The Sol Goldman Pancreatic Cancer Research Center


Advances and Discoveries Made at Johns Hopkins


New marker for pancreatic cancer (December 2001):
Researchers at Johns Hopkins identified a new marker for pancreatic cancer. This marker was discovered using "SAGE" a technology developed at Johns Hopkins to help scientists determine which genes are expressed (made) by a cancer. Dr. Argani found that almost all pancreatic cancers express the gene called "mesothelin" at levels much higher than those found in normal, non-cancerous, tissues. The discovery that mesothelin is made at high levels in pancreatic cancer has potential diagnostic, imaging, and therapeutic implications. For example, scientists in Dr. Liz Jaffee's lab are already conducting studies in the laboratory to see if mesothelin can be used as an immune target to treat patients with pancreatic cancer.

Clinical Cancer Research (Volume 7, pages 3862-3868)



New prognostic marker for pancreatic cancer (December 2001):
It can be very hard to predict the prognosis for patients with pancreatic cancer. Dr. M. Tascilar and colleagues at Johns Hopkins studied 249 patients with pancreatic cancer who underwent a Whipple resection for pancreatic cancer. Patients with pancreatic cancers that expressed (made) the SMAD4 protein had significantly longer survival (19.2 months) than did patients whose cancers did not express (make) the SMAD4 protein (14.7 months). This SMAD4 survival benefit persisted after adjustment for known prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. From this, Dr. Tascilar was able to conclude that patients undergoing Whipple resection for pancreatic cancer survive longer if their cancers express SMAD4.

This study helps confirm the importance of the SMAD4 gene in pancreatic cancer.

Clinical Cancer Research (Volume 7, pages 4115-4121)

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Unraveling the genetic changes in pancreatoblastomas (August 2001):
While scientists have made great strides in advancing our understanding of pancreatic ductal adenocarcinoma, little is known about rare tumors that arise in the pancreas. Pancreatoblastoma is a rare pancreatic tumor with a distinctive microscopic appearance that generally affects infants and young children. Researchers at Johns Hopkins analyzed a series of nine pancreatoblastomas for genetic alterations (changes in the DNA sequence of the tumors). They found three interesting things. First, pancreatoblastomas are genetically very different from the more common ductal adenocarcinomas of the pancreas. Pancreatoblastomas show alterations (mutations) in the beta-catenin/APC genes. Second, they also showed that chromosome 11p is frequently altered in pancreatoblastomas. Chromosome 11p is frequently altered in hepatoblastomas (a rare pediatric tumor in the liver), suggesting that pancreatoblastomas are more closely related to hepatoblastomas than they are to pancreatic ductal adenocarcinomas. Finally, one of the patients included in the series of pancreatoblastomas had the clinical syndrome called "familial adenomatous polyposis" or "FAP." Patients with familial adenomatous polyposis develop numerous polyps in their colon at an early age and this study demonstrates that they can also develop pancreatoblastomas. An understanding of the variants of pancreatic cancer helps us understand why some tumors occur in adults and some in children. In addition, it should form a basis for targeting specific therapies to specific tumor types.

American Journal of Pathology (Volume 150, pages 1619-1627)

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Markers of cancer invasion (July 2001):
There is a great effort underway to identify new ways to detect cancers early. A major approach is to identify "tumor-specific" and "tissue-specific" markers. For example, useful markers can be substances found to be produced by cancer cells in both tissue culture (cancer cells grown artificially outside the body) and in patient samples. Such markers would not be normally found in normal tissues at a high level. These are the invasion-specific markers. Dr. Ryu and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins searched for such genes. Dozens of invasion-specific markers were identified in invasive cancers obtained from patient samples. Many of these were new markers not previously considered as cancer markers and many of the genes are expressed not by the tumor cells but instead by the patient's response to the tumors. Some of these markers are known to be secreted and to be detectable in simple blood samples. A strong effort is underway to examine these candidates and develop markers for use in the early detection of cancer, to aid medical imaging and to serve as targets for the development of invasion-specific anticancer therapy.

Cancer Research (Volume 61, pages 1833-8)

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Activin receptors-A new anticancer signal in human tumors (June 2001):
The major problem with human tumors is that they do not obey the signals from their surrounding cells that should restrain their growth. To date, very few of such signals have been defined, and this limits our ability to understand and counter this basic abnormality. Because we need to understand these signals, there has been a great effort to identify genes that are mutated and turned off in tumors. These are the "tumor-suppressor genes." The inactivation of these genes allows tumors to escape from the normal growth controls that the surrounding cells and tissue are trying to place on them. Activin is a protein secreted by normal cells. To exert its action, it must bind receptors on a cell.

The receptors propagate a signal to the cell but it was not previously known that these signals were able to suppress tumor growth. Mutations within the activin receptor gene were found in some pancreatic and biliary cancers by Dr. Gloria Su and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins. In tumors that lack the mutations, someday it might be possible to administer activin as a therapeutic strategy. It might also be possible to mimic the effects of activin on tumor cells by a precise molecular targeting using specially designed new drugs that directly activate the signal pathway without the need for intact receptors. This is a new idea that was previously unknown, but now can be explored. It is our hope that one can design a therapy to attack the most vulnerable components of pancreatic cancer.

Proc Natl Acad Sci USA (Volume 98, pages 3254-7)

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Hopkins' scientists use molecular tool to discover new markers of hepatopancreatico-biliary cancer (June 2001):
Dr. Argani and colleagues from Johns Hopkins discover a new marker of pancreatic cancer. This new marker called "prostate stem-cell antigen" (PSCA) was discovered by using a technique developed at Johns Hopkins called "serial analysis of gene expression" (SAGE). Since the original description of SAGE, a group of cooperating scientists from a number of institutions have created an online database of gene expression that includes SAGE data on a variety of tissues and cancers (http://www.ncbi.nlm.nih.gov/SAGE/). The investigators at Johns Hopkins used this database to compare the gene expression levels in pancreatic cancer tissues with those seen in non-cancerous pancreatic tissues. The goal was to identify genes selectively "turned-on" in the cancers. One of the genes found using this approach is called "prostate stem-cell antigen." Prostate stem-cell antigen is a gene originally thought to be largely restricted to prostate cells. Dr. Argani and colleagues demonstrate that prostate stem-cell antigen (PSCA) is, in fact, highly overexpressed in approximately 60% of primary pancreatic cancers. It is not expressed in the normal pancreas. These findings are exciting for several reasons. First, they demonstrate the power of new technologies such as SAGE to discover new tumor markers. Second, PSCA, because it is selectively overexpressed in pancreatic cancers, might be a useful marker for pancreatic cancer. Third, other groups have shown that PSCA can be an immune target and therefore PSCA is being explored as a target for the immune treatment of cancers. The demonstration of PSCA expression in pancreatic cancer suggests a new avenue for treating pancreatic cancers, immunotherapy directed at cells expressing PSCA.

Cancer Research (Volume 61, pages 4320-4324)

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Molecular and immunohistochemical analysis of small cell carcinoma of the gallbladder: An unusual entity (May 2001):
Dr. Argani and colleagues published the largest series of cases examining small cell carcinomas of the gallbladder, a highly unusual neoplasm that has been described only recently. Dr. Maitra characterized the clinical, histopathologic, immunohistochemical and molecular features of 12 small cell carcinomas of the gallbladder. It was discovered that only half of these rare cancers are "pure" and half are combined with other neoplasms (e.g., adenocarcinoma, squamous carcinoma, and rarely, carcinosarcoma). These cancers were studied using molecular and immunohistochemical techniques. We found that the molecular changes in small cell carcinomas were similar to those of adenocarcinomas occurring at this site, with a high frequency of p53 and p16INK4a abnormalities, and a low frequency of deleted in pancreatic carcinoma-4 (Dpc-4) inactivation and K-ras codon 12 mutations. In contrast to small cell carcinomas of the lung, p16INK4a function appears to be abrogated more frequently in these carcinomas. We hope these results will help us develop a rational approach to the diagnosis and therapy of these unusual tumors.

American Journal of Surgical Pathology (Volume 25, pages 595-601)

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Molecular analysis of bile duct carcinomas (April 2001):
Using immunohistochemical labeling, Dr. Argani and colleagues were able to show that the DPC4, a tumor suppressor gene discovered at Johns Hopkins that is known to play a major role in pancreatic cancer, is also targeted in bile duct carcinomas. Loss of Dpc4 protein was identified in a significant percentage of bile duct carcinomas. However, not all bile duct carcinomas were equal: we were able to demonstrate that distal common bile duct carcinomas (those located near the pancreas) were far more likely to demonstrate loss of DPC4 than proximal bile duct cancers (Klatskin tumors and cholangiocarcinomas of the liver). In fact, the frequency of DPC4 loss that we demonstrated in distal bile duct carcinomas (55%) is identical to that which was demonstrated in pancreatic cancer. Similarly, we were able to show that the p53 gene product was abnormally expressed far more frequently in distal bile duct cancers than proximal ones. These results show that distal common bile duct cancers have some of the same genetic alterations as pancreatic cancers, while other bile duct cancers are biologically distinct. We hope that these results will allow us to develop more rational therapies for these tumors.

Cancer (Volume 91, pages 1332-1341)

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Familial pancreatic cancer (March 2001):
For years, isolated reports in the medical literature have suggested that pancreatic cancer runs in some families. For example, it has been reported that former President Jimmy Carter lost his father, two sisters and brother to pancreatic cancer. A. Tersmette and colleagues from Johns Hopkins report that first-degree relatives (brothers and sisters, parents and children) of patients with "familial pancreatic cancer" have a significantly increased risk of developing pancreatic cancer. Tersmette and colleagues followed 341 families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) and found that the first-degree relatives of familial pancreatic patients had an 18-fold increased risk of developing pancreatic cancer when compared to the general population (the "SEER" database). In this study, familial pancreatic cancer was defined as at least a pair of first-degree relatives with pancreatic cancer in a family. Remarkably, if there were three or more family members with pancreatic cancer when the family enrolled in the NFPTR, then the risk of other family members developing pancreatic cancer jumped to 57-fold greater than the general population. This study firmly establishes that "Familial Pancreatic Cancer" is a real entity and it provides a quantitative measure of the risk of pancreatic cancer in these families. Studies such as this will form the basis for identifying individuals at-risk for developing pancreatic cancers who might benefit from new screening tests as they are developed.

Clinical Cancer Research (Volume 7, pages 738-744)

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New vaccine to treat pancreatic cancer (January 2001):
Dr. Elizabeth Jaffee and colleagues at Johns Hopkins report the result of a phase I clinical trial of a novel vaccine treatment for patients with a pancreatic cancer. The vaccine was produced by genetically altering pancreatic cancer cells growing in culture so that the cells would produce large quantities of an immune activating factor called "Granulocytic-macrophage colony-stimulating factor" (or GM-CSF for short). Dr. Jaffee treated 14 patients with this vaccine in a phase I dose escalation trial. The patients underwent surgery at Johns Hopkins after which they received various doses of the vaccine. No dose-limiting toxicities were encountered. Instead, Dr. Jaffee was able to demonstrate that the vaccine induced an anti-tumor immune response in three patients who received the highest dose of the vaccine (>10x107 vaccine cells). Remarkably, these three patients remained alive and free of disease more than 36 months after diagnosis. Based on these results, Dr. Jaffee and her team will conduct phase II trials of the GM-CSF vaccine. These trials are scheduled to begin in the late summer.

The Journal of Clinical Oncology (Volume 19, pages 145-156)

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Consistent overexpression of Fatty Acid Synthase (FAS) in biliary tract carcinomas: A novel target for anti-biliary tract cancer drug development (January 2001):
Fatty Acid Synthase (FAS) is the primary enzyme involved in the breakdown of fats. FAS has been demonstrated to be overexpressed in several human cancers (breast, endometrial, prostate, colon). In some cancers, high levels of FAS expression have been associated with poor prognosis, suggesting that FAS expression may promote tumor growth and virulence. Recently synthesized inhibitors of FAS have demonstrated antitumor activity without concurrent toxicity to normal tissues, and hence hold promise as therapy for tumors that overexpress FAS (Cancer Res 2000; 60: 213-218) (PNAS 2000; 97: 3450-3454). FAS expression had not been studied in biliary tract carcinomas, which are highly aggressive and often do not respond to conventional therapy. Dr. Argani and colleagues recently examined 107 biliary tract carcinomas for FAS overexpression using an immunohistochemical assay on formalin-fixed, paraffin-embedded tissue. FAS was overexpressed in 93% of carcinomas of the biliary tract. Therefore, FAS inhibitors hold promise as a new therapy for biliary tract carcinomas.

Modern Pathology (Volume 14, page 192A)

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New Marker for pancreatic cancer
In the December 2001 issue of Clinical Cancer Research Dr. Argani and colleagues from Johns Hopkins reported the identification of a new marker for pancreatic cancer. This marker was discovered using "SAGE" a technology developed at Johns Hopkins to help scientists determine which genes are expressed (made) by a cancer. Dr. Argani found that almost all pancreatic cancers express the gene called "mesothelin" at levels much higher than those found in normal, non-cancerous, tissues.

Why is this important?
The discovery that mesothelin is made at high levels pancreatic cancer has potential diagnostic, imaging, and therapeutic implications. For example, scientists in Dr. Liz Jaffee's lab are already conducting studies in the laboratory to see if mesothelin can be used as an immune target to treat patients with pancreatic cancer.

Clin Cancer Res 2001 Dec;7(12):3862-8

Top



New prognostic marker for pancreatic cancer
It can be very hard to predict the prognosis for patients with pancreatic cancer. Dr. M. Tascilar and colleagues at Johns Hopkins studied 249 patients with pancreatic cancer who underwent a Whipple resection for pancreatic cancer. Patients with pancreatic cancers that expressed (made) the SMAD4 protein had significantly longer survival (19.2 months) than did patients whose cancers did not express (make) the SMAD4 protein (14.7 months). This SMAD4 survival benefit persisted after adjustment for known prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. From this, Dr. Tascilar was able to conclude that patients undergoing Whipple resection for pancreatic cancer survive longer if their cancers express SMAD4.

Why is this important?
This study helps confirm the importance of the SMAD4 gene in pancreatic cancer. While SMAD4 may be useful as a marker for prognosis, one should always keep in mind, as stated by Stephen Jay Gould, that "the median isn't the message".(www.cancerguide.org)

Clin Cancer Res 2001 Dec;7(12):4115-21

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Unraveling the genetic changes in pancreatoblastomas
While scientists have made great strides in advancing our understanding of pancreatic ductal adenocarcinoma, little is known about rarer tumors that arise in the pancreas. Pancreatoblastoma is a rare pancreatic tumor with a distinctive microscopic appearance that generally affects infants and young children (click here for more information on pancreatoblastomas and other rarer variants of pancreas cancer). Dr. Abraham analyzed a series of nine pancreatoblastomas for genetic alterations (changes in the DNA sequence of the tumors). She found three interesting things. First, pancreatoblastomas are genetically very different from the more common ductal adenocarcinomas of the pancreas. Pancreatoblastomas show alterations (mutations) in the beta-catenin/APC genes. 2) Dr. Abraham also showed that chromosome 11p is frequently altered in pancreatoblastomas. Chromosome 11p is frequently altered in hepatoblastomas (a rare pediatric tumor in the liver), suggesting that pancreatoblastomas are more closely related to hepatoblastomas than they are to pancreatic ductal adenocarcinomas. 3) Finally, one of the patients included in Dr. Abraham's series of pancreatoblastomas had the clinical syndrome called "familial adenomatous polyposis" or "FAP". Patients with familial adenomatous polyposis develop numerous polyps in their colon at an early age and Dr. Abraham demonstrates that they can also develop pancreatoblastomas.

Why is this important?
An understanding of the variants of pancreatic cancer helps us understand why some tumors occur in adults and some in children. In addition, it should form a basis for targeting specific therapies to specific tumor types.

American Journal of Pathology 159:1619-1627, 2001

Top



Markers of Cancer Invasion
In an effort to identify new ways to identify cancers that otherwise would remain undetected for too long, Dr. Ryu and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins searched for genes ("markers") produced by the invasive tumor or the body's reaction to it. Dozens of invasion-specific markers were identified in invasive pancreatic cancers obtained from patient samples. Many of these were new markers not previously considered as cancer markers, and many of the genes are expressed not by the tumor cells but instead by the patient's response to the tumors. Some of these markers are known to be secreted and to be detectable in simple blood samples.

Why is this important?
A strong effort is underway to examine these candidate genes and to develop markers for use in reliable assays for cancer that can be done on serum, to aid medical imaging, and to serve as targets for the development of invasion-specific anticancer therapy.

Cancer Res 61: 1833-1838, 2001

Top



Activin Receptors - A New Anticancer Signal in Human Tumors
The major problem with human tumors is a social one. Tumor cells do not obey the signals from their surrounding cells that should restrain their growth. To date, very few of such signals have been defined, and this limits our ability to understand and counter this basic abnormality.

Because of the need to understand these signals, there has been a great effort to identify genes that are mutated and turned off in tumors. These are the tumor-suppressor genes. The inactivation of these genes allows tumors to escape from the normal growth controls that the surrounding cells and tissue are trying to place on them.

Activin is a protein secreted by normal cells. To exert its action, activin must bind receptors on a cell. The receptors propagate a signal to the cell, but it was not previously known that these signals were able to suppress tumor growth. Mutations within the activin receptor gene were found recently in some pancreatic cancers by Dr. Gloria Su and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins.

Why is this important?
In tumors that lack the mutations, someday it might be possible to administer activin as a therapeutic strategy. It might also be possible to mimic the effects of activin on tumor cells by a precise molecular targeting using specially designed new drugs that directly activate the signal pathway without the need for intact receptors. This is a new idea that was previously unknown, but now can be explored. It is our hope that one can design a rational therapy that would specifically attack the most vulnerable components of pancreatic cancer.

Proc Natl Acad Sci USA. 98: 3254-3257, 2001

Top



Discovery of New Markers of Pancreatic Cancer
In the June 1st issue of Cancer Research Dr. Argani and colleagues from Johns Hopkins described the discovery of a new marker of pancreatic cancer. This new marker called "prostate stem-cell antigen" (PSCA) was discovered by using a technique developed at Johns Hopkins called "serial analysis of gene expression". Since the original description of SAGE, a group of cooperating scientists from a number of institutions have created an online database of gene expression that includes SAGE data on a variety of tissues and cancers (www.ncbi.nlm.nih.gov/SAGE/). The investigators at Hopkins used this database to compare the gene expression levels in pancreatic cancer tissues with those seen in non-cancerous pancreatic tissues. The goal was to identify genes that were selectively "turned-on" in the cancers. One of the genes the Hopkins found using this approach coded for a protein called "prostate stem-cell antigen." Prostate stem-cell antigen is a gene that was originally thought to be largely restricted to prostate cells. Dr. Argani and colleagues demonstrate that prostate stem-cell antigen (PSCA) is, in fact, highly overexpressed in approximately 60% of primary pancreatic cancers. It is not expressed in the normal pancreas.

Why is this important?
These findings are exciting for several reasons. First, they demonstrate the power of new technologies such as SAGE to discover new tumor markers. Second, PSCA, because it is selectively overexpressed in pancreatic cancers, maybe a useful marker for pancreatic cancer. Third, other groups have shown that PSCA can be an immune target and therefore PSCA is being explored as a target for the immune treatment of cancers. The demonstration of PSCA expression in pancreatic cancer suggests a new avenue for treating pancreatic cancers. That is, immunotherapy directed at cells expressing PSCA.

On an important side note, this work was supported, in large part, by generous donations from the friends and family of Michael Rolfe demonstrating the power of private giving to advance pancreatic cancer research.

Cancer Research 61:4320-4324, 2001.
(http: //cancerres.aacrjournals.org/cgi/content/full/61/11/4320)

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Familial Pancreatic Cancer
For years, isolated reports in the medical literature have suggested that pancreatic cancer runs in some families. For example, it has been reported that former President Jimmy Carter lost his father, brother and two sisters from pancreatic cancer.

Tersmette and colleagues from Johns Hopkins report that first-degree relatives (brothers and sisters, parents and children) of patients with "familial pancreatic cancer" have a significantly increased risk of developing pancreatic cancer. Tersmette and colleagues followed 341 families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins and found that the first-degree relatives of familial pancreatic patients had an 18-fold increased risk of developing pancreatic cancer when compared to the general population (the "SEER" database). In this study, familial pancreatic cancer was defined as at least a pair of first-degree relatives with pancreatic cancer in a family. Remarkably, if there were three or more family members with pancreatic cancer when the family enrolled in the NFPTR, then the risk of other family members developing pancreatic cancer jumped to 57-fold greater than the general population.

Why is this important?
This study firmly establishes that "Familial Pancreatic Cancer" is a real entity and it provides a quantitative measure of the risk of pancreatic cancer in these families. Importantly, studies such as this will form the basis for identifying individuals at-risk for developing pancreatic cancer who might benefit from new screening tests as they are developed.

If you have a strong family history of pancreatic cancer and would like to join the research studies currently underway at Hopkins, please consider joining the NFPTR. If you would like to join, please contact the Coordinator of the NFPTR, Mirian Tillery.

Clin Cancer Res 7:738-744, 2001
(http://clincancerres.aacrjournals.org/cgi/content/full/7/3/738)

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New Vaccine to Treat Pancreatic Cancer
In the January issue of The Journal of Clinical Oncology (volume 19; 2001: pages 145-156), Dr. Elizabeth Jaffee and colleagues at Johns Hopkins reported the result of a phase I clinical trial of a novel vaccine treatment for patients with a pancreatic cancer. The vaccine was produced by genetically altering pancreatic cancer cells growing in culture so that the cells would produce large quantities of an immune activating factor called "Granulocytic-macrophage colony-stimulating factor" (or GM-CSF for short). Dr. Jaffee treated 14 patients with this vaccine in a phase I dose escalation trial. The patients underwent surgery at Hopkins after which they received various doses of the vaccine. No dose-limiting toxicities were encountered. Instead, Dr. Jaffee was able to demonstrate that the vaccine induced an anti-tumor immune response in three patients who received the highest dose of the vaccine (>10x107 vaccine cells). Remarkable, these three patients remained alive and free of disease more than 25 months after diagnosis.

Why is this important?
Based on these results, Dr. Jaffee and her team are conducting phase II trials of the GM-CSF vaccine. As much as Dr. Jaffee would like to offer the vaccine to everyone, eligibility criteria had to be established for this study. Patients with adenocarcinoma of the pancreas who have surgery Johns Hopkins Hospital to remove their pancreas cancer and who have no clinical evidence of spread of the cancer outside the pancreas will be eligible for this study. Patients with bile duct cancer or neuroendocrine tumors or islet cell cancer are not eligible. Please contact Dr. Elizabeth Jaffee or Barbara Biedrzycki, R.N. for more information on eligibility criteria.

The Journal of Clinical Oncology 19:145-156, 2001

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