pathology week 17 p1-15

7/30/2019 Pathology Week 17 p1-15

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Pathology Review Block I, Neoplasia, Breast, Heme 12/06/10

TYPES OF NECROSIS:COAGULATIVE InfarctsLIQUIFACTIVE AbscessCASEATION TB GranulomaFAT (ENZYMIC) Pancreas and Breast

Fat Necrosis (L) and Normal Pancreas (R)

Above (left): MI coagulation necrosis. This is an early, unfixed one. Looks like coagulum that you would see in awound, with the serum moving in and clotting.Above (middle): Triangular-shaped architecture of infarction/coagulation necrosis.Above (right): Old infarct (scar) turns white with time.

Abscess neutrophils.

If you have a bacterial infection in the lung (staphinfection), there will probably be an abscess.Likewise, if you see an abscess in the lung, it isprobably caused by something likeStaphylococcus.

Necrotizing granulomas caseous.

If you see this microscopically, however,cannot tell could just as easily be Histoas TB. But if you see the cheese-likematerial grossly, MUST be TB.

Two types of fat necrosis:enzymic and traumatic. Enzymic

is due to destruction of thepancreas release of lipases.In enzymic fat necrosis, there istotal destruction of tissue nooutline of normal tissue (as incoagulation necrosis) and noneutrophils (as in liquefactive).


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More on Markers:Troponin I

Is a specific indicator of MI Appears 4-6 hours post infarction, maybe not until 12 hours Peaks at 16 hours and decrease in 9-10 days persists

CK-MB MB fraction is specific for cardiac muscle, esp when there is no skeletal muscle damage in patient's history Appears to rise 4-6 hours post MI Not elevated in all patients until 12 hours post MI Level returns to baseline in 36-48 hours

Myoglobin Elevates within 1-4 hours, most sensitive during early time period Lacks specificity

BNP (marker for CHF) Beta natriuretic peptide is the active product of a split prohormone in response to atrial or ventricular wall stretch. In this case it is a response to the acute congestive heart failure secondary to acute myocardial infarction. 400 CHF likely (MI survivors are likely to develop heart failure)

Six weeks post-MI, this 56-y.o. male has chest pain, SOB, precordial friction rub. Hedies within days. The cause of the pathology (photo) is?

A. Granulomatous inflammationB. Dresslers syndromeC. Metastatic carcinomaD. Ruptured LVE. Viral infection

Dresslers syndrome several weeks post-MI autoimmune disease can develop.Results in fibrinous pericarditis.

Above: Fibrinous pericarditis

On the final exam, there will be questions about apoptosis and its role in different tumors and infections. In some thingslike follicular lymphoma and HPV, apoptosis is inhibited allows cells to continue to divide. In other things like infections

by pneumocystis, the organism causes the macrophages to undergo apoptosis and eliminate them.

Above (left) is the apoptotic cell in Lichen Planus a Civatte body. Since Civatte bodies are undergoing apoptosis, youcan assume that any of the enzymes involved in apoptosis are active (caspases, etc.) Remember the diagram above intrinsic and extrinsic pathways of apoptosis.


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Defective Apoptosis: Tumors with p53 mutations Follicular lymphomas express high levels of bcl-2 (translocation of bcl-2 gene) HPV- protein E6 binds and inactivates p53 EBV- proteins that mimic or increase production of bcl-2 Autoimmune disorders

Sensitivity, specificity and predictive value: No question on this test. Forget until May. Screening tests Confirmatory tests Prevalence and predictive value

Given the photo, what enzyme abnormality would you expect? A. Increased alkaline phosphataseB. Decreased alkaline phosphataseC. Decreased gamma GTD. Markedly increased AST and ALTE. Decreased direct bilirubin

Answer: A, increased AP: The photos show a gall bladder w/stones bile backs up, damages cells lining the canaliculi release alkalinephosphatase. If you have an obstructive lesion in the biliary tree, could bea stone, pancreatic tumor, bile duct tumor, etc. Alkaline phosphatase

would be markedly elevated in any of these cases.

In this case, the transaminases (which come from the hepatocytes) will not be markedly elevated. If AST and ALT aremarkedly elevated, it means that the liver parenchymal cells are dying more associated w/toxins, hepatitis, etc.

Be able to recognize koilocytes HPV triggers production of proteins E6 and E7 inhibitboth p53 and Rb genes. In HPV, you are inhibitingapoptosis and stimulating cell production.

Figure A = normal cellsB = low grade dysplasia (low grade HPV types like 6, 11)C = moderate dysplasia (nucleus is half the cell)D = severe dysplasia (nucleus is most of the cell)

C and D associated with HPV 16 (high risk type)

Dysplasia: Atypical proliferative changes due to chronic irritation or inflammation; PREMALIGNANT CHANGE

Normal cervix CIS (dysplasia/enlarged nuclei involve the full thickness)


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Metaplasia: A REVERSIBLE change in which one ADULTcell type is replaced by another ADULT cell type.

Different types of metaplasia: Cervix squamous dysplasia. Esophagus glandular dysplasia (Barretts esophagus).Vitamin A deficiency problem of maturation, get metaplasia in the lung. Children who are Vitamin A deficient are muchmore likely to get certain viral infections (measles) and bacterial infections.

This brain tumor superficially invades bone, but not brain tissue. Namethe tumor.

A. Glioblastoma multiforme/astrocytoma grade IVB. Meningioma

C. Metastatic lung CAD. Metastatic breast CAE. Metastatic melanoma

B meningioma. There is no invasion of the brain parenchyma. The tumor iswell demarcated but can kill by compression of the brain. It can locally invadebone, but does not metastasize.

Make sure you can recognize it because it WILL be on final exam eithergross or microscope.

This cut-section of liver is c/w: A. CongestionB. CirrhosisC. HepatitisD. Metastasis

Answer: D, metastasis

The tumor nodules are diffuse (not a primary) and are too big to be cirrhotic nodules there is also an absence of whiteconnective tissue. Multiple nodules of variable sizes metastatic disease.

There will be a gross liver specimen on the final exam will be yellow/red/green/etc. must formulate diagnosis.Variably-sized nodules, diffusely spread through the liver = metastasis. Not primary disease.

Fatty change: In gross specimen, Oil Red O or Sudan Black demonstrates fat.fresh = yellowy/orange. Fixed = pale.

Above and below: meningioma


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NOT cardinal red brick red. Iron granules fine, powdery granules. Green = bile. Will see bile plugs in bile ducts.Hemosiderosis or hemochromatosis. in islets or in hepatocytes

Bile plugs in bile ducts. Solid black material melanin.

Above (right): Cirrhotic liver w/nodules. Be able to recognize microscopically and grossly. Many cases of cirrhosis aredue to viral infections. Both Hep B and C are associated w/hepatocellular carcinoma, so if you see a cirrhotic liver, dontbe surprised if you also have hepatocellular carcinoma present.

Cancer Precursor Lesions Adenomatous polyp Colon AdenoCA Actinic keratosis SC SA Hyperpl./breast Ductal CA Ulcerative Colitis Adeno CA colon

Endom. Hyperplasia Adeno CA endom. Esoph. Metaplasia (Barretts) Esoph. Adeno CA Gastric metaplasia (Helicobacter) Gastric Adeno CA/lymphoma Cirrhosis Adeno CA liver

In any malignancy, it is COMMON to have 4, 5, 6 steps before you ever reach malignancy.

Be able to recognize stages of tumors. Different depending on where you are make sure to identify basementmembrane (BM). In the breast, its the BM of the duct if it goes through that, its invasive cancer. In the skin, if it goesthrough the epidermis into the underlying dermis, its an invasive lesion. In cervix, if it goes through the BM of theepithelium, its invasive. In intestine, its different because the muscularis mucosa is considered to be the BM. If you havea lesion in the intestinal tract that is limited to epithelium, its CIS. If it penetrates the muscularis mucosa, it becomesinvasive.

Below: TNM Staging System.

Helicobacter presents two problems hyperplasia increases the risk foradenocarcinoma, and hyperplasia of

lymphoid material leads to an increased riskfor MALT (low grade B cell) lymphoma.Same kind you get in Hashimotos thyroiditis.


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METASTASIS: LIVER: (portal circulation) GI tract and pancreas; lung, breast,

melanomas LUNG: breast, stomach, sarcomas, renal cell carcinoma (vena caval

system) BONE: 3

rdmost frequent site for metastases; lung, breast, prostate,

kidney, thyroid; PROSTATE to bone gives osteoblastic lesions on Xray(more dense) and high serum alkaline phosphatase

ADRENAL: most common endocrine site

Organs that empty into the portal circulation metastasize to liver. If theyempty into the vena cava, more likely to go to lung and other sites.

Metastasis #1 marker of malignancy. Exceptions: gliomas (astrocytomas) of the brain and basal cell

carcinomas of the skin RARELY metastasize; also, meningiomasLOCALLY invade skull bone, but do not metastasize and are consideredbenign.

Always asked on tests what is number one marker of metastasis?ALWAYS pick malignancy. If its not a choice, pick invasiveness.

Venous Drainage Portal: liver Caval: lungs Paravertebral plexus: thyroid and prostate carcinomas metastasize to the

vertebrae. Renal Cell CA: invades renal vein and grows in the vena cava

In metastasis, have lots of proteins/enzymes. There will be questions on upregulation and downregulation things thatallow cells to stay attached (if they are downregulated, more likely to metastasize). Less cadherin more likely tometastasize. Increased laminin receptors for tumors to attach to upregulated, more likely to metastasize.

Different kinds of lung carcinoma:

A = Squamous CA B = Adeno CA C = Small cell (oat cell) undifferentiated carcinoma D = Large cell CA

A B

C D


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Squamous pearls and intercellular bridges indicate that its squamous CA. Anaplastic tumor: Poorly differentiated.

There was a tumor producing parathormone on the last test the answer was large cell carcinoma. Remember, in lungcancer there are two types of tumors clinically: small cell (aka oat cell, metastatic, treat w/chemotherapy) and large cell.Large cell w/squamous differentiation = squamous cell. Large cell w/glandular differentiation = adenocarcinoma. Largecell without any of that differentiation = large cell. Large cell = bigger than small cell and behaves differently (can treatw/surgery).

Both large cells and squamous cells make parathormone and cause hypercalcemia. Adenocarcinomas do not do this.

Breast Pathology Review

Normal breast: Ducts Terminal ducts lobular units (TDLUs)

o Lined by 2 layers of cells Epithelial (luminal) Myoepithelial (basal) Benign diseases have both cells types Malignant lesions have only one.

Males and females are different.M ducts but no lobules (nothing is connected)F ducts and lobules.

Figure 1: Can see lobules. Each smaller unit is a duct. Normal breasttissue looks like this. Can see double layer myoepithelial layer (seesimilar layer in prostate) and glandular layer. Presence of myoepitheliallayer indicates that it is benign.

Figure 2: Again, can see myoepithelial layer and glandular layer (=benign).

Fibrocystic changes: With age, breast undergoes fibrocystic changes(fibrosis and cystic change).

Terminology--fibrocystic changes, fibrocystic disease, chroniccystic mastitis, periductal mastitis, mammary dysplasia, cystic

mastalgia Three dominant morphologic patterns:

o Cystic formation and fibrosiso Epithelial hyperplasiao Sclerosing adenosis

Demographicso Microscopically extremely common, present to some

degree in 60 to 90% of breasts in routine autopsies Etiology: Variable end-organ response to hormonal stimuli

Fibrocystic disease: blue-dome cyst Not melanoma or malignant. Big cyst filled w/fluid. Slightly bluish tinge.

1

2


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Fibrocystic changes: Cysts and fibrosis Mass and or Microcalcifications Unopened cysts are brown to blue (blue-dome cysts) Very common type - characterized by an increase in

fibrous stroma associated with dilatation of ducts andformation of cysts of various sizes.

Gross cysts > than 3 mm, micro cysts smaller Cysts often lined by large polygonal cells with abundant

eosinophilic cytoplasm--so called apocrine metaplasia.

Fibrocystic changes: cysts and apocrine metaplasia Apocrine metaplasia = benign.

Apocrine metaplasia expanding breast duct Fibrocystic changes: Epithelial hyperplasia

Commonly coexists with fibrosis, cysts, adenosis Microscopically, proliferation causes an increase in the

layers of the duct-lining epithelium beyond the usualdouble layer

Mild, moderate or florid The presence of architectural and/or cellular atypia

warrants a diagnosis of atypical hyperplasia

Epithelial hyperplasia (non-atypical). Increased numbers ofepithelial cells, but they do not completely fill up the lumen. If it was asolid sheet of tumor cells or if necrosis was present within the duct, itwould signify malignant change.

Sclerosing adenosis Clinical- hard cartilaginous consistency that begins to

approximate that found in breast cancer. Can mimic breast cancer on mammography. Microcalcifications frequent Proliferation of both epithelial and myoepithelial cells Minimal or no increased risk for cancer.

We would never be expected to recognize sclerosing adenosis microscopically except to identify that its benign.

Familial Breast Cancer: BRCA1

o Younger women, high grade tumors, ER- BRCA2

o Relatively older, low grade (lobular) tumors Others

o p53, Chk2, ATM, pTENo unknown


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Carcinoma in-situ: Types of ductal carcinoma in-situ (DCIS lesions that are

limited to the breast duct)o Based on ARCHITECTURE (old)

Solid Comedo: On cut section, central necrosis

leads to easily extruded by slight pressuregiving rise the term comedocarcinoma

Cribriform Papillary Micropapillary Usual variants: Apocrine, Clinging, Clear cell

o Based on NUCLEAR GRADE Low Intermediate

High

Figure (above, right): DCIS. No myoepithelial layer.Monotonous sheet of cells completely fills up the breast duct. Cansee foci of microcalcification.

Figure: DCIS note circumscription and cribriformarchitecture In this lesion, the duct was completely filled w/these cells thenstarted undergoing necrosis. Classically described as looking likea cookie-cutter (punched-out lesions in the breast consistentw/malignant change). A big area of necrosis in the middle is alsoa malignant feature = comedocarcinoma.

In both of these lesions, there doesnt appear to be anything going on outside, so it is CIS. Considered curable, but only92% curable in breast. CIS in the cervix is 100% curable. Lower in breast because you cant see all the material (maysee 1 focus of CIS, but there can be other foci). The only way to eliminate it would be a total mastectomy. In the cervix,can visualize all the material and can do a cone biopsy to remove all the diseased material.

Pagets disease:

Specialized form of ductal carcinoma that arises in the mainexcretory ducts of the breast and extends to involve the skinof the nipple and areola.

Clinically, eczematoid changes occur in the nipple andareola.

Ductal carcinoma, with or without invasion, invariablyantedates the skin change.

30 to 40% of women have metastases at the time of surgery Histologic hallmark of this entity is the involvement of the

epidermis by malignant cells, referred to as Paget cells

Figure: Pagets disease of the nipple. Note nests of tumor cellsin epidermis

Figure: Pagets disease If you see these malignant cells in the epithelium of the nipple, alwaysindicates an underlying malignant change/adenocarcinoma may beinvasive or ductal CIS. If you stain w/mucin, they are glandular sowould be mucin+ (not melanin+).


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Above (left): Gross photo of infiltrating carcinoma, note stellate shape. Malignant biopsy w/fat surrounding. Whitishstuff is the tumor can see spicules/fingers going out into the fat (malignant feature).Above (right): Infiltrating ductal carcinoma, note duct-like structures and desmoplastic stroma . See the same thingmicroscopically glands/sheets of tumor cells surrounded by fibrosis desmoplasia. One of the most common places tosee desmoplasia is in invasive breast cancer.

Tumor grading:

Architecture (glands) 1-3Mitoses 1-3Nuclear pleomorphism 1-3

Grade of tumor: In determining how malignant a breast tumor is, it depends on the architecture. Are there glands?Normal tissue has lots of ducts, so lots of ducts are a good thing. Mitoses bad. Want little or none. Nuclearpleomorphism bad if bizarre-looking, clear/dark areas. Want them to be uniform.

Above (left): If a tumor has invaded vascular spaces/lymphatics, it is inflammatory carcinoma. Woman presentsw/swollen red breast, warm to the touch, indicates lymphatic invasion (probably stage 4 lesion widely metastatic).Above (middle): Can stain for estrogen receptors and Her2neu in breast tumors.Above (right): Some tumors (minority of tumors) may have overexpression of Her2neu. If so, are more aggressive patient will not live as long. However, in a subpopulation of people w/a bad prognosis, can be treated w/Herceptin(directed against Her2neu).

Variants of ductal carcinoma:

Good prognosis: Not a lot of malignant cells. Get bigger in volume but not as much cell multiplication.o Tubular carcinoma aka well-differentiated adenocarcinoma of the breasto Mucinous carcinomao Medullary carcinomao Adenoid cystic carcinoma

Bad Prognosis:o Metaplastic carcinomao Squamous cell carcinomao Carcinoma with osteoclast-like giant cellso Apocrine carcinoma


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Tubular carcinoma: Mucinous carcinoma:

Low-grade lesion. Get really big because they make lots of mucin.

Lots of volume but not too many malignant cells.

Invasive lobular carcinoma: WHO definition composed of uniform cells resembling

those of lobular carcinoma in situ and usually having a lowmitotic rate.

The cells grow typically in a single-file, linear arrangement,or appear individually embedded in fibrous tissue.Targetoid growth pattern and identification of remnants oflobular carcinoma in situ aid in the diagnosis.

Signet-ring cells may be seen.

TNM Staging clinical T-Primary tumor based on size

T1: 2cm 5 cm T4: any size with extension to skin/chest wall

N-Regional lymph nodes NX: regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis N1: Metastasis to movable ipsilateral axillary nodes(s) N2: Metastasis to ipsilateral axillary node(s) fixed to one another or to other structures N3: Metastasis to ipsilateral internal mammary lymph nodes

M - Distant metastasis MX: Presence of distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis (includes metastasis to supraclavicular lymph nodes

Prognosis for invasive Breast carcinoma:10-year disease free survival

80% for T1N0 90% for T1N0 < 1 cm.

70% for T2N0 60% for T3N0

Mixed Epithelial and Stromal tumors: Fibroadenoma

Benign Glandular and stromal elements Does not undergo malignant change

Phyllodes tumor More cellular stroma than FA Cellular pleomorphism, necrosis May be benign or malignant

Benign morphology is poor predictor of behavior

INDIAN FILING

The worse the stage, the worse theprognosis. Most important thing to determinefor a tumor is the STAGE. In most cases,stage is more important than grade.


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Fibroadenoma:

Left: carcinoma, star-shaped finger-like extensions.Right: fibroadenoma. Well-circumscribed (= benign, usually).

Hematopathology Review

Tumor Markers:PSA Prostate cancer = prostate specific antigen

CEA Colorectal/PancreaticCA 19-9 PancreaticAlpha-fetoprotein Hepatic/Yolk sacBeta-HCG Choriocarcinoma/Molar pregnancyCA 125 Ovarian cancerS-100 Melanoma/AstrocytomaThyroglobulin Thyroid cancer (follicular carcinoma)Calcitonin Medullary carcinoma of Thyroid

Catecholamines Pheochromocytoma/NeuroblastomaTRAP stain Hairy cell leukemia = tartrate resistant acid phosphatase

Alkaline phosphatase Mets to bones, Pagets disease of bone

Remember that AFP can be seen in liver cancer and testicular cancer.Lots of neural tumors are S-100 positive.

If you have a clinical history (M or F) of high alkaline phosphatase but nothing going on in biliary tree, remember thatosteoblasts also make alkaline phosphatase . In lots of metastatic tumors to the bone, more osteoid is made increasedalkaline phosphatase. If male patient has urinary symptoms and high alkaline phosphatase, probably have prostatecancer metastatic disease.

There will be 1 peripheral blood smear and 2 lymph nodes on labexam. Know RBC changes: target cells thalassemias; immaturecells pumped out of marrow something else is filling up themarrow (leukemia, fibrosis, etc.); HJ bodies spleen is notfunctioning properly or is absent.

Lots of fibrosis and gland-like spaces. Oftensqueezed into trenches that are formed. Benignlesion.

Translocations:t (9;22) CML (bcr-abl)t (8;14) Burkitts lymphoma (c-myc)t (14;18) Follicular lymphoma (bcl-2)t (15;17) AML M3 (promyelocytic

leukemia)t (1;14) T-cell Lymphoblastic lymphomat (11; 22) Ewings sarcomat (11; 14) Mantle cell lymphoma (bcl-1)t (11; 18) MALT lymphoma (API-2)

t (1; 14) MALT lymphoma (bcl-10)


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Above (left): MAHA see schistocytes. Also seen in malfunctioning heart valve. Reticulocytes seen in anything thatcauses hemolysis (RBCs live less than 120 days)Above (right): Fe deficiency hypochromic microcytic anemia. Funny shaped cells. Fe deficiency in an old person MUST worry about occult malignancy (most common is in colon or stomach). Other occult malignancies can also result inFe deficiency. Nutritional Fe deficiency is nearly impossible in the US.

CBC for patient with this blood smear Hgb 5.9MCV 56.2RDW 20.2WBC 5,900Plt 383,000

In Fe deficiency, MCV will be low and RDW will be high indicatesvariation in size of RBCs.

Platelet count tends to be elevated in Fe deficiency because when youhave less RBCs, it stimulates erythropoietin has no effect on RBCsbecause theres no iron, so it also stimulates the platelets. Could see500,000-1,000,000 platelets in patients w/Fe deficiency.

Before the patient leaves your office you should?A. Order TSH and T3B. Order TSH and T4C. Prescribe multivitamins with ironD. Perform stool exam for occult blood ALWAYS check if patient is an older person w/iron deficiency anemia.E. Perform stool exam for hookworms and other parasites

Megaloblastic anemia: see neutrophils w/too many lobes (5+) seen in B12 or folate deficiency. In B12/folatedeficiency, the cells are also often oval in shape.

CBC:Hgb 6 LowMCV 130 HighWBC 6,000 NormalPlt 220,000 Normal


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Peripheral blood smearSee schistocytes and spherocytes. Dont immediately think hereditaryspherocytosis if you see spherocytes. If there are both, think something else, likeMAHA. When these cells get sheared, sometimes are very irregular in shape(schistocytes) but sometimes will round up (spherocytes).

CBC:Hgb 7.0MCV 77RDW 23

WBC 17,000Plt 14,000

Peripheral blood smearSpherocytosis hemolytic anemia (see reticulocytes, too). Platelets present doesnt seem to be MAHA. Not really any schistocytes but lots of spherocytes.

CBC:Hgb 11MCV 84WBC 6,000

Plt 350,000

LEUKEMIA:AcuteALL and AMLHi/Low WBC (unpredictable)Rapidly fatal if untreated (matter of weeks); anemic andthrombocytopenic (almost always. Patient is very sick.)

Curable

ChronicCLL and CMLAlways high WBCSlowly progressive- patient lives many yearsDifficult to cure

Acute Leukemias:

5a. In Acute Leukemias you will almost always find:A. Normal hct, normal plateletsB. Normal hct, decreased plateletsC. Decreased hct, increased palteletsD. Anemia, thrombocytopeniaE. WBC count >100,000

D: Patient is always really sick.

5b. In Chronic Leukemias you will almost always

find:A. Anemia, thrombocytopeniaB. WBC count >50,000C. Normal hct, increased plateletsD. Anemia, thrombocytosisE. Circulating blasts

pathology week 17 p1-15

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