topics

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Ductal adenocarcinomas tend to infiltrate into vascular, lymphatic, and perineural spaces. At the time

of resection, most ductal carcinomas have already metastasized to regional lymph nodes. In addition to

the lymph nodes, PDAC frequently metastasize to the liver (80%), peritoneum (60%), lungs and pleurae

(50% to 70%), and adrenal glands (25%). They also can directly invade the duodenum, stomach,

transverse mesocolon, colon, spleen, and adrenal glands.

1 The histologic examination of a pancreas resected for cancer frequently reveals the presence of

precursor lesions in the pancreatic ducts and ductules adjacent to the cancer. This suggests that much

like colon cancer, which arises from benign adenomas, pancreatic cancer may also demonstrate

progression to malignant from benign precursor lesions. These precursor lesions are referred to as

pancreatic intraepithelial neoplasia (PanIN). Briefly, PanIN-1A and PanIN-1B are proliferative lesions

without remarkable nuclear abnormality that have a flat and papillary architecture, respectively. PanIN3 is associated with severe architectural and cytonuclear abnormalities, but invasion through the

basement membrane is absent. The older term for PanIN-3 includes carcinoma in situ (CIS). PanIN-2 is

an intermediate category between PanIN-1 and PanIN-3 and is associated with a moderate degree of

architectural and cytonuclear abnormality.7 Several lines of evidence suggest that PanINs are precursors

of infiltrating pancreatic cancer: PanINs are often found in association with ductal adenocarcinomas,

three-dimensional mapping techniques that demonstrated a stepwise transformation from mild dysplasia

to severe dysplasia in pancreatic duct lesions, and PanINs demonstrate some of the same genetic

changes seen in infiltrating adenocarcinomas, most notably activating point mutations in codon 12 of Kras and mutations in the p16 and p53 tumor-suppressor genes.

Figure 55-2. Microscopic appearance of ductal adenocarcinoma of the head of the pancreas demonstrating glands from an

adenocarcinoma embedded in a fibrous matrix.

Adenosquamous Carcinomas

Adenosquamous carcinoma is a rare variant of ductal adenocarcinoma that shows both glandular and

squamous differentiation. This variant appears to be more common in patients who have undergone

previous chemoradiation therapy. The biologic behavior of adenosquamous carcinoma appears to be

similar to that of ductal adenocarcinoma, with similar rates of perineural invasion, lymph node

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metastases, and dissemination.

Acinar Cell Carcinomas

Acinar cell carcinomas account for only 1% of pancreatic exocrine tumors. Acinar tumors are typically

smooth, fleshy, lobulated, hemorrhagic, or necrotic. Histologically, they form acini, and the cells

display an eosinophilic, granular cytoplasm. Immunohistochemical staining demonstrates expression of

trypsin, lipase, chymotrypsin, or amylase. These tumors are more common in males with a male-tofemale predominance of approximately 3:1. The age of diagnosis is usually in the fifth to seventh

decades. These tumors tend to be larger than ductal adenocarcinomas, often being larger than 10 cm.

Although data are limited, it appears that patients with acinar cell carcinoma have a slightly better

prognosis than patients with ductal carcinoma.8 Therefore, surgical resection is the treatment of choice.

Giant Cell Carcinomas

Giant cell carcinomas account for less than 1% of nonendocrine pancreatic cancers. They tend to be

large, with average diameters greater than 15 cm. Microscopically, they contain large, uninucleated or

multinucleated tumor cells, many of which are pleomorphic. The nuclei contain prominent nucleoli and

numerous mitotic figures. Giant cell carcinomas are associated with a poorer prognosis than ductal

adenocarcinomas. There is a variant of giant cell carcinoma termed giant cell carcinoma with osteoclastlike giant cells. These lesions tend to be well circumscribed with nonpleomorphic giant cells and are less

aggressive than standard giant cell carcinomas.

Pancreatoblastoma

Pancreatoblastomas occur primarily in children ages 1 to 15 years. Pancreatoblastomas contain both

epithelial and mesenchymal elements. The epithelial component appears to arise from acinar cells. The

tumors are typically larger than 10 cm and often contain areas of degeneration and hemorrhage. The

prognosis appears to be more favorable than that for typical ductal adenocarcinoma if the tumor can be

resected.

Cystic Epithelial Tumors

Cystic neoplasms also arise from the exocrine pancreas. Cystic neoplasms are less common than ductal

adenocarcinomas, tend to occur in women, and are evenly distributed throughout the gland. Many

pancreatic and peripancreatic cysts are actually benign inflammatory pseudocysts. It is important to

identify cystic neoplasms because their management is very different from that of nonneoplastic cysts.

With advancements in imaging technology, cystic lesions of the pancreas are being detected with

increased frequency. With routine application of cross-sectional imaging to early diagnostic processes in

medicine, pancreatic cysts are often detected incidentally.9 Although many of these lesions are small

and asymptomatic, they can have malignant potential. Therefore, the management of these patients is

complex, and knowledge of pancreatic cyst natural history and predictors of neoplasia are important.

Serous Cystic Neoplasms

Serous cysts are epithelial neoplasms composed of uniform cuboidal glycogen-rich cells that usually

form numerous small cysts containing serous fluid. Serous cystadenomas or microcystic adenomas are

more common in women than in men (3:1 preponderance). These tumors can vary from a few

centimeters to more than 10 cm in size. Twenty-five percent to 30% of patients are asymptomatic;

however, most patients present with symptoms such as abdominal or epigastric pain, dyspepsia, nausea,

or vomiting. Serous cystadenomas can be located anywhere in the pancreas – head, body, or tail – and

usually do not communicate with the pancreatic ducts. Plain computed tomography (CT) shows a

honeycomb pattern of microlacunae, with thin septa separating different segments. Serous cystic

neoplasms can have a sunburst pattern of central calcification, which is seen in 10% to 30% of cases.

Grossly, they appear as spongy, well-circumscribed, multiloculated cysts. Microscopically, they consist

of a layer of simple cuboidal cells separated by dense fibrous bands. Most serous cystic neoplasms are

benign, although malignant behavior has been reported rarely (<1% with metastases to the liver or

peripancreatic lymph nodes). Symptomatic cysts or cysts that cannot be differentiated from other

potentially malignant cysts should undergo surgical excision.

Mucinous Cystic Neoplasms

Mucinous cystic neoplasms (MCNs) are neoplasms composed of mucin-producing epithelial cells

associated with an ovarian-type of stroma. These cysts usually do not communicate with the larger

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pancreatic ducts. MCNs are relatively uncommon but account for almost 30% of all cystic neoplasms.

The mean age at diagnosis is between 40 and 50 years. MCNs are more common in women with a

female-to-male ratio of 9:1. Most patients with MCNs present with vague abdominal symptoms that

include epigastric pain or a sense of abdominal fullness. The majority (70% to 90%) of MCNs arises in

the body or tail of the pancreas, and only a minority (10% to 30%) involves the head of the gland.

Microscopically, the cysts are lined by tall columnar mucin-producing epithelium. These columnar cells

have basal nuclei and abundant intracytoplasmic apical mucin and can form flat sheets or papillae. The

walls of the cysts contain a very distinctive “ovarian-type” stroma. This stroma is composed of densely

packed spindle cells with sparse cytoplasm and uniform elongated nuclei. All MCNs are considered to be

premalignant lesions and should be completely resected to prevent progression to malignancy.

Invasive mucinous cystadenocarcinomas are MCNs associated with an invasive carcinoma, whereas

noninvasive mucinous neoplasms can be categorized into MCNs with low-grade dysplasia (adenoma),

MCNs with moderate dysplasia (borderline) neoplasms, and MCNs with high-grade dysplasia (carcinoma

in situ) based on the degree of architectural and cytologic atypia of the epithelial cells. In surgical series

between 15% and 30% of all MCNs are associated with invasive carcinoma. Patients with mucinous

cystadenocarcinomas tend to be 5 to 10 years older than patients with benign MCNs. The extent of

invasive and in situ carcinomas in MCNs can be very focal. Therefore, a benign diagnosis cannot be

established on biopsy alone and the lesions should be completely resected. The prognosis for patients

with resected benign or borderline tumors is excellent. Patients with mucinous cystadenocarcinoma tend

to do better than patients with ductal adenocarcinoma, with a 5-year survival of approximately 50%.

Intraductal Papillary-Mucinous Neoplasms

Intraductal papillary-mucinous neoplasms (IPMNs) are intraductal mucin-producing neoplasms with tall,

columnar, mucin-containing epithelium with or without papillary projections. These neoplasms

extensively involve the main pancreatic ducts and/or major side branches. In addition, IPMNs lack the

ovarian stroma characteristic of MCNs. Similar to the well-defined adenoma–carcinoma sequence in

PDAC (PanIN to invasive ductal carcinoma), IPMNs seem to follow a similar pattern progressing from

IPMN with low-grade dysplasia to invasive carcinoma. Microscopically, they consist of papillary

projections lined by columnar mucin-secreting cells. They show varying degrees of cellular atypia. The

noninvasive IPMNs are graded on the basis of greatest degree of dysplasia and classified into low-grade,

moderate-grade, and high-grade dysplasia or carcinoma in situ. Invasive IPMNs are either colloid or

tubular, with the latter having a worse prognosis. The mean age of patients with invasive carcinoma is

approximately 5 years older than patients with noninvasive IPMNs suggesting an approximately 5-year

lag period for progression to malignancy. Further histologic subtyping of epithelial differentiation is

based on the cell lineage, the morphology of the papillae, and the immunophenotype, and includes

classification into intestinal, gastric, pancreaticobiliary, and oncocytic subtypes.

IPMNs are subclassified as main- and branch-duct types and as a mixed type that contains elements of

both. Main-duct IPMN is characterized by involvement of the duct of Wirsung, which is dilated to more

than 1 cm in diameter. Branch-duct IPMN originates in the side branches of the pancreatic ductal system

and appears as a multilobular cystic lesion communicating with a nondilated main pancreatic duct.

Typically, branch-duct IPMN occurs in the uncinate process–head of the gland, but it can also be seen in

the neck and distal pancreas. If the main duct is dilated with synchronous involvement of the branch

ducts, it is described as a mixed IPMN.

IPMNs are usually found in individuals in their 60s to 80s. Some patients may experience symptoms

that include: abdominal pain, steatorrhea, weight loss, jaundice, diabetes, and chronic pancreatitis. A

substantial number of these lesions are also detected as incidental findings on cross-sectional imaging

studies performed for other indications. IPMNs appear to be more common in the head, neck, and

uncinate process of the pancreas but can be found diffusely throughout the whole gland. CT scans will

typically reveal a cystic mass in the head of the pancreas that appears to communicate with the

pancreatic ductal system. On endoscopy, mucin can be seen oozing from the ampulla of Vater.

Endoscopic retrograde cholangiopancreatography (ERCP) can be used to confirm that the cysts

communicate with the pancreatic ducts.

MCNs are the main entity to consider in the differential diagnosis of IPMNs (Table 55-5). Two

morphologic features distinguish IPMNs from MCNs: IPMNs communicate with ducts, mucinous cysts do

not; IPMNs also lack an ovarian stroma that is present in mucinous cysts. In addition, mucinous cysts

are usually seen in the tail of the pancreas and occur in middle-aged women, whereas IPMNs are found

in the head of the pancreas and occur in older individuals of either sex.

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94. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic resections of islet cell tumors.

Surgery 1996;120:1051–1054.

95. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of

laparoscopic and open approaches. Ann Surg 2008;248:438–446.

96. Venkat R, Edil BH, Shulick RD, et al. Laparoscopic distal pancreatectomy is associated with

significantly less overall morbidity compared to the open technique: a systematic review and metaanalysis. Ann Surg 2012;255:1048–1059.

97. Tantia O, Jindal MK, Khanna S, et al. Laparoscopic lateral pancreaticojejunostomy: our experience

of 17 cases. Surg Endosc 2004;18:1054–1057.

98. Palanivelu C, Rajan RS, Rangarajan M, et al. Evolution in techniques of laparoscopic

pancreaticoduodenectomy. a decade long experience from a tertiary center. J HBP Surg

2009;16:731–740.

99. Kendrick ML, Cusati D. Total laparoscopic pancreaticoduodenectomy: feasibility and outcome in an

early experience. Arch Surg 2010;145:19–23.

100. Asbun HJ, Stauffer JA. Laparoscopic vs open pancreaticoduodenectomy: overall outcomes and

severity of complications using the Accordion Severity Grading System. J Amer Coll Surg

2012;215:810–819.

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Chapter 55

Neoplasms of Exocrine Pancreas

Attila Nakeeb, Michael G. House, and Keith D. Lillemoe

Key Points

1 Recent evidence supports that pancreatic ductal adenocarcinoma arises from precursor lesions

referred to as pancreatic intraepithelial neoplasia (PanIN) with progression from proliferative lesions

without nuclear abnormality to carcinoma in situ, known as PanIN-3.

2 Intraductal papillary mucinous neoplasms (IPMNs) are intraductal mucin-producing tumors that

range from benign adenomas to invasive carcinoma.

3 Contrast-enhanced computed tomography (CT) is the preferred noninvasive imaging test for the

diagnosis and staging of pancreatic cancer.

4 Perioperative mortality rates following pancreatoduodenectomy have fallen to the range of 2% to

5% although perioperative complications occur in approximately 40% of patients.

5 Survival after pancreatoduodenectomy for pancreatic cancer is approximately 20% at 5 years with

factors influencing survival including tumor size, margin status, and lymph node status.

6 Adjuvant chemotherapy is beneficial for patients following resection of pancreatic cancer.

7 Endoscopic palliation of patients with incurable pancreatic cancer located in the head may require

biliary and duodenal stenting.

8 Patients found to be unresectable at laparotomy for head of pancreas cancer should be considered for

biliary bypass, gastrojejunostomy, and chemical splanchnicectomy to palliate the symptoms of

jaundice, duodenal obstruction, and pain, respectively.

INTRODUCTION

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and second

only to colorectal cancer as a cause of gastrointestinal cancer-related death. The overall 5-year survival

for patients with pancreatic cancer is 7%.1 Surgical resection offers the only chance for long-term cure.

Unfortunately, because of the late presentation, only 15% to 20% of patients are candidates for surgical

intervention. Five-year survival after pancreaticoduodenectomy (PD) is about 25% to 30% for nodenegative and 10% for node-positive disease.2 The nonspecific symptoms associated with early pancreatic

cancer, the inaccessibility of the pancreas to examination, the aggressiveness of the tumors, and the

technical difficulties associated with pancreatic surgery make pancreatic cancer one of the most

challenging diseases treated by surgeons and oncologists.

In recent years, significant advances have been made in our understanding of the pathogenesis and

clinical management of pancreatic cancer. This chapter will review the epidemiology and risk factors

associated with pancreatic cancer, discuss recent developments in the field of molecular genetics, and

provide an update on the current clinical management of pancreatic cancer.

EPIDEMIOLOGY AND RISK FACTORS

In the United States, it is estimated that nearly 48,960 new cases of pancreatic cancer will be diagnosed

with almost 40,560 people dying of the disease in 2015. Pancreatic cancer accounts for 3% of all cancers

in the United States and is responsible for 7% of all cancer deaths. The incidence of pancreatic cancer in

the United States is 12.4 per 100,000 populations. The lifetime risk for developing pancreatic cancer is

1.5%.1 The incidence of pancreatic cancer has slowly been increasing, with an average increase of 0.8%

per year over the last 10 years (Fig. 55-1). The risk for the development of pancreatic cancer is related

to age, race, sex, tobacco use, diet, and specific genetic syndromes (Table 55-1). The incidence increases

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with advancing age. More than 80% of cases occur in persons between the ages of 60 and 80 years, and

pancreatic cancer is rare in people younger than 40 years. The incidence and mortality rates for

pancreatic cancer in African Americans of both sexes are higher than those in whites. The gender

differences in pancreatic cancer have been equalizing during recent years. Pancreatic cancer is still more

common in men than in women, but the incidence and mortality rates have increased in women while

they have stabilized or slightly decreased in men.

Environmental and dietary factors have also been implicated as risk factors for the development of

pancreatic cancer. The most consistently observed environmental risk for the development of pancreatic

cancer is cigarette smoking. It has been estimated that cigarette smoking can increase the risk for

pancreatic cancer between one and a half and five times. The mechanism is unknown, but carcinogens in

cigarette smoke have been shown to produce pancreatic cancers in laboratory animals. In addition,

autopsy studies have documented hyperplastic changes in pancreatic ductal cells with atypical nuclear

patterns in smokers. Alcohol consumption does not seem to be a risk factor for pancreatic cancer despite

conflicting past reports. Recent studies suggest that past studies linking pancreatic cancer to alcohol use

may have been confounded by tobacco use. Similarly, coffee consumption and exposure to ionizing

radiation have been shown not to be associated with an increased pancreatic cancer risk.

Several epidemiologic investigations have suggested that diet may play an important role in the

development of pancreatic cancer. An apparent association has been noted between pancreatic cancer

and an increased consumption of total calories, carbohydrate, cholesterol, meat, salt, dehydrated food,

fried food, refined sugar, soy beans, and nitrosamines. The risks are unproven for the ingestion of fat,

beta-carotene, and coffee. A protective effect has been reported for dietary fiber, vitamin C, fruits, and

vegetables.3

Figure 55-1. U.S. pancreatic cancer new cases, death rate, and 5-year survival. Adapted from EER Cancer Statistics Factsheets:

Pancreas Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/pancreas.html. Accessed March 10,

2016.

In addition to well-defined genetic syndromes, a number of common conditions have been thought to

be etiologic factors in the development of pancreatic cancer. An apparent association between diabetes

and pancreatic cancer has been suggested. Approximately 80% of patients diagnosed with pancreatic

cancer have impaired glucose metabolism, impaired glucose tolerance, or diabetes mellitus. It is unclear

if alterations in glucose tolerance/metabolism are a causative factor for pancreatic cancer or represent

reaction to an enlarging malignancy in the pancreas. Among patients with newly diagnosed diabetes,

0.85% went on to be diagnosed with pancreatic cancer within 3 years.4 Type II diabetes of at least 5

years duration has been shown to increase the risk of pancreatic cancer twofold.

The risk of pancreatic cancer has been shown to increase as body mass index increases. Examination

of data from the Nurses’ Health Study and the Health Professional’s follow-up study show a 1.72

relative risk (95% CI 1.19–2.48) of pancreatic cancer in patients with a BMI >30 kg/m2 as compared to

individuals with a BMI <23 kg/m2.

Chronic pancreatitis of any cause has been associated with a 25-year cumulative risk for the

development of pancreatic cancer of approximately 4%. Other conditions for which a possible

association with pancreatic cancer has been demonstrated include thyroid and other benign endocrine

tumors, cystic fibrosis, and pernicious anemia.

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Most cases of pancreatic cancer have no obvious predisposing factors. However, it is believed that

between 5% and 10% of pancreatic cancers arise because of a familial predisposition. Six genetic

syndromes have been associated with an increased risk for the development of pancreatic cancer (Table

55-2). These include hereditary nonpolyposis colon cancer, familial breast cancer associated with the

BRCA2 mutation, Peutz–Jeghers syndrome (PJS), ataxia–telangiectasia syndrome, familial atypical

multiple mole–melanoma syndrome, and hereditary pancreatitis.

Table 55-1 Risk Factors for Pancreatic Cancer

Table 55-2 Genetic Syndromes Associated with Hereditary Pancreatic Cancer

MOLECULAR GENETICS

Invasive pancreatic ductal adenocarcinoma (PDAC) are genetically very complex, with wide-spread

chromosome abnormalities, numerous losses and gains of large segments of DNA, and on average, more

than 60 exomic alterations in each cancer.5 PDAC harbors an average of 63 genome alterations, of

which the majority are point mutations. Four key genes are frequently altered in PDAC: KRAS,

CDKN2A, TP53, and SMAD4 (Table 55-3). The most common gene alteration is in KRAS (Kirsten rat

sarcoma viral oncogene homolog), where mutations occur in codons 12, 13, and 61. More than 90% of

PDAC contain KRAS mutations. Point mutations of the K-ras oncogene impair the intrinsic guanosine

triphosphatase activity of its gene product; the result is a protein that is constitutively active in signal

transduction and activates various downstream signaling pathways, including the mitogen-activated

protein kinase (MAPK) cascades. Ras proteins are involved in a variety of cellular functions, including

proliferation, differentiation, and survival. Cyclin-dependent kinase inhibitor 2A gene (CDKN2A) is also

inactivated in up to 90% of PDAC, due to intragenic mutations in association with allelic loss,

homozygous deletion, or hypermethylation of the gene promoter. CDKN2A encodes a cyclin-dependent

kinase inhibitor that controls G1–S transition in the cell cycle. Inactivation of CDKN2A leads to the loss

of an important cell cycle checkpoint and therefore relatively unchecked proliferation. TP53 is one of

the most frequently mutated genes in many types of cancer, and is inactivated in about 75% of PDAC,

mainly due to point mutations or small deletions. The p53 gene product is a DNA-binding protein that

acts as both a cell-cycle checkpoint and an inducer of apoptosis. Inactivation of the p53 gene in

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pancreatic cancer leads to the loss of two important controls of cell growth: regulation of cellular

proliferation and induction of cell death. SMAD4 (DPC4, SMAD family member 4 gene). SMAD4 encodes

a transcription factor that mediates signaling of the transforming growth factor-β (TGF-β) superfamily.

SMAD4 is a tumor-suppressor gene that has been identified on chromosome 18q. This chromosome has

been shown to be missing in nearly 90% of pancreatic cancers. The SMAD4 gene is inactive in almost

50% of pancreatic carcinomas. The mutation appears to be a homozygous deletion in 30% of pancreatic

cancers, and a point mutation in another 20% of tumors. SMAD4 mutations are more specific than p53

or p16 mutations for pancreatic cancer.

Table 55-3 Genetic Alterations in Pancreatic Adenocarcinomas

Germline mutations in BRCA2 and CDKN2A, and less frequently in BRCA1, PALB2 and ATM have been

identified in a small subset of patients with familial pancreatic cancer. The inactivation of BRCA2, which

encodes a protein involved in DNA damage repair, is associated with a 3.5- to 10-fold increased risk of

pancreatic cancer, as well as increased risk of breast and ovarian cancer. In addition, patients with

Lynch syndrome (caused by germline mutation in one of the mismatch repair genes MLH1, MSH2,

MSH6, or PMS2) and PJS (caused by germline mutation of the STK11 gene) are at increased risk of

pancreatic cancer. Approximately 4% of pancreatic cancers can be characterized by disorders of DNA

mismatch–repair genes.6

PATHOLOGY

Tumors of the exocrine pancreas can be classified based on their cell of origin (Table 55-4). The most

common neoplasms of the exocrine pancreas are ductal adenocarcinomas. Approximately 65% of

pancreatic ductal cancers arise in the head, neck, or uncinate process of the pancreas; 15% originate in

the body or the tail of the gland; and 20% diffusely involve the whole gland.

Solid Epithelial Tumors

Ductal Adenocarcinomas

Ductal adenocarcinomas account for more than 75% of all nonendocrine pancreatic cancers. Grossly,

they are white–yellow, poorly defined, hard masses that often obstruct the distal common bile duct or

main pancreatic duct. They are often associated with a desmoplastic reaction that causes fibrosis and

chronic pancreatitis. Microscopically, they contain infiltrating glands of varying size and shape

surrounded by dense, reactive fibrous tissue (Fig. 55-2). The epithelial cells sometimes form papillae

and cribriform structures, and they frequently contain mucin. The nuclei of the cells can show marked

pleomorphism, hyperchromasia, loss of polarity, and prominent nucleoli.

CLASSIFICATION

Table 55-4 Histologic Classification of 645 Cases of Primary Nonendocrine

Cancer of the Pancreas

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