method to distinguish between cancer and immune disease patients.     

Pancreatic Cancer Genetics

Although relatively rare, pancreatic tumors are highly lethal [1]. In the United States, an estimated 48,960 individuals will be diagnosed with pancreatic cancer and 40,560 will die from this disease in 2015 [1]. Globally, 337,872 new pancreatic cancer cases and 330,391 deaths were estimated in 2012 [2]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving; in the US, it is predicted to become the second leading cause of cancer related deaths by 2030 [3, 4]. The vast majority of tumors arise in the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of tumors. Tumors arising in the endocrine pancreas (pancreatic neuroendocrine tumors) represent less than 5% of all pancreatic tumors [5]. Smoking, type 2 diabetes mellitus (T2D), obesity and pancreatitis are the most consistent epidemiological risk factors for pancreatic cancer [5]. Family history is also a risk factor for developing pancreatic cancer with odds ratios (OR) ranging from 1.7-2.3 for first-degree relatives in most studies, indicating that shared genetic factors may play a role in the etiology of this disease [6-9]. This review summarizes the current knowledge of germline pancreatic cancer risk variants with a special emphasis on common susceptibility alleles identified through Genome Wide Association Studies (GWAS).     

ADAMl0在胰腺癌患者血清中表达及其临床意义

目的：探讨ADAM10在胰腺癌患者外周血中的表达及其临床意义。方法：应用酶联免疫吸附试验法（ELISA）检测40例胰腺癌患者和20例健康体检者的外周血ADAM10的表达水平,分析其与临床病理特征的关系。结果：胰腺癌患者血清ADAM10水平显著高于正常对照组（P〈0.01）;胰腺癌患者血清中ADAM10的表达水平与胰腺癌淋巴结转移、远处转移及TNM分期密切相关（P〈0.05）,且行根治性手术切除的胰腺癌患者ADAM10表达水平低于姑息性手术切除的患者（P〈0.05）;ADAM10对胰腺癌诊断的敏感度、特异性分别为51.7%、76.9%,联合检测CA19-9有助于提高胰腺癌诊断敏感度,但特异性有所下降;根治性切除后胰腺癌患者血清中ADAM10水平明显下降。结论：胰腺癌癌患者血清中ADAM10水平明显增高,检测血清ADAM10有助于胰腺癌的诊断和治疗。     

Inhibition of Amyloid Precursor Protein Processing Enhances Gemcitabine-mediated Cytotoxicity in Pancreatic Cancer Cells

Pancreatic adenocarcinoma or pancreatic cancer is often diagnosed at a very late stage at which point treatment options are minimal. Current chemotherapeutic interventions prolong survival marginally, thereby emphasizing the acute need for better treatment options to effectively manage this disease. Studies from different laboratories have shown that the Alzheimer disease-associated amyloid precursor protein (APP) is overexpressed in various cancers but its significance is not known. Here we sought to determine the role of APP in pancreatic cancer cell survival and proliferation. Our results show that pancreatic cancer cells secrete high levels of sAPPα, the α-secretase cleaved ectodomain fragment of APP, as compared with normal non-cancerous cells. Treatment of cells with batimastat or GI254023X, inhibitors of the α-secretase ADAM10, prevented sAPPα generation and reduced cell survival. Additionally, inhibition of sAPPα significantly reduced anchorage independent growth of the cancer cells. The effect of batimastat on cell survival and colony formation was enhanced when sAPPα downregulation was combined with gemcitabine treatment. Moreover, treatment of batimastat-treated cells with recombinant sAPPα reversed the inhibitory effect of the drug thereby indicating that sAPPα can indeed induce proliferation of cancer cells. Down-regulation of APP and ADAM10 brought about similar results, as did batimastat treatment, thereby confirming that APP processing is important for growth and proliferation of these cells. These results suggest that inhibition of sAPPα generation might enhance the effectiveness of the existing chemotherapeutic regimen for a better outcome.     

Clinical Analysis of 36 Cases of Autoimmune Pancreatitis in China

Background

To improve the early identification of autoimmune pancreatitis in China by a retrospective analysis of clinical data from AIP patients.

Methodology/Principal Findings

The analysis included 36 patients admitted by the surgery department of our hospital from January 2003 to October 2011 whose postoperative pathological confirmations were consistent with the histological criteria of Honolulu Consensus Document. The clinical phenotypes associated with the histopathologic patterns of LPSP and IDCP were referred to as type 1 and type 2 of AIP, respectively. A retrospective analysis of clinical features, serological data, pathological findings and imageological records was performed in line with the subtypes of AIP. Type 1 showing a sex predilection (males) was commonly more dominant than type 2 in all AIP. Type 2 without a gender predilection was, on average, a decade younger than type 1. Type 1 was inferior to type 2 in ALT, ALP and γ-GT with statistical significance (P = 0.044, 0.025 and 0.013). Type 1 was inferior to type 2 in AST with difference close to statistical significance (P = 0.072). Histopathology revealed frequent lymphoplasmacytic infiltration with less frequent infiltration of neutrophils, eosinophils and fibroblasts. Diffuse and intensive interstitial fibrosis could be seen. The changes of pancreatic head were more frequently seen in type 2 than in type 1 (P = 0.05). Plasma cells staining of IgG4 at a density of over 30 or more cells per high-power field appeared to be a specific finding in China with type 1. Imageology found a diffusely or focally enlarged pancreas, most frequently a mass or enlargement in the pancreatic head, characteristic capsule-like rim, calcification or pancreatic calculus and cystic degeneration.

Conclusions/Significance

AIP is a unique type of chronic pancreatitis and has distinctive serological, pathological and imageological characteristics, which should be used for differentiation from pancreatic cancer.     

未折叠蛋白反应在胰腺癌发生发展中的作用及意义

胰腺癌是一种致死率相当高的消化系统肿瘤，其起病隐蔽导致早期诊断困难。近期研究发现，内质网应激 (endoplasmic reticulum stress，ERS) 状态下的未折叠蛋白反应 (unfolded protein response，UPR) 通路的调节作用，对于胰腺癌发生发展至关重要。UPR通路伴侣蛋白 GRP78 抑制了胰腺导管腺癌 (pancreatic adenocarcinoma，PDAC)细胞的凋亡，并增强了其化学抗性和耐药性。而 UPR 途径及其调节因子对于血管内皮生长因子 (vascular endothelial growth factor，VEGF) 的调节作用，有助于胰腺癌抵抗缺血缺氧环境。尝试靶向 UPR 途径关键调节因子的药物来控制胰腺癌的研究，可以为胰腺癌的治疗开辟新的途径。本文通过对近年来 UPR 在胰腺癌发生发展中的作用及意义进行综述，希望为通过调控 UPR 通路作为针对治疗胰腺癌的关键过程的一种新型抗癌方法研究提供参考。     

未折叠蛋白反应在胰腺癌发生发展中的作用及意义

胰腺癌是一种致死率相当高的消化系统肿瘤,其起病隐蔽导致早期诊断困难。近期研究发现,内质网应激 (endoplasmic reticulum stress,ERS) 状态下的未折叠蛋白反应 (unfolded protein response,UPR) 通路的调节作用,对于胰腺癌发生发展至关重要。UPR通路伴侣蛋白 GRP78 抑制了胰腺导管腺癌 (pancreatic adenocarcinoma,PDAC)细胞的凋亡,并增强了其化学抗性和耐药性。而 UPR 途径及其调节因子对于血管内皮生长因子 (vascular endothelial growth factor,VEGF) 的调节作用,有助于胰腺癌抵抗缺血缺氧环境。尝试靶向 UPR 途径关键调节因子的药物来控制胰腺癌的研究,可以为胰腺癌的治疗开辟新的途径。本文通过对近年来 UPR 在胰腺癌发生发展中的作用及意义进行综述,希望为通过调控 UPR 通路作为针对治疗胰腺癌的关键过程的一种新型抗癌方法研究提供参考。     

S100A4在胰腺癌中的研究进展

胰腺癌最重要的生物学特性是容易发生转移和侵袭,致使很多患者无法得到根治性治疗。外科手术是胰腺癌惟一可能治愈的手段,但仅有10-20%的患者有机会手术治疗。错过早期诊断、常规疗法普遍不明显及快速肿瘤扩散共同导致患者的预后不良。胰腺癌的发生、发展受多基因调控。S100A4基因是近几年发现的一种具有促肿瘤作用的基因,目前研究认为该蛋白在胰腺癌的侵袭和转移中起重要作用.本文主要就S100A4与胰腺癌的有关研究进展加以综述。     

XIAP在胰腺癌化疗耐药及治疗中的研究进展

X连锁的凋亡抑制蛋白(X-linked inhibitor of apoptosis protein,XIAP)是凋亡抑制蛋白家族中的一员,具有抗凋亡作用.研究发现XIAP在胰腺癌中呈高表达,并且能诱导胰腺癌细胞及组织对化疗耐药.通过在基因水平及蛋白水平降低XIAP的表达对胰腺癌的治疗具有重要意义.AEG 35156是针对XIAP的反义寡核苷酸分子,能够抑制胰腺癌细胞及组织生长.RNAi能够稳定下调胰腺癌细胞中XIAP水平,从而加强TRAIL诱导的细胞凋亡,并能提高胰腺癌细胞对化疗的敏感性.针对XIAP的小分化合物能够抑制XIAP的功能,释放被XIAP抑制的凋亡起始和效应分子以及XIAP抑制的其他促凋亡蛋白,提高多种肿瘤细胞的凋亡指数及对放化疗的敏感性.XAFl能抑制XIAP的抗凋亡作用.本文就XIAP在胰腺癌化疗耐药及治疗中的研究进展做一综述.     

S100A4 在胰腺癌中的研究进展

胰腺癌最重要的生物学特性是容易发生转移和侵袭,致使很多患者无法得到根治性治疗。外科手术是胰腺癌惟一可能治愈的手段,但仅有10-20%的患者有机会手术治疗。错过早期诊断、常规疗法普遍不明显及快速肿瘤扩散共同导致患者的预后不良。胰腺癌的发生、发展受多基因调控。S100A4基因是近几年发现的一种具有促肿瘤作用的基因,目前研究认为该蛋白在胰腺癌的侵袭和转移中起重要作用.本文主要就S100A4与胰腺癌的有关研究进展加以综述。