Early diagnosis of pancreatic canc讲义er：胰腺癌的早期诊断

FFOR SEVERAL MONTHS, Peter Janko, 66, has been bothered by abdominal gas and diarrhea. Over the past few weeks he’s also had intermittent epigastric pain that tends to worsen after eating. His primary care provider orders an ultrasound of the abdomen, which shows a vague density in the pan-creas. Mr. Janko then has a com-puted tomography (CT) scan of the abdomen, which confirms a 4-cm mass in the body of the pancreas.These findings raise a high sus-picion of pancreatic cancer. In this article, I’ll detail how this insidious malignancy develops, the diagnos-tic and treatment options, andwhat you can do to help Mr. Janko.Many vital functionsThe pancreas is a spongy , tube-shaped gland lying obliquely behind the stomach. (See Putting the pancreas in perspective .) An endocrine gland, it produces hor-mones: insulin and glucagon. Also an exocrine gland, it produces pan-creatic enzymes that aid digestion of protein, carbohydrates, and fat.Because the pancreas performs such critical functions, disease there wreaks havoc on other body processes. For example, a patient with pancreatic disease has a high risk of developing diabetes mellitus and malabsorption syndrome.The American Cancer Society (ACS) predicts approximately 37,170 new cases of pancreatic cancer and 33,370 deaths due to this malignancy in the United States in 2007.1It ranks as the fourth leading cause of cancer death in this country . Yet although the mortality rate is high, the etiol-ogy is poorly understood.Risk factors for pancreatic can-cer include the following 1: • advanced age.The diagnosis is most common in people between ages 65 and 79.• cigarette smoking.Smokers devel-op pancreatic cancer more than twice as often as nonsmokers.• diet.A high intake of red meat and pork—especially processed meat such as bacon—has been associated with the disease.• medical history .This malignancy is more common among people with a history of cirrhosis, chronic pancreatitis, or diabetes.• environmental factors.Long-term exposure to certain chemicals,such as gasoline and related com-pounds and certain insecticides,may increase the risk.• genetic predisposition.In up to 10% of pancreatic cancers, inheri-tance may be a factor.• obesity .Very overweight people are 20% more likely to develop pancreatic cancer.Indigestion, pain, and moreEarly signs and symptoms of pan-creatic cancer, typically vague and nonspecific, depend on the loca-tion of the tumor and the type of surrounding tissue mon complaints include indigestion, gas, and abdominal pain.Signs and symptoms that are more specific to pancreatic cancer develop later and reflect loss of pancreatic function or invasion or obstruction of nearby structures.According to the ACS, pain in the abdomen or back is a very com-mon sign of advanced pancreatic cancer.1Your patient may describe persistent epigastric pain as severe and radiating to his back. Addi-tional late signs and symptoms include jaundice, nausea, diarrhea,constipation, excessive amounts of fat in the stool (steatorrhea), and hyperglycemia. Because pancreatic cancer is usually advanced before diagnosis, the prognosis is poor.(See Why cure is difficult .)Depression can be a late symp-tom of pancreatic cancer too.A patient with this devastating diseaseneeds plenty of support.Learn how you can help him manage thedisease and its complications.BY MARIE RIEHL, RN, OCNHelp your patient cope withpancreatic cancerWhether it’s related to release of circulating tumor cells or to the patient’s understanding of his poor prognosis is unclear.Reaching a diagnosisDiagnosis of pancreatic cancer is usually based on the patient’s histo-ry and symptoms, physical exami-nation, and identification of a mass on abdominal ultrasound or a CT scan. Another diagnostic study ,endoscopic retrograde cholangio-pancreatography , may provideimages of stenosis or obstruction of the common bile or pancreatic duct and offers the option of get-ting a biopsy specimen.T echnical improvements have led to the development of endo-scopic ultrasonography (EUS),which is useful for getting tissue for diagnosis and providing infor-mation on tumor size and type,location, and possible paroscopy , also used for diagno-sis and staging, lets the surgeon identify peritoneal or liver metas-tases. An EUS with biopsy shows that Mr. Janko has an adenocarci-noma of the pancreas.Once the diagnosis is made,positron emission tomography and magnetic resonance imaging can help stage the disease and deter-mine treatment. The American Joint Committee on Cancer staging criteria for adenocarcinoma of the pancreas appear in Staging pancre-atic cancer .2However, because pre-cise staging isn’t possible without surgery , clinicians commonly group cancers according to the likelihood of successful surgical removal:• resectable:localized to the pan-creas• locally advanced, unresectable:local spread prevents removing the cancer but surgery may relieve problems such as obstruction ofPutting the pancreas in perspectiveAbout 6 inches long, the pancreas consists of glandular tissue.Surgery for pancreatic cancer can be very complex. It may involve removing part of the pancreas, the distal third of the stomach, the gallbladder, the cystic duct and common bile duct, the duodenum, part of the jejunum, and surrounding lymph nodes.The headof the pancreas is on the right side of the abdomen,tucked within the curve of the duodenum.The bodyis located anterior to the first and second lumbar vertebrae.The tail ,extending to the left side of the abdomen, touches the spleen ante-rior to the superior pole of the left kidney.The pancreatic duct ,through which pancreatic enzymes flow, joins with the common bile duct at a short, dilated tube called thehepatopancreatic ampulla(ampulla of Vater), which emptiesinto the duodenum.LiverGallbladder Cystic ductCommon bile duct Ampulla of VaterStomachSpleenDuodenumHepatic ductthe bile duct or intestinal tract • metastatic:distant spread, but surgery may relieve symptoms. Surgery, chemotherapy, radia-tion therapy, or a combination are options for treating pancreatic cancer.Complex surgeryOnly 8% to 20% of patients with pancreatic cancer are candidates for resection.1,3The nature and extent of surgery depend on tumor location and size, regard-less of whether metastases are present. In most cases, a pancre-aticoduodenectomy or “Whipple procedure” is performed by sur-geons who are specially trained and experienced at this very complex procedure. When per-formed in smaller hospitals by less-experienced surgeons, the procedure is associated with high intraoperative and postoperative morbidity and mortality.The Whipple procedure involves removing the distal third of the stomach, the gallbladder, the cystic and common bile duct, the head of the pancreas and pos-sibly parts of the body and tail, the duodenum, proximal 10 cm of the jejunum, and the superior mesen-teric, peripancreatic, and hepato-duodenal lymph nodes. A patient whose tumor is in the tail of the pancreas may undergo a distal pancreatectomy in which the tail of the pancreas, a portion of the body of the pancreas, possibly the spleen, and surrounding lymph nodes are removed. Postoperative nursing care Immediately after surgery, your patient will be N.P.O. and have a nasogastric tube, an indwelling urinary catheter, and a biliary drainage tube in place. Key post-operative nursing measures include pain control and moni-toring for signs and symptoms ofbleeding, bile leaks, and infec-tion.• Closely monitor his level of con-sciousness and vital signs.• Obtain lab tests as ordered andmonitor the results. Postoperativeblood work typically includes acomplete blood cell count, a com-prehensive metabolic panel, a liverprofile, and coagulation studies.(Most patients receive postopera-tive prophylaxis against venousthromboembolism.)• Monitor your patient’s fluidbalance by accurately measuringand documenting his intake andoutput.• Assess the amount and character-istics of his biliary tube drainage.• As his diet is advanced from clearliquid to house diet, assess forsigns and symptoms of malabsorp-tion, which may result from thetumor blocking release of pancreat-ic enzymes or a postoperative de-crease in enzyme release. Fatigue,flatulence, diarrhea, bloating,cramping, and weight loss mayindicate malabsorption syndromeand call for assessment of the pa-tient’s nutritional status.• Assess for signs and symptoms ofa bile leak at the anastomosis creat-ed during surgery. They include ab-dominal pain, fever, and peritonitis.• T each your patient the signs andsymptoms of malabsorption andwhy he’ll need to use prescriptionpancreatic enzymes. Emphasizethe importance of taking enzymesupplements with meals andsnacks to aid absorption of fatsand proteins.• If he’s had a total pancreatecto-my, administer insulin as ordered.Reinforce his education with acertified diabetes educator byreviewing how to monitor hisblood glucose levels and remind-ing him that he’ll need to useinsulin for the rest of his life. Staging pancreatic cancerFew patients with pancreatic cancer undergo surgical resection of the pancreas and adjacent lymph nodes, so the American Joint Committee on Cancer’s tumor, node, metastasis classification combines both clinical and pathologic features in order to help clinicians plan appropriate treatment.Primary tumor (T)TX Primary tumor can’t be assessedT0No evidence of primary tumorTis Carcinoma in situT1Tumor limited to the pancreas, 2 cm or less in greatest dimensionT2Tumor limited to the pancreas, more than 2 cm in greatest dimensionT3Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric arteryT4Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)Regional lymph nodes (N)NX Regional lymph nodes can’t be assessedN0No regional lymph node metastasisN1Regional lymph node metastasisDistant metastasis (M)MX Distant metastasis can’t be assessedM0No distant metastasisM1Distant metastasisSource: American Joint Committee on Cancer, Chicago, Ill.2How chemotherapy and radiation help Chemotherapy and radiation therapy may be indicated for patients with pancreatic cancer that’s considered too far advanced for surgery. Neoadjuvant(preoper-ative) therapy is given to increase the opportunity for surgical resec-tion and to improve overall sur-vival. A few studies suggest that neoadjuvant chemotherapy and radiation therapy can convert selected patients with unre-sectable disease to a resectable status or increase the overall suc-cess rate of resection. Adjuvant (postoperative) therapy is an option for patients whose disease is resectable.Therapy typically consists of a 5- to 6-week course of external beam radiation to the tumor site plus chemotherapy using either fluorouracil or gemcitabine. Fluorouracil is the conventional option for managing unresectablelocal regional pancreatic cancer.Second-line chemotherapy mayconsist of gemcitabine in patientsnot previously treated with thisagent. Gemcitabine may be com-bined with cisplatin, oxaliplatin,or irinotecan when standardfrontline therapy has failed. (SeeDrug News on page 28 for the lat-est on gemcitabine.)If your patient is about to starttreatment with chemotherapy orradiation, teach him about poten-tial adverse reactions, such asnausea, diarrhea, poor appetite,fatigue, and bone marrow sup-pression possibly leading to infec-tion. Focus your teaching onmanaging these signs and symp-toms.Advise your patient to drinkplenty of fluids and to report anyvomiting or diarrhea. Explain thathe may experience signs andsymptoms of malabsorption andteach him to manage them withsupplemental pancreatic enzymes.Encourage him to ask questionsand to attend classes or supportgroups for patients planning tostart chemotherapy. (Look for sup-port groups at the PancreaticCancer Action Network Web site,.)Manage pain andprovide supportPancreatic cancer can cause bothacute and chronic pain.T ell yourpatient that pain control is a highpriority in his care and review theoptions, which include medicationand nonpharmacologic measuresto help maintain his quality of life.He may receive long-acting opioidsfor chronic pain and medicationsfor breakthrough pain preopera-tively and postoperatively. Celiacplexus nerve blocks—injectingcorticosteroids and analgesic med-ications intraoperatively or endo-scopically—provide very effectivetemporary pain relief.The diagnosis of pancreaticcancer can frighten and over-whelm your patient and his fami-ly. Support them throughout deci-sion making and guide them toappropriate resources. For exam-ple, knowing he’s at risk fordepression and may experienceanticipatory grieving, refer himand his family to social servicesand support groups. If he’s aboutto stop active treatment, speakwith them about the benefits ofhospice care and arrange for avisit with a hospice representativeif he’s willing.Facing many challengesA patient with pancreatic cancermust face many challenges. Byunderstanding the implications ofhis disease and its treatments, youcan help him throughout diagnosisand treatment and may provide theguidance he needs for end-of-lifecare.‹›REFERENCES1. American Cancer Society. Pancreatic cancer./116.00/116.00.pdf.Accessed January 17, 2007.2. Greene FL, et al. (eds). AJCC Cancer StagingManual,6th edition. New York, N.Y., Springer-Verlag, 2002.3. DeOliveira ML, et al. Assessment of complica-tions after pancreatic surgery: A novel gradingsystem applied to 633 patients undergoing pan-creaticoduodenectomy. Annals of Surgery.244(6):931-939, December 2006.RESOURCESCasciato DA. Manual of Clinical Oncology, 5thedition. Philadelphia, Pa., Lippincott Williams &Wilkins, 2004.Coleman J, et al. The effect of a frequently askedquestions module on a pancreatic cancer Website patient/family chat room. Cancer Nursing.28(6):460-468, November/December 2005.DeVita VT, et al. (eds). Cancer: Principles & Prac-tice of Oncology,7th edition. Philadelphia, Pa.,Lippincott Williams & Wilkins, 2005.Itano JK, Taoka KN. Core Curriculum for Oncol-ogy Nursing,4th edition. Philadelphia, Pa., W.B.Saunders, 2005.Shaheen NJ, et al. The burden of gastrointestinaland liver diseases, 2006. American Journal of Gas-troenterology.101(9):2128-2138, September 2006.Marie Riehl is a staff nurse in the ambulatory caredepartment at Fox Chase Cancer Center inPhiladelphia, Pa.Why cure is difficultPancreatic cancer is most curable when the tumor is localized to the pancreas. Yet only 18% to 24% of patients with localized disease, a tumor less than 2 cm, no lymph node metastases, and no extension beyond the capsule of the pancreas survive 5 years after undergoing complete surgical resection. Whether the cancer affects exocrine (most cases) or endocrine (islet cell) tissue plays an important role in survival. Patients with endocrine tumors have a more favorable prognosis.Pancreatic cancer is rarely found early for these reasons:• The pancreas is located behind the stomach so early tumors can’t be palpated.• Currently, no reliable screening tests are readily available.• Patients typically don’t develop signs and symptoms until the can-cer has spread to other organs.。

Bob Barrett: This is the podcast from Clinical Chemistry. I am BobBarrett.Early cancer detection before metastasis inasymptomatic patients is one of the primaryobjectives of cancer research initiatives. Earlydetection generally means more opportunities forintervention that ultimately lead to improvements inpatient outcomes.The January 2013 issue of Clinical Chemistry isdevoted to the area of cancer and cancer diagnostics.Joining us in this podcast is Dr. Danijela Konforte,author of a perspective article, asking if earlydetection of cancer with circulating biomarkers isfeasible.Dr. Konforte is a graduate of the postdoctoraldiploma program in Clinical Chemistry at theUniversity of Toronto, and is currently a clinicalbiochemist at LifeLabs, a community laboratory inToronto.Doctor, many blood-based cancer biomarkers arecommonly used in clinical practice for riskstratification, prognosis, surveillance, and formonitoring therapy, but effective blood-basedbiomarkers for early diagnosis of cancer, those arelacking. Why are biomarkers for early detection ofcancer so important?Dr. Danijela Konforte: Well, detecting any disease early, including cancer, isvery important because it usually means moreopportunities for different interventions andtherapies, with increased potential for improvingpatient survival and quality of life.For instance, there are many studies that haveshown that early detection of breast cancer in womenover 50 years of age with annual mammogramscreening programs, improved survival by about 20-25%.Also patients at stage one ovarian cancer detected bytransvaginal ultrasound, have a five-year survivalrate of about 93% compared to only 30% forpatients with stage 3 to stage 4 disease at diagnosis.Some other examples of cancer screening proceduresand biomarkers that have considerably improvedpatient outcomes, include Pap tests and nowmolecular tests for cervical cancer, colonoscopy,sigmoidoscopy, and fecal occult blood test for coloncancer, blood human chorionic gonadotropin or hCGfor testicular cancer and for gestational trophoblasticdisease, and also blood alpha-fetoprotein or AFP inthose people who are at high risk of developinghepatocellular carcinoma.Bob Barrett: What criteria should a circulating biomarker for earlydetection of cancer fulfill?Dr. Danijela Konforte: As you mentioned in your introduction, Bob, only afew tumor biomarkers in clinical use are suitable forpopulation screening and for early diagnosis.So a biomarker test for early detection of cancershould be sufficiently sensitive and specific, and hereI refer to both diagnostic and analytical sensitivityand specificity. Also it should be relativelyinexpensive and safe to be applied to masspopulations. It should also be relatively non-invasiveand provide sufficient lead time.A lead time is the time interval from screen detectedcancer to clinical diagnosis in the absence of suchscreening. So in other words it is the time betweenasymptomatic disease and metastasis. The lead timefor early cancer detection using a blood biomarkerdepends on the growth trajectory of a cancer.An aggressive tumor will have a significantly shorterlead time than a slow progressing tumor. Usuallyimproved lead time means more effectiveinterventions which leads to improved diseaseoutcomes and improved survival.Another important requirement for bringing blood -based biomarker into routine clinical use isdeveloping a high throughput, easy-to-use laboratorytest to reproducibly and accurately measure suchbiomarker.In addition to these requirements, clinical benefitsprovided by the tumor marker should clearlyoutweigh any potential harm. Two examples are overdiagnosis and over treatments of indolent cancersthat will not lead to symptoms or cause death.Another potential harm is the lead time bias, and thisrefers to early diagnosis of a cancer that does notlead to improved survival.One good example of a blood biomarker for earlycancer detection whose benefits and harms are stillhotly debated is Prostate Specific Antigen or PSA.There is still not sufficient evidence to definitelyanswer the question of whether early detection ofprostate cancer always improves quality of lifeand/or patient survival.Bob Barrett: Well, given this long list of requirements, howfeasible is it to identify circulating biomarkers forearly detection of cancer?Dr. Danijela Konforte: This is exactly the question that researchers SharonHori and Sanjiv Gambhir from Stanford UniversitySchool of Medicine tried to tackle in their articlepublished in Journal Science Translational Medicine atthe end of 2011.The first objective of this study was to usemathematical modeling to quantify the time requiredfor growing malignant tumor to reach a sufficient sizeso that its blood biomarker levels can be detected bycurrently available blood tests.Ovarian cancer and CA-125 biomarker were used toprovide realistic baseline values for model simulation.Ovarian cancer was chosen because it remainsrelatively asymptomatic until advanced and there is asignificant opportunity for improvements in earlydetection.CA-125 is considered a gold standard biomarker testfor surveillance of women with epithelial ovariancancer. It is not a screening test, but the mainadvantage is that it has been sufficiently studied withall the required model parameter values availablefrom the literature.The second object of the study by Hori and Gambhirwas to use the model to identify biomarker relatedparameters that most greatly affect early cancerdetection, and also quantifies through simulationshow much each baseline parameter value has tochange to achieve early tumor detection.Tumor biomarker parameters that were tested in themodel included grade of tumor biomarker sheddinginto the blood, tumor marker clearance, and thepercentage of the tumor volume consisting of tumorcells.They also modeled in analytical sensitivity ofclinically available biomarker tests. The authorschose a solid tumor with the diameter of onemillimeter as their goal for early detection. This isquite an ambitious goal in my opinion and I will comeback to this point a bit later in the discussion.Briefly, the model was designed to predict changes inthe blood biomarker levels as a function of time, andto relate them to the corresponding tumor burden,meaning tumor volume or tumor diameter.Two growth models were used in the study. The firstmodel assumed exponentially growing tumor,starting from its genesis. The second and morephysiologically plausible model assumed both mono-exponential growth as well as tumor decay.For each growth model the authors tested twoscenarios. In one scenario a biomarker was 100%tumor specific, and in the other, a biomarker wassecreted by both tumor and normal self.So here I described a study model in very broadstrokes and I would like to encourage our listeners toread the original article for more details on thespecifics of the mathematical model used.Bob Barrett: Well, let’s get to the last page of that, can yousummarize the main findings of that study by Horiand Gambhir?Dr. Danijela Konforte: Well, the simulation based analysis identifiedparameters that are useful in improving early cancerdetection, and those are tumor marker sheddingrates, biomarker specificity, and assay analyticalsensitivity.Importantly, the study also identified parametersthat do not improve early detection, and those arefraction of the biomarker reaching bloods, and ratesof its elimination from the circulation.In addition the model quantified how far theparameters I have just mentioned must be perturbedto achieve early--in this case, submillimeter--detection of cancer.So the estimated time until detection by current CA-125 test was found to be 10.6 to 12.6 years at whichpoint ovarian tumor is about 4 centimeters indiameter and this agrees with what is currently seenwith the transvaginal ultrasound process.According to the model to detect a tumor with adiameter of 1 millimeter would require a biomarkerthat is almost 100% tumor specific, and hasshedding rates of about 10,000 times higher thanthat of any known protein tumor biomarker.Additionally, further improvements in the analyticalsensitivity of current clinical assays by 10,000 foldwould also be required. This way the tumor would bedetected in 5.6 years which would provide us reallywith about 4 to 6 years of lead time advantage overcurrent detection methods.Collectively as you can see these results indicate thatit may not be feasible to use a single circulatingbiomarker for early detection of cancer.Bob Barrett: Every study has its limitations, what are thelimitations of this study?Dr. Danijela Konforte: Well direct extrapolation of the model predictions tothe clinical use is hard to validate for severalreasons. One, tumor age cannot be accuratelymeasured at clinical diagnosis.And two, there are no patient data correlating tumorsize with blood biomarker levels either before andafter cancer diagnosis or for multiple time pointsthroughout the natural course of disease progression.So this relationship between tumor size and bloodbiomarker levels that the model is based on is notreally well understood.The model may not be useful for cancers whoseparameters are not available from the literature, i.e.those cancers that haven’t been extensivelyresearched like ovarian cancer. This means a lot ofassumptions have to made in the modeling itself.A target of one millimeter for early detection that theauthor sets, may not be applicable or even necessaryin my opinion for every type of cancer. The onemillimeter target is more appropriate for earlydetection of an aggressive tumor with a shortdoubling time, than for a slow growing indolenttumor with a long doubling time.So a small improvement in early detection will affectthe lead time of indolent tumors much moreappreciably than that of aggressive tumors.I think that the goals of early cancer detection stillneed to be debated among researchers andclinicians, so when selecting criteria for a bloodbiomarker of interest, researchers have to considerthe type of cancer and its aggressiveness.Bob Barrett: How do you think the international researchcommunity can benefit from this and similarmathematical models in their efforts to identify thosebiomarkers for early detection of cancer?Dr. Danijela Konforte: I think models like this can be used to address thepotential and limitations of tumor biomarkers in theearly investigative stages. They can certainly helpresearchers to identify criteria for prioritizingbiomarkers.For example, some may be more feasible to studythan others. This can not only save time, but canalso help focus valuable resources that are so difficultto come by these days.Furthermore, mathematical models like this one canbe used to perform simulations quickly across a widerange of biomarker related parameters.Such simulations can also encompass the large inter-and intra- individual biomarker variation, in otherwords biological variability, that may exist for sometypes of cancer, and would make the modelgeneralizable for any solid cancer that secretes thebiomarker into circulation.With the current version of this model, only one ortwo tumor related parameters can be manipulated ata time. Future versions should include simulationsthat are simultaneous of multiple parameters. Myhope also is that models like this will be freelyavailable to the researchers.Bob Barrett: Well finally, doctor, where do you think researchersshould aim their efforts in order to make blood basedbiomarkers for early detection of cancer a reality?Dr. Danijela Konforte: I think the study by Hori and Gambhir clearly showsthat mathematical models can be important tools inthe evaluation of relevant parameters of bloodbiomarkers for early detection of cancer.However, we have to understand that the models areas good as the assumptions they are based on, andas good as the baseline clinical parameters obtainedfrom biological data which are used in simulationstudies.So what is needed in the future? For one I think weneed to expand our knowledge of the natural processof cancer initiation and progression. We need to domore research to better understand how tumor sizerelates to biomarker blood levels.For instance what are in vivo biomarker sheddingrates, what are the effects of tumor micro-environment on those shedding rates? What fractionof biomarker is reaching the blood, and how do theseparameters change with time?These findings will clearly lead to development ofmulti-scale predictive mathematical models that canmore accurately select characteristics of biomarkersthat are necessary to improve early detection.Also advancements in the areas such as nanotechnology will help improve much needed analyticalsensitivity of tumor biomarker assays.We usually talk about protein biomarkers. However,the research should also include non-protein bloodbiomarkers such as tumor specific microRNAs,epigenetic biomarkers, mitochondrial DNA markers,post translational modification, as well as anti-tumorimmune response markers.As this study showed it may not be feasible to rely ona single blood test for early detection of cancer. Acombination of a panel of circulating biomarkers anddiagnostic imaging procedures is more likely to dothe job.Bob Barrett: Dr. Danijela Konforte is a Clinical Biochemist atLifeLabs, a community laboratory in Toronto. She hasbeen our guest in this podcast from ClinicalChemistry. I am Bob Barrett, thanks for listening.。

Chinese guidelines for diagnosis and treatment of pancreatic cancer2018(English version)National Health Commission of the People's Republic of Chinadoi：10.21147/j.issn.l000-9604.2019.02.03View this article at:https:///!0.21147/j.issn」000-9604.2019.02.03Contents1.Introduction2.Diagnostic techniques and applications2.1Risk factors for pancreatic cancer2.2Clinical manifestations2.3Physical examination2.4Radiological examinations2.4.1Ultrosound2.4.2Computed tomography(CT)2.4.3Magnetic resonance imaging(MRI)and magneticresonance cholangio-pancreatography(MRCP)2.4.4Positron emission tomography-CT(PET-CT)2.4.5Endoscopic ultrasonography2.4.6Role of ERCP in the diagnosis of pancreatic cancer2.4.7Cytology diagnosis via ERCP2.4.8ERCP combined with intraductal ultrasound(IDUS)2.4.9Bone scans2.5Blood immunologic and biochemical examinations2.5.1Blood biochemical examinations2.5.2Serum tumor markers tests2.6Histologic and cytological diagnosis2.6.1Cytological pathology diagnosis2.6.2Histopathology diagnosis of pancreatic cancer2.6.3Immunohistochemistry2.6.4Pathologic reports2.7 Differential diagnosis of pancreatic cancer2.7.1Chronic pancreatitis2.7.2Carcinoma of ampulla2.7.3Pancreatic cystadenoma and cystadenocarcinoma2.7.4Choledocholithiasis2.7.5Other lesions of pancreas3.ClassiHcation and staging of pancreatic cancer3.1Histologic classification of pancreatic cancer3.2Staging of pancreatic cancer(AJCC,the8th edition)3.2.1Definition of T,N and M in pancreatic TNM staging3.2.2TNM staging for pancreatic cancer4.Management of pancreatic cancer4.1Principles4.2 Surgery4.2.1Principles of surgery4.2.2Preoperative biliary drainage4.2.3Indications for radical resection4.2.4Operation methods4.2.5Pancreatic anastomosis4.2.6Perioperative drug management4.2.7Management principles of postoperativecomplications4.2.8Surgical management of potentially resectablepancreatic cancer4.2.9Surgical management of locally advancedunresectable pancreatic cancer4.3Medical treatment4.3.1Chemotherapy effect for pancreatic cancer4.3.2Chemotherapy strategies for pancreatic cancer 4.4Radiotherapy4.4.1Indications for pancreatic cancer radiotherapy4.4.2Radiotherapy techniques4.4.3Radiotherapy target area4.4.4Radiotherapy dose4.4.5Concurrent chemotherapy4.4.6Intraoperative radiotherapy4.5ERCP and related treatment4.5.1ERCP for preoperative biliary drainage inpancreatic cancer4.5.2Application of ERCP in unresectable pancreaticcancer4.6Interventional therapy4.6.1Principles of intervention therapy4.6.2Transarterial infusion chemotherapy4.6.3Ablation therapy4.6.4Interventional therapy for pancreatic cancercomplications4.7Supportive care4.7.1Pain control4.7.2Nutritional status improvement4.8Traditional Chinese medicine treatment forpancreatic cancer5.Diagnosis and treatment flowchart and follow-up5.1Diagnosis and treatment flowchart for pancreatic cancer 5.2Follow-upChinese Journal of Cancer Research,Vol31,No2April2019279*1.IntroductionPancreatic ductal adenocarcinoma is one of the common pancreatic neoplasms,with extremely high malignancy. The latest statistical data from National Cancer Center of China showed that the incidence of pancreatic cancer had increased dramatically from2000to2011.In2015,the incidence of pancreatic cancer in China ranked ninth among malignant tumors,and the mortality rate was the sixth in malignant tumors.Recently,with the development of radiology,endoscopy and pathology,the diagnosis of pancreatic cancer has been improved;w让h the development of new concept and technology of surgery(such as laparoscopy and robotics), locoregional therapy methods(such as stereotactic body radiation therapy,nanoknife ablation and radioactive particles implantation),and ant让umor drugs[such as gemcitabine(GEM),nano albumin-bound paclitaxel,S-l, capecitabine,irinotecan,oxaliplatin and nimotuzumab], new opportunities and progress have been made for the management of pancreatic cancer.For the standard treatment of pancreatic cancer in China,this clinical practice guidelines was made.However, not all the clinical scenarios were included.2・Diagnostic techniques and applications2.1Risk factors for pancreatic cancerThe precise etiology for pancreatic cancer has never been elucidated,however,epidemiological investigation showed many risk factors.Nonhered让ary factors included long­term smoking,old age,high-fat diet,high body mass index, chronic pancreatitis or concomitant diabetes.About10% pancreatic cancer was hereditary,and these risk factors included hereditary pancreatitis,Peutz-Jeghers syndrome, familial malignant melanoma syndrome,and so on. CD K N2A,B R CA1/2and PALB2mutation have also been proved related to familial pancreatic cancer.2.2Clinical manifestationsPancreatic cancer is a very malignant tumor and progresses rapidly,but its onset is occult and its early symptoms are atypical,and most patients are diagnosed at middle to late stage.The in让ial symptoms often depend on the location and extent of the tumor,for example,obstructive jaundice may occur in early pancreatic head cancer,however, jaundice generally does not occurred in early pancreatic body and tail tumors.Major clinical manifestations include: (1)Abdominal discomfort or pain:It's a common initial symptom.The majority of pancreatic cancer patients only presented w让h epigastric discomfort or dull pain,blunt pain and flatulence,which was often confused with symptoms of gastrointestinal and hepaticobiliary diseases.If there is an obstruction of pancreatic juice outlet,pain or discomfort may be aggravated after food intaking. Persistent severe abdominal pain may occur in the middle and late stage of tumor when invading the celiac plexus. (2)Weight loss and fatigue:At the initial stage of the disease,80%-90%of pancreatic cancer patients would experience wasting,fatigue and weight loss,which was related to lack of appetite,anxiety and tumor-induced debilitation.(3)Alimentary symptoms:When the tumor blocks the lower portion of the common bile duct and pancreatic duct, bile and pancreatic fluid can not flow into the duodenum, then patients often present with dyspepsia.Impairment of pancreatic exocrine function may lead to diarrhea.When advanced pancreatic cancer invades the duodenum,it could lead to gastrointestinal obstruction or bleeding.(4)Jaundice:It's the primary clinical manifestation of pancreatic head cancer,and it's related to the obstruction of bile duct outlet.It might be accompanied by skin itching,deep brown urine and clay stool.(5)Other symptoms:Such as persistent or intermittent low-grade fever and abnormal blood glucose,but generally without biliary tract infection.2.3Physical examination(1)Weight loss:Most patients would experience cachexia at late stage.(2)Jaundice:It often occurred in pancreatic head cancer, and it's often caused by the obstruction of bile duct outle匚(3)Hepatomegaly:As a result of cholestasis or liver metastasis,the liver is hard,mostly painless,smooth or nodular.(4)Enlarged gallbladder:A cystic,smooth and removable gallbladder without tenderness may be touched in some patients,known as Courvoisier sign,which is a characteristic of periampullary carcinoma.(5)Abdominal lump:The abdominal mass can be touched at the late stage,and it's mostly located in the upper abdomen,deep,nodular,hard and irremovable.(6)Other signs:Such as supraclavicular lymph nodes enlargement,ascites,periumbilical nodes,or nodes in280Chinese guidelines for pancreatic cancerDouglas pouch in the late-stage pancreatic cancer patients.2.4Radiological examinationsTo choose the optimal radiological techniques according to patient's situation is the prerequisite for the accurate diagnosis of pancreatic lesions.The radiological examination should obey the basic rule which is entire (including the whole pancreas),dedicate(1-2mm thin slice),dynamic(dynamic enhancement,regular follow-up) and three-dimensional(multiplanar reconstruction,to evaluate the relationship w让h neighboring tissues).The pre-treatment and post-treatment radiological examination flowcharts were shown in Appendix1{Figure Al)and Appendix2(Figure A2)in detail.2.4.1UltrosoundIt's simple,noninvasive and nonradioactive,and it's an important examination methods for pancreatic cancer. Conventional ultrasound can display the internal structure of pancreas,observe the obstruction of bile duct and the location of obstruction,and find out the cause of obstruction.Color Doppler ultrasound can help to determine whether the tumor has compressed or invaded the surrounding big vessels.Real-time contrast-enhanced ultrasound can reveal the hemodynamic changes of tumors, help to differentiate and diagnose tumors of different properties,and relying on the flexibility of real-time imaging and multi-section imaging,it has advantages in evaluating tumor microvascular perfusion and guiding interventional therapy.The limitations of ultrasonography include small vision field,and interference by gastrointestinal tract gas and patient body shape,which makes it difficult to observe the pancreas completely,especially the tail of pancreas.2.4.2Computed tomography(CT)With good spatial and temporal resolution,CT is the best noninvasive imaging method for pancreatic cancer,which is mainly used in the diagnosis,differential diagnosis and staging of pancreatic cancer.Plain scan can show the size and location of the lesion,but it cannot accurately diagnose pancreatic lesions and the relationship between the tumor and the surrounding structure is shown poorly.Three-phase contrast-enhanced scan can better display the size, location,shape,internal structure and relationship with surrounding structures of the pancreatic tumor,and can accurately judge if there are liver metastases or enlarged lymph nodes.Various post-processing techniques of CT [including multiplanar reconstruction(MPR),maximum intensity projection(MIP),minimum intensity projection (MinP),shaded surface display(SSD),volume rendering technique(VRT)]can accurately provide information of pancreatic cancer itself,and of the relationship between the lesion and dilated pancreatic duct and its surrounding structures.Among them,MIP and MPR are the most commonly used post-processing techniques.In recent years,CT perfusion imaging technique is becoming more and more mature.It can reflect the blood flow and vascular characteristics of tumor quantitatively,in order to distinguish benign and malignant tumor,to evaluate the treatment response of tumor,and to predict the degree of malignancy and prognosis of tumor,etc.2.4.3Magnetic resonance imaging(MRI)and magnetic resonance cholangio-pancreatography(MRCP)MRI is not the first choice for diagnosis of pancreatic cancer.It is a complementary method for CT when it's difficult to diagnose the pancreatic lesions and it's also the alternative to CT when the patient is allergic to CT contrast medium.MRCP and multi-phase enhanced scan have advantages in qualNative diagnosis and differential diagnosis of pancreatic cancer.It has been reported that MRI can be used to diagnose occult pancreatic head carcinoma using specific tissue contrast agents.MRI can also be used to monitor pancreatic cancer and predict the recurrence,vascular invasion and the invasiveness of pancreatic cancer,which could be a predictor of survival. MRCP can clearly display the panorama of the pancreaticobiliary system and help to judge the location of the lesion,thus helping to detect and differentiate the tumors around the pared to endoscopic retrograde cholangiopancreatography(ERCP)and percutaneous transhepatic cholangiography(PTC),MRCP has the advantage of noninvasiveness.In addition,MR functional imaging can quantitatively reflect tumor metabolic information from a microscopic perspective, including diffusion-weighted imaging(DWI),perfusion-weighted imaging(PWI)and magnetic resonance spectroscopy(MRS),which should be closely combined with conventional MR sequences to play a greater role in diagnosis,differential diagnosis and treatment response evaluation of pancreatic cancer.2.4.4Positron emission tomography-CT(PET-CT)It could show the tumor metabolic activity and burden.It has obvious advantages in detecting extrapancreaticChinese Journal of Cancer Research,Vol31,No2April2019281metastasis and evaluating systemic tumor load.It is not recommended as the routine radiological examination method for the diagnosis of pancreatic cancer and it has l让tie efficacy in the diagnosis of small pancreatic cancer. PET-CT has an advantage in excluding and detecting distant metastatic lesions.It is recommended for patients w让h large primary lesions,suspected regional lymph node metastasis and significantly increased carbohydrate antigen 19-9(CAI9-9).During the follow-up after treatment of pancreatic cancer,PET-CT could differentiate between postoperative or post-radiotherapy change and local tumor recurrence.PET-CT could also help to diagnose and localize the recurrence and metastases when CA19-9level is increased,but the conventional imaging was negative. Early monitoring of the response can be achieved by changes in tumor glucose metabolism in patients who are unable to be operated and receive chemoradiation,which could provide evidences for timely changes of treatment plan and adoption of more active treatment methods.2.4.5 Endoscopic ultrasonography(EUS)It could be used to improve the sensitivity and specifity of diagnosis of pancreatic cancer,especially the EUS-guided fine needle aspiration(EUS-FNA),which is the most accurate method for the localization and qualitative diagnosis of pancreatic cancer.In addition,EUS is also helpful in tumor staging.(1)Early diagnosis:EUS is performed by inserting the probe into the stomach and duodenum,which are close to the pancreas.Because the endoscopic probe is close to the pancreas,the probe frequency is high,and the gastrointestinal gas interference is avoided,the sensitivity of the diagnosis of pancreatic diseases is greatly improved. Pancreatic cancer with a diameter less than1cm can be detected,which is of great value in the diagnosis of small pancreatic cancer.(2)TNM staging:EUS can show the size of pancreatic cancer,whether the tumor invades peripheral blood vessels, common bile duct,duodenal wall,liver,or adrenal gland and whether there are metastatic lymph nodes,so it has a higher accuracy of TNM staging.EUS can provide more information than CT and MRI for patients who have highly suspected pancreatic lesions,which have not been found in the first imaging examination.EUS can also provide more information than CT and MRI for surrounding vascular invasion and lyinph node metastases, and so it can be an important supplement to CT and MRU.(3)EUS-guided intervention technology1)EUS-FNA:EUS-FNA has a high accuracy in the diagnosis of pancreatic cancer and is the first choice for pathological diagnosis of pancreatic tumors.For most pancreatic tumors,EUS-FNA can provide enough tissue for pathological evaluation.It could be used in the following situations:(a)To acquire the pathological diagnosis before chemoradiation.(b)To repeat FNA if the first biopsy result was negative.(c)To differentiate the diagnosis of pancreatic lesions.(d)To confirm the diagnosis of potential metastases in unresectable patients.2)Endoscopic ultrasound guided fine needle injection(EUS-FNI):It's a newly developed treatment technique based on EUS・FNA for middle-to late-stage patients,including oncolytic adenovirus injection,photodynamic treatment, radiofrequency ablation,physical treatment(hyperthermic or hypothermic)and radioactive particles implantation.3)Endoscopic ultrasound guided biliary drainage(EUS-BD): EUS provides accurate imaging and EUS-BD is less invasive than percutaneous transhepatic biliary drainage. EUS-BD is used in the following situations:routine ERCP failure;gastrointestinal obstruction or abnormality due to surgery(such as Whipple procedure,Billroth-II gastrojejunostomy,hepatojejunostomy and gastric bypass procedure);and congenital abnormality(parapapillary diverticulum).4)EUS-guided pancreatic duct drainage:It's used to alleviate abdominal pain induced by pancreatic duct obstruction due to high pressure of pancreatic duct and parenchyma,especially after ERCP failure.5) For some patients with pancreatic tumors who cannot be surgically resected,it is feasible to block the celiac plexus under the guidance of EUS to relieve the pain and improve the quality of life of the patients.6) EUS-guided gastrojejunostomy(EUS-GJ):Compared with duodenal stenting,EUS-GJ can prevent repeating duodenal stents due to previous stents being blocked or displaced by tumors.EUS-GJ can effectively alleviate obstruction in the long term by a minimally invasive pared with the previous open gastro・jejunostomy,this operation has the advantages of less trauma,shorter operation time,less pain and faster recovery,which fully reflects the advantage of endoscopic minimally invasive surgery.2.4.6Role of ERCP in the diagnosis of pancreatic cancer The most common ERCP manifestations of pancreatic cancer were proximal stenosis and distal dilatation of the282Chinese guidelines for pancreatic cancermain pancreatic duct：stenosis,interruption or dis­placement of the main pancreatic duct,uneven acinar shadow of the pancreatic parenchyma,retention of the contrast agent,filling defect of pancreatic juice contrast agent or displacement of branch pancreatic duct.Cancer of the head of the pancreas may show dilated double-duct sign when it compresses the main pancreatic duct and the common bile due匚ERCP cannot directly show tumors,it mainly makes the diagnosis of pancreatic cancer depending on the change of pancreatic duct and the morphology of the common bile duct,which has great value for the lower portion of the biliary duct and pancreatic duct obstruction or abnormal changes.In addition,pancreatic cancer also has some special ERCP signs,such as double-duct sign and soft rattan sign,which have specific diagnostic value for pancreatic cancer.2.4.7Cytology diagnosis via ERCPThe bile and pancreatic fluid was collected by ERCP intubation into the pancreaticobiliary duct and the cells were brushed or the tissues pinched in the pancreatico­biliary due匸Then the exfoliative cytology of pancreatic juice and bile or the pathological diagnosis was performed. Especially for the patients with obstructive jaundice who can not be operated on,the operation of biliary drainage and pathologic and cytological examinations can be completed simultaneously,which should be the first choice for the patients with obstructive jaundice without surgical indication.However,the sensitivity and specificity of biopsy and cytological brushing under ERCP are not satisfactory,and the effect needs to be further improved.2.4.8ERCP combined with intraductal ultrasound(IDUS) IDUS under ERCP is a technique,which can obtain high-resolution pancreaticobiliary duct images.The probe can do360-degree scanning and can be easily inserted into the bile duct without duodenal papilla incision.IDUS can provide high-resolution images of the whole bile duct and 让s surrounding tissues in real time,which is superior to EUS in distinguishing benign and malignant bile duct stenosis.It has high sensitivity.When combined with pancreaticobiliary duct biopsy,IDUS can probe the lesion wall and biopsy location more accurately,making tissue acquisition more accurate,so as to improve the sensitivity of diagnosis.2.4.9Bone scansBone scans is the most widely used,cost-effective,and highly sensitive method for detection of malignant bone metastasis.Preoperative bone scans can be routinely performed in patients with pancreatic cancer who are highly suspected of bone metastasis2.5Blood immunologic and biochemical examinations2.5.1Blood biochemical examinationsNo specific blood biochemical changes are detected at the early stage.Elevated serum ALT,AST,bile acids and bilirubin levels would be detected when pancreatic cancer invades liver and the bile duct is obstructed.At the late stage of the tumor,electrolyte disturbances and hypo-albuminemia may occur with cachexia.In addition,changes in blood glucose are also associated with the onset or progression of pancreatic cancer.2.5.2Serum tumor markers testsThe commonly used serum tumor markers clinically are CA19-9,carcinoembryonic antigen(CEA),and CA125,of which CAI9-9is the most common used one for pancreatic diagnosis,treatment response evaluation and recurrence surveillance.However,about3%—7%of the pancreatic patients do not express CA19-9for their special Lewis antigen negative blood type.Serum CAI9-9level would be falsely positive when bile duct is obstructed or infected, which can not indicate a tumor or a late-stage disease. Therefore,preoperative detection of CAI9-9levels is best performed after biliary tract decompression and when bilirubin level is normal.2.6Histologic and cytological diagnosis2.6.1Cytological pathology diagnosisCytological diagnosis of pancreatic cancer is composed by sampling techniques,slice preparation techniques and diagnosis reports.The cell specimen sampling techniques:commonly used sampling techniques include:1)Image(CT or ultrasound-guided FNA；2)EUS-FNA；3)Intraoperative FNA；and4) Cell brush of the pancreatic duct and the lower portion of common bile duct by ERCP.Cell specimen preparation techniques：Cell specimen preparation techniques include routine smears,liquid-based slices and cell-block sections.Conventional smear is the most commonly used method of slice preparation.FNA or brushed cells are directly smeared on the glass,then wet dried and fixed by95%alcohol.If the cystic fluid is acquired by FNA puncture,the liquid-based method willChinese Journal of Cancer Research,Vol31,No2April2019283enrich the cells in the cystic fluid,thus obtaining a more abundant smear than the conventional smear.The main purpose of cell block preparation is to perform immuno-cytochemical staining.In addition,some small tissue structures can be restored in the slice of cell block,which is helpful for morphological diagnosis.According to their own conditions and the nature of the lesion,each center chooses different methods of slice preparation,and it can help to improve the accuracy of diagnosis if the three methods are taken at the same time. Some centers can also carry out s让e assessment of cell samples if possible to improve the rate of sampling satisfaction.Cytological diagnosis reports:The six-grade report system recommended by American Papanicolaou Society of Cytopathology was taken.In this report system cytopathology diagnosis was divided into the following six grades:Grade I,can not diagnosis;Grade II,no sign of malignancy;Grade III,untypical;Grade IVA,benign neoplasm；Grade IVB,neoplastic lesions,other;Grade V, suspected malignancy;Grade VI,malignancy.The most challenging diagnostic grading is u neoplastic lesions,other (IVB),”in which capsular coated cells of intraductal papillary mucinous neoplasms and mucinous cystic tumor can be mild,moderate,or even severe atypical.Cells with severe atypical changes are difficult to differentiate from adenocarcinoma cells.In addition,the diagnosis of some small round cell tumors,such as solid-pseudopapillary tumor,neuroendocrine tumor and acinar cell carcinoma often need to be detected by cell block immunocytochemistry. Cytological diagnosis details are shown in Appendix3 (Table Al).2.6.2Histopathology diagnosis of pancreatic cancer(1)Pathological diagnosis criteria of pancreatic cancer: Pancreatic carcinoma is diagnosed by histopathology and/or cytology of the biopsy tissue or resected specimen of the pancreatic lesion or the metastatic lesion. Pathological diagnosis should be combined with clinical evidences,including understanding the clinical manifestations and imaging findings of the patients thoroughly.(2)Pathological diagnosis guidelines of pancreatic cancer:It is composed by specimen processing,specimen sampling, pathologic examination and pathologic report.1)Key points of specimen processingThe surgeon should mark the location,type and number of the specimens on the pathological application sheet,and mark the surgical margins and important lesions w让h dye staining or suture.The tumor specimen should be delivered completely to the pathology department for incision and fixation within 30min after resection as far as possible.Specimen should be fixed w让h10%neutral formalin solution for12-24h.2)Specimen sampling and examinationSpecimen after pancreaticoduodenectomy:The tumor is opened perpendicular to the common bile duct from the duodenal papilla to the common bile duct with a probe,and the relationship between the tumor and the common bile duct and the duodenal wall is observed.The margins of stomach,pylorus,small intestine,pancreas and common bile duct are taken respectively.As to the tumor mass (including the deepest portion of infiltration and the relationship with surrounding tissues or organs),according to the tumor size,at least one block is taken per1cm；According to the color of each surface,areas of different texture should also be sampled.Specimen after splenectomy and resection of the body and tail of the pancreas:The tumor mass is opened in the form of a leaf,and at least one block per1cm is taken according to the tumor size,including the pancreatic capsule,the pancreatic duct,the margin of the pancreas, the surrounding pancreas,the relationship between the pancreas and the spleen,and so on.All lymph nodes are sampled including peripancreatic lymph nodes and splenic hilar lymph nodes.Pancreatic tissues between tumors are required to be sampled if there are multiple tumors.2.6.3ImmunohistochemistryCommonly used immunohistochemical markers for differential diagnosis include vimentin,CK,EMA,CEA, CAI9-9,CK19,CK7,CK20,MUC1,MUC4,CDX2,PR, CD10,syn,CgA,CD56,ACT,AAT,p-cantenin,and Ki-67.A reasonable combination of immunohistochemical markers should be used for differential diagnosis of pancreatic endocrine tumors and various types of pancreatic cancer.2.6.4Pathologic reportsThe pathologic diagnosis report of pancreatic cancer is composed by gross specimen description,microscopic description,immunohistochemical staining results, pathologic diagnosis names,invasion areas(especially the relationship between the tumor and the common bile duct, duodenum and spleen.If the portal vein margin is involved,284Chinese guidelines for pancreatic cancerit should be reported),lymphatic and vascular tumor embolus,neural invasion,the invasion of pancreatic capsule,lymph node metastases and TNM staging.The gross specimen description is demonstrated in Appendix4 and Appendix5in detail.In addition,the results of molecular pathology related to drug target detection, biological behavior evaluation and prognosis judgement are attached for clinical reference.2.7Differential diagnosis of pancreatic cancer2.7.1Chronic pancreatitis(1)Chronic pancreatitis patients have a long history;serum amylase will increase when acute attack,but these patients seldom have jaundice.(2)Abdominal CT showed irregular pancreatic contour, nodular bulge and heterogeneous pancreatic parenchyma.(3)Abdominal plain scan and CT showed calcification in pancreas in patients with chronic pancreatitis.(4)Elevated serum IgG4level is the characteristic of autoimmune pancreatitis,which is one special type of chronic pancreatitis.In case of equivocal radiological diagnosis,pathologic biopsy is often needed.2.7.2Carcinoma of ampulla(1)Intermittent jaundice might happen due to tumor necrosis and subsequent remission of bile duct obstruction.(2)Hypotonic duodenography might show“double contour sign^^due to duodenal papilla filling defect and mucosal destruction.(3)Ultrasound,CT,MRI and ERCP might reveal bile duct and pancreatic duct dilation,distant bile duct obstruction,“double duct sign”and ampulla occupation.(4)Endoscopic ultrasound：As a new diagnostic technique, EUS is of special value to differentiate carcinoma of pancreas from carcinoma of ampulla,for it could catch sight of small lesions and detect the invasion depth and extent and peripheral enlarged lymph nodes,and so on.2.7.3Pancreatic cystadenoma and cystadenocarcinoma Clinically pancreatic cystic neoplasms are rare,and more common in women.Radiologic examinations are important methods to differentiate them from pancreatic cancer,and the tumor marker CAI9-9is often normal.Ultrasound,CT and EUS could show intra-pancreatic cystic lesions with regular cavity,however,cystic degeneration with irregular cavity only happened after central necrosis of pancreatic cancer.2.7.4CholedocholithiasisPatients with choledocholithiasis often have a long disease history of recurrence,and serum bilirubin level fluctuates greatly.Patients with acute cholangitis often experience the triad of abdominal pain,chills and fever and jaundice.2.7.5 Other lesions of pancreasThey include pancreatic pseudocyst,insulinoma,solid pseudopapillary tumor,and so on.Clinically these lesions often grow slowly,and patients often have a long disease history and specific clinical manifestations,such as insulinoma with paroxysmal hypoglycemic symptoms and pancreatic pseudocyst w让h acute pancreatitis history.It's not difficult to differentiate them from pancreatic cancer when combined with radiological examinations such as CT and definite biopsy pathology if necessary.3・Classification and staging of pancreatic cancer 3.1Histologic classification of pancreatic cancerReferring to2010World Health Organization(WHO) histologic classification of pancreatic cancer(Appendix6). 3.2Staging of pancreatic cancer(AJCC,the8th edition)3.2.1Definition of T,N and M in pancreatic TNM staging (1)Primary tumor(pT)pTx:Primary tumor cannot be assessedpTO:No evidence of primary tumorpTis:Carcinoma in situ.This includes high-grade pancreatic intraepithelial neoplasia(PanIn-3),intraductal papillary mucinous neoplasm w让h high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia,and mucinous cystic neoplasm with high-grade dysplasia.pTl：The maximum diameter of tumor<2cmpTla：The maximum diameter of tumor<0.5cm pTlb：The maximum diameter of tumor<1cm,>0.5cm pTlc：The maximum diameter of tumor1-2cmpT2:The maximum diameter of tumor>2cm,<4cmpT3:The maximum diameter of tumor>4cmpT4:Tumor involves the celiac axis,superior mesenteric artery,and/or common hepatic artery,regardless of size. (2)Regional lymph nodes(pN)pNx:Regional lymph nodes cannot be assessed.pNO：No regional lymph node metastases。

•临床报道•腹腔镜胃癌根治术后胰痿导致迟发性十二指肠残端痿一例柴伟张执全刘汝海河北省沧州市中心医院普通外一科061000通信作者：刘汝海,Email:chaiwei007686@,电话：************【摘要】腹腔镜胃癌根治术后胰痿发生率相对较低，但一旦发生往往会造成较为严重的后果，本案例介绍了腹腔镜胃癌根治术后胰痿并最终导致十二指肠残端迟发痿的病情演变过程，从原因分析到治疗措施等方面进行归纳总结，以此提高大家对胃癌术后胰痿的认知及治疗水平。

【关键词】胃肿瘤；胰腺痿；十二指肠残端痿DOI：10.3760/cma.j.issn.l15807-20200114-00011One case of delayed duodenal stump fistula caused by pancreatic fistula after laparoscopic gastrectomyChai Wei,Zhang Zhiquan,Liu RuhaiDepartment of General Surgery,Cangzhou Central Hospital,Cangzhou061000,ChinaCorresponding author:Liu Ruhai,Email:chaiivei007686@,Tel:0317-*******[Abstract]The incidence of pancreatic fistula after laparoscopic gastrectomy is relatively low,but once ithappens,it will often cause serious consequences.This case introduces the evolution process of pancreatic fistulaafter laparoscopic gastrectomy and the ending of delayed duodenal stump fistula.It summarizes the causes andtreatment measures,so as to improve the cognition and treatment of pancreatic fistula after gastric cancer surgery.[Key words]Stomach neoplasms;Pancreatic fistula;Duodenal stump fistulaDOI：10.3760/cma.j.issn.l15807-20200114-000111病例资料患者女性，58岁，因“纳差、乏力半月”入院。

99胰腺癌与糖尿病相关性研究进展余静(综述)1李晓燕(审校)2671000云南大理州人民医院肾内科1650032昆明医学院第一附属医院消化内科2doi:10．3969/j．issn．1007－614x．2011．02．095在20世纪早期，人们就认识到胰腺癌(pancreatic cancer，PC)和糖尿病(dia-betes mellitus)存在相互关系。

随后国内外的许多两者相关性研究发现，糖尿病患者中胰腺癌的发病率显著高于一般人群［1，2］，提示糖尿病可能导致胰腺癌。

而血糖升高也可作为胰腺癌的早期表现之一［3］。

胰腺癌中合并糖尿病的患者可达40%，且其中以新发糖尿病［4］尤为多见［5］，提示胰腺癌可能导致糖尿病。

胰腺癌对糖尿病是病因还是结果一直存在争议。

本文对此作一简要综述。

糖尿病致胰腺癌的相关研究国外的Pormert等［6］及Fisher［7］的研究认为，胰腺癌患者与普通人群相比，其糖尿病的发生率更高，72%的胰腺癌患者患有2型糖尿病，尤其是糖尿病的初发年龄大于60 70岁时，并且5年以上的糖尿病史增加了胰腺癌的患病风险。

韩国的一项为期10年的大型前瞻性研究［8］显示:空腹血糖升高以及糖尿病是一些肿瘤发生的独立危险因素，并且危险性与空腹血糖值呈正比。

国内匡天涛等［9］、金爱花等［10］研究认为，胰腺癌患者的糖尿病患病率明显高于对照组，且糖尿病病程的延长可使患胰腺癌的风险增加，糖尿病病程＞10年的患者胰腺癌的发病率明显高于对照组。

卢瑜等［11］调查了16890例新诊断恶性肿瘤患者，9.57%的肿瘤患者在初次诊断时已患糖尿病，且胰腺癌排首位，糖尿病患病率达18.76%。

这也证实了恶性肿瘤发病中，糖尿病与胰腺癌的关系更为密切，糖尿病可导致胰腺癌。

关于糖尿病致胰腺癌的可能机制，研究认为:①胰岛素样生长因子－1(insulin－like growth factor－1，IGF－1)的作用。

研究发现糖尿病人群中恶性肿瘤患者血浆IGF－1浓度较正常人高［12，13］。

2022年第8卷第8期Vol.8，No.8，2022中西医结合护理Chinese Journal of Integrative Nursing4例下肢血管腔内治疗术后并发急性胰腺炎的护理体会方晓梅1，刘焕萍2，王婷1（1.中国中医科学院西苑医院血管外科，北京，100091；2.中国中医科学院西苑医院护理部，北京，100091）摘要：本文总结4例下肢血管腔内治疗术后并发急性胰腺炎患者的护理体会，为介入术后的精细化护理提供参考。

护理要点包括：实施心理护理，给予术前合理水化、饮食指导，加强病情观察，积极预防并发症发生，提供营养支持，完善用药护理。

2例重症急性胰腺炎患者中，1例最终因多脏器功能衰竭死亡，另1例转入ICU 治疗后出院；2例轻症急性胰腺炎患者经药物治疗后痊愈。

腔内治疗术后并发急性胰腺炎是一种罕见的血管造影并发症，不易早期发现，当患者在介入手术后出现腹痛、肌酐升高或多器官衰竭时，必须考虑急性胰腺炎的可能性，做到早发现、早诊断、早治疗，有利于提高术后并发症的治愈率。

关键词：急性胰腺炎；血管腔内治疗术；并发症；营养支持；心理护理中图分类号：R 473.6文献标志码：A文章编号：2709-1961（2022）08-0051-04Nursing of four patients with acute pancreatitis after lower extremity endovascular interventionFANG Xiaomei 1，LIU Huanping 2，WANG Ting 1（1.Department of Vascular Surgery ，Xiyuan Hospital of China Academy of Chinese Medical Sciences ，Beijing ，100091；2.Department of Nursing ，Xiyuan Hospital of China Academy of Chinese Medical Sciences ，Beijing ，100091）ABSTRACT ：This paper summarized the nursing measures for four patients with acute pancreatitis after lower extremity endovascular intervention ，and provided a reference for the postoperative nursing of vascular intervention surgery.Key issues of nursing included psychological care ，preoperative hydration ，guidance of dietary ，observation of illness condition ，prevention of complications ，nutrition support and medication care.There are two severe cases of acute pancreatitis ，one of which eventually died due to multiple organ failure ，and the other was cured after drug treatment.In addition ，two mild cases of acute pancreatitis ，which were cured after drug treatment.As rare angiographic complication ，acute pancreatitis is not easy to be detected early.The possibility of acute pancreatitis must be con⁃sidered when a patient presents with abdominal pain ，elevated creatinine ，or multiple organ failure following an interventional procedure.Early detection and diagnosis ，and timely treatment are beneficial to improve the cure rate of postoperative complications.KEY WORDS ：acute pancreatitis ；endovascular intervention ；complications ；nutrition support ；psychological careDOI ：10.55111/j.issn 2709-1961.202206074·周围血管疾病护理及质量管理·收稿日期：2022-05-01基金项目：中国中医科学院科技创新工程项目（C 12021A 02144）第一作者简介：方晓梅，本科学历，主管护师，中国中医科学院西苑医院血管外科/妇科护士长。

Aug. 2011, Volume 8, No. 8 (Serial No. 81), pp. 501-504Journal of US-China Medical Science, ISSN 1548-6648, USAIdiopathic Fibrotic Pancreatitis: A Rare Case PresentationMithat Gunaydin1, Rıza Rızalar1, Ögunç Apaydın1, Asudan Tugçe Bozkurter1, Ayhan Gazi Kalaycı2, Ender Arıtürk1 and Ferit Bernay11. Pediatric Surgery Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey2. Pediatric Gastroenterology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun, TurkeyAbstract: We report here a case of Idiopathic fibrosing pancreatitis (IFP). IFP is a rare condition affecting children, which can be a cause of recurrent abdominal pain and obstructive jaundice. A five-year-old female patient admitted with nonspesific abdominal pain and jaundice. MR cholangiography revealed a noduler lesion, causing obstruction with dilatation at pancreatic duct. Pancreas was diffusely stiff from head to tail. The intrapancreatic portion of the CBD was compressed by head of pancreas. Cholecystectomy and Roux-en-Y choledocojejunostomy was performed to provide bile passage. The biopsy revealed chronic inflammation and fibrosis at pancreas tissue.Approximately, 59 cases have been reported so far including ours.Key words: Pancreatitis, childhood, idiopathic.1. IntroductionA symptomatic pancreatic lesion is a dilemma for both diagnosis and treatment. Benign lesions may mimic malignant ones and the follow-up for benign lesions is not clearly defined [1]. Chronic pancreatitisis a rare cause of obstructive jaundice in children [2-4]. Among the entities leading to noncalcific chronic pancreatitis, idiopathic fibrotic pancreatitis is a rare clinical condition and a rare cause of biliary obstructionin infants and adolescents [2, 3]. This entity was first described by Comfort et al. in 1946 [5]. So far 58 cases were defined. IFP may cause recurrent abdominal pain and obstructive jaundice. The obstruction is followed by the circular compression of intrahepatic segment of common bile duct by the fibrotic head of the pancreas. IFP is hard to diagnose and most of the cases in literature have undergone exploratory laparatomy to rule out malignancy [2]. Sphincteroplasty, choledocoduedonostomy, cholecystoduodenostomy,Corresponding author:Mithat Gunaydin, MD, assistant professor, research field: pediatric surgery. E-mail: ************************.cholecystojejunostomy and Roux-en-Y choledocojejunostomy are surgical procedures enabling biliary decompression [6-8]. IFP may rarely regress on conservative follow-up [1, 9].2. CaseFollowing three weeks of follow-up and evaluationat a local hospital, a five-year-old girl with abdominalpain and jaundice was referred to our clinic at March.She had no history of febrile disease, no familial pancreatitis or hepatobiliary disease and cystic fibrosis. Physical examination was otherwise normal. She hadmild abdominal tenderness and jaundice. Blood biochemistry was as follows; total bilirubin 17 mg/dl,direct bilirubin 14 mg/dl, ALP 3999 IU/L, GGT 869IU/L, AST 548 IU/L, ALT 521 IU/L, amylase 296IU/L, lipase 837 IU/L, alfa-1-antitrypsin 507 (50-200), caeruloplasmin124 ve INR 1.43. Hepatitis markerswere negative. IgG and IgE levels were normal. Ultrasonography showed that the liver had a 102 mm vertical diameter with slight granulation at parenchyme.The common bile duct was dilated (7 mm). AbdominalX-ray was normal. MR cholangiopancreticographyAll Rights Reserved.Idiopathic Fibrotic Pancreatitis: A Rare Case Presentation 502demonstrated a 19×14 mm nodular lesion at the distal end of common bile duct and to the posterior of the head of the pancreas, causing dilatation and obstruction, showing evident contrast absorption, hyperintense on T2 and hypointense on T1 (Fig. 1). Preoperatively, Ursodeoxycholic acid (UDCA) was commenced at a dose of 10 mg/kg/day. But, clinical and laboratory findings did not regress. Therefore, a laparotomy was indicated. At laparatomy, pancreatic tissue was diffusely stiff from head to tail. The intrapancreatic site of common bile duct was compressed by head of the pancreas. There was no nodular lesion as defined at MRI. We sent a biopsy from the rather stiff head portion for frozen section examination, which showedFig. 1 (A): Axial T2-weighted MRI with contrast cross-section enhancement in the localization of pancreatic head, showing vague contours of the mass lesion ( * ); (B): Coronal MR cholangiography sections showing obstruction at distal end of choledoc (white arrow) and dilatation at proximal choledoc and intrahepatic bile ducts. inflammatory cells but no malignancy. Therefore we took a relatively larger wedge biopsy. Then a cholecystectomy and Roux-en-Y choledocojejunos- tomy was performed to enable bile drainage. A penrose drain was placed close to the anastomosis site. Postoperatively, total parenteral nutrition and octreotide infusion were administrated. Nasogastric tube was removed on the 6th postoperative day and enteral feeding was started on the 8th postoperative day. She was discharged on the 14th postoperative day. Pathologic evaluation revealed chronic inflammation and fibrosis at pancreatic tissue (Fig. 2). On the 10-month-follow up, she was asymptomatic with normal biochemistric evaluation. At ultrasonographic and MRI examination, the diameter of the common hepatic bile duct returned to normal postoperatively.Fig. 2 Lobule structure was partially maintained in the pancreatic tissue atrophied acinar component, fibrosis along with chronic inflammation, which disrupts ductal structures.A (x10, HE),B (x20, HE)All Rights Reserved.Idiopathic Fibrotic Pancreatitis: A Rare Case Presentation 5033. DiscussionIdıopathic fibrotic pancreatitis (IFP) is a rare form of chronic pancreatitis seen in infants and adolescents [2, 3, 6]. The cases presented in the literature were between 4 months to 20 years and it is more frequently seen in boys [6, 8]. It presents with abdominal pain with or without obstructive jaundice. Fiftyfour percentof the cases present with abdominal pain and jaundice. 78% of the cases have abdominal pain with or without jaundice while only about 17% of the cases present with painless jaundice [3, 8, 10]. In case hereditary pancreatitis, cystic fibrosis, hipercalcemia, hiperlipidemia, sclerozing cholangitis and congenital anomaly of the liver and bile ducts are ruled out, idiopathic fibrotic pancreatitis should be suspected [2, 7].Although any acute or subacute disease, seen at spring and certain geographic distribution point to infectious etiologies, and our case was seen in March, she had no history of febrile disease [8].Most of the reported cases had normal or slightly elevated liver function tests, bilirubin and amilase levels. Abdominal ultrasonography generally shows dilatation at the intra-extrahepatic bile ducts [2]. The improvement in ERCP technology enables easier diagnosis of pancreatic diseases in children. But ERCP necessiates canulisation of the pancreatic duct and common bile duct and has some serious complicationsas pancreatitis, infection, hemorrhage and bile leakage [11]. When this disease is suspected, MR cholangiopancreotography (MRCP) may be a relaible, non-invasive alternative to ERCP in demonstarting the structural anomalies of pancreaticobiliary ducts [12, 13].In children with distal long segment common bile duct stricture and non-calcified fibrotic pancreatitis resulting with biliary obstruction, IFP should be kept in mind in differential diagnosis [7]. Since IFP may leadto pancreatic insufficiency in long term, and to rule out malignancy, exploratory laparotomy is performed for both diagnosis and treatment [2, 3].Laparotomy demonstrates a stiff, fibrotic and stone-hard pancreas causing obstruction. Intraoperative cholangiography and pancreas biopsy is routinely done. After ruling out malignancy and to avoid obstruction, biliary-enteric by-pass surgery may be needed [2, 3, 6, 8]. Biliary decompression techniques include sphincteroplasty, choledocoduodenostomy, cholecystojejunostomy and Roux-en-Y choledocojejunostomy [6-8]. Roux-en-Y choledocojejunostomy is superior to others [6, 7]. Sylvester et al reported four patients with IFP treated by a choledocal stent placed via ERCP but 3 of them eventually had pancreatic insufficiency [10]. Some reports suggest that IFP may spontaneously regress on conservative follow-up [1, 9]. Some authors suggest a considerable increase of malignant tranformation subsequent to bilio-enteric by-pass procedures in patients with benign condition [10, 14]. Rosenbaum and et al. proposed Ursodeoxycholic acid (UDCA) in the management of IFP, because of its effect on reducing biliary viscosity [15]. Sclerosing pancreatitis is a rare form of pancreatitis, characterized by hypergammaglobulinaemia [16, 17].As conclusion, a symptomatic pancreas lesion is both hard to diagnose and treat. Among the noncalcific chronic pancreatitis causes, idiopathic fibrotic pancreatitis is a rare but important condition. It should be kept in mind while evaluating patients with abdominal pain and jaundice and USG, MRCP, ERCP should be done to eliminate other pathologies. The definitive diagnosis is challenging and most of the time laparotomy and histopathological evaluation may be necessary. Biliary diversion, conservative follow-up, the use of UDCA recommended for treatment in the literature. Although conservative management and UDCA treatment are suggested in the recent literature, surgery is generally needed. The common bile duct compress completely by stiff pancreas, therefore UDCA can not be beneficial in every case. İn patients with severe clinical and labaratory findings, and especially in these whom malignancy needs to be ruled out a bilio-enteric by-pass surgery may become unpredictable.All Rights Reserved.Idiopathic Fibrotic Pancreatitis: A Rare Case Presentation504References[1] M. T. Cartmell, E. Cusick and M. Ashworth et al., Idiopathic fibrosing pancreatitis and spontaneous resolution of pancreatic masses in children, Pediatr Surg Int 23 (2007) 897-901. [2] L. Harb and H. Naon, Idiopathic fibrosing pancreatitis in a 3-year-old girl: A case report and review of the literature, J Pediatric Surg 40 (2005) 1335-1340. [3] R. Keil, J. Snajdauf and J. Kalousova et al., Idiopathic fibrosing pancreatitis presenting with obstructive jaundice in a child, Eur J Pediatr Surg 11 (2001) 328-330. [4] J. M. Van Camp, T. Z. Polley and A. G. Coran, Pancreatitis in children: Diagnosis and etiology in 57 patients, Ped Surg Int 9 (1994) 492-497. [5] M. W. Comfort, E. E. Gambill and A. H. Baggenstoss, Chronic relapsing pancreatitis, Gastroenterology 6 (1946) 239-285. [6] A. V. Deshpande, E. R. LaHei and A. Shuna et al., Idiopathic fibrosing pancreatitis in children–A single-center experience, J Pediatric Surg 41 (2006) 1987-1991. [7] R. P. Krishna, R. Lal and S. S. Sikora et al., Unusual causes of extrahepatic biliary obstruction in children: A case series with review of literature, Pediatr Surg Int 24 (2008) 183-190. [8] J. S. Barkin, N. Stollman and J. Friedman et al., Idiopathic fibrosing pancreatitis causing obstructive jaundice in young adults: Two case reports and literature review, Am J Gastroenterol 89 (1994) 2063-2065. [9] W. El-Matary, D. Casson and S. Hodges et al., Successfulconservative management of idiopathic fibrosingpancreatitis in children, Eur J Pediatr 165 (2006) 560-565.[10] F. A. Sylvester, B. Shuckett and E. Cutz et al., Management of fibrosing pancreatitis in children presenting with obstructive jaundice, Gut 43 (1998) 715-720.[11] P. W. Bearcroft and D. J. Lomas, Magnetic resonance cholangiopancreatography, Gut 41 (1997) 135-137. [12] E. M. Armstrong, D. J. M. Tolan and C. S. Verbeke et al.,Evolution of idiopathic fibrosing pancreatitis–MRI features, The British Journal of Radiology 81 (2008) e225-e227.[13] T. Shimizu, R. Suzuki and Y. Yamashiro et al., Magnetic resonance cholangiopancreatography in assessing the cause of acute pancreatitis in children, Pancreas 22 (2001)196-199 [14] R. W. Strong, Late bile duct cancer complicating biliary-enteric anastomosis for benign disease, Am J Surg177 (1999) 472-474. [15] J. Rosenbaum, G. Alex and T. Clarnette, Ursodeoxycholic acid’s role in avoiding diversionary surgery in idiopathic fibrosing pancreatitis, Journal of Paediatrics and ChildHealth 45 (2009) 681-683. [16] G. H. Neild, M. Rodriguez-Justo and Catherine Wall et al., Hyper-IgG4 disease: report and characterisation of a new disease, BMC Medicine 4 (2006) 23-41. [17] Hamano H, Kawa S and Horiuchi A. et al., High serum IgG4 concentrations in patients with sclerosing pancreatitis, N Engl J Med 344 (2001) 732-738.All Rights Reserved.。

Early detection of pancreatic cancerFrancisco J Morera-Ocon【期刊名称】《World Journal of Clinical Cases》【年(卷),期】2024(12)17【摘要】The diagnosis of pancreatic cancer associates an appalling significance.Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease.Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development.Pancreatic intraepithelial neoplasms(PanIN)are the most frequent precursors of pancreatic adenocarcinoma(PDAC),and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC.Unfortunately,PanINs are not detectable on radiologic exams.Nevertheless,they can associate indirect imaging signs which would rise the diagnostic suspicion.When this suspicion is established,the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging,which will cost in the best-case scenario a burden of healthcare systems,and potential mortality in the worst-case scenario when the patient underwent resection surgery,worthless when there is no moderate or high grade dysplasia in the final histopathology.This issue will be avoid having at its disposal adiagnostic technique capable of detecting high-grade PanIN lesions,such is the cytology of pancreatic juice obtained by nasopancreatic intubation.Herein,we review the possibility of detection of early malignant lesions before they become invasive PADC.【总页数】4页(P2935-2938)【作者】Francisco J Morera-Ocon【作者单位】Department of General Surgery General de Requena 46340【正文语种】中文【中图分类】R73【相关文献】1.Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of PancreaticCancer2.Artificial intelligence for pancreatic cancer detection: Recent development and future direction3.Detection of K-ras gene mutation at codon 12 by pancreatic duct brushing for pancreatic cancer4.Molecular detection of epithelial-mesenchymal transition markers in circulating tumor cells from pancreatic cancer patients:Potential role in clinical practice5.Early Detection of Pancreatic Cancer Using Jaundiced Eye Images因版权原因，仅展示原文概要，查看原文内容请购买。