What's New
11/4/98

Although we don't generally think of them this way, cancer cells have a lot in common with normal cells. Kind of like the "good kid" that commits some horrendous crime. That's why we can't sweep the criminals off the streets, and why we can't easily imagine powerful cancer drugs that do their magic without any unintended side effects. In all likelihood, most of the rules a cancer cell lives by, are the same rules the other cells in your body live by. This makes cancer therapy hard.

But certainly, this can't be right. We get televisions fixed when only a single small part breaks. The same holds for cars, houses, and bicycles. Maybe if we exactly just what was broke in a cancer cell, we could fix it. This is the goal known as the search for "rational therapy". Many people don't realize it, but virtually none of our current anticancer drugs were originally designed to cure cancer. They were, in actuality, found by chance, often through the screening of tens of thousands of compounds to see which ones happened to work. It is no wonder that they are a disappointing answer to the cancer problem.

But this analogy still has problems. What if your auto mechanic knew exactly the part needed for your car, but he couldn't order it because no one made the spare parts for your vehicle? And this is why rational therapy in cancer is not currently available. The parts do not yet exist. Although the genetic revolution in cancer research has shown us what parts are missing, more efforts need to be devoted to design those spare parts and the tools needed to install them.

A major step towards this is now underway for pancreatic cancer. Drug companies have been trying to develop drugs that turn off the overactive mutant K-ras gene that exists in over 90% of pancreatic cancers, so far without success, but with continued hope. Recently, Dr. Kern's laboratory at Hopkins has published its studies that begin to build a foundation for rational therapy based on the tumor-suppressor gene, DPC4.

First they needed to know what was "broken" in pancreatic cancer. DPC4 helps receive and then implement a suppressive signal that controls the behavior of cells. But how it did that was unknown. Jiale Dai, a postdoc in the laboratory, discovered that the DPC4 could bind to specific sequences of DNA. This was published last March (Molecular Cell 1998, 1:611). That paper outlined how DPC4 can identify certain locations on DNA. Once it is attached to DNA at these sites, it stimulates the production of protein from the nearby genes. These proteins then presumably cause the cell to slow its growth, causing an important tumor-suppressive effect and preventing the cell from growing like a cancer. This effect is lost when DPC4 gets deleted or mutated in many pancreatic cancers.

In follow-up work just published this month (Cancer Research 1998, 58:4592), Dr. Dai presented a comprehensive study of these small mutations in DPC4. He was able to classify the various mutations into three types. One type directly interferes with the ability of DPC4 to bind to DNA. Another class of mutations allows DPC4 to bind to DNA, but interferes with its ability to increase the production of the nearby genes. A third type of mutation interfered with the ability of DPC4 to receive the suppressive signals that it is supposed to help transmit. Indeed, even when DPC4 is not lost or mutant (which is the case in half of pancreatic cancers), there is often a weakness in this original signal. Normally, these "upstream" signals cause DPC4 to move from the outer part of the cell (the cytoplasm) to the nucleus of the cell, where DNA and genes are located.

Dr. Dai then proposed a therapeutic strategy, a completely new drug design that could act to help overcome some of these problems. He proposed that a drug which attached to DPC4 and caused it to relocate to the nucleus might augment any defective upstream signals, potentially aiding the cell's own tumor suppression system and specifically overcoming some of the cancer defects. He then tested some newly-engineered forms of DPC4 protein that he could send to the nucleus at will. These were able to enhance the weakened signals of some pancreatic cancer cells, and even returned some function to mutant DPC4 proteins (those in the third class described above). This is the first experimental evaluation of a designer drug strategy to turn on the broken tumor-suppressor genes in pancreatic cancer.

The science of the new millennium will admit its shortcomings if its promising ideas do not at first produce fruit. But the search for rational drug design will persevere. This research will be exciting, expanding in scope and sophistication. We will tackle cancer without leaving the task to chance alone.

We are creating a new section for this web site! This section will cover Frequently Asked Questions about PC. It is currently being designed and will be added to this site in early 1999. We want this to be a useful resource for new visitors as well as for the repeat visitors that have been dealing with PC for some time.

I am asking for your suggestions for Frequently Asked Questions. What are the questions you had or still have in dealing with this disease? I am particularly interested in those questions that will benefit from a visual explanation (a drawing, photograph, diagram, chart, list, animation, etc.).

You may want to respond in a "Top Ten" format with #1 being the most urgent or confusing topic. This will give me a good sense of what is most important to PC patients, family and friends. The questions could be related to the anatomy or function of the pancreas, symptoms, treatments, surgery, adjuvant therapy, post-operative care, genetics, metastases, etc.

Please don't hesitate to include ANY question or suggestion. Think of this as a virtual brainstorming session. You can remain anonymous if you want and your suggestions will be confidential, or feel free to include a return e-mail address. I will be collecting suggestions over the next month.

In the July, 1998 issue of the Annals of Surgery, Toby Gordon ScD and colleagues examined the statewide in-hospital mortality rate for pancreaticoduodenectomies (Whipple resections) performed in Maryland over a 12-year period. A total of 795 pancreaticoduodenectomies were performed in Maryland at 43 hospitals from 1984 to 1995. During this period, one institution (Johns Hopkins) increased its yearly share of pancreaticoduodenectomies from 20.7% to 58.5%. This increase in regionalization of the surgery (performance of the surgery at specialized high volume centers such as Hopkins) was associated with a remarkable decline in the statewide in-hospital mortality rate for the procedure from 17.2% to 4.9%. After adjustment for patient characteristics and study year, hospital share (the number of Whipples the hospital performs per year) remained a significant predictor of mortality. Remarkably, an estimated 61% of a decline in the statewide in-hospital mortality rate for pancreas cancer surgery was attributable to the increase in share of surgeries performed at the high volume provider (Hopkins). These data confirm previous observations by Toby Gordon and others that suggest that pancreaticoduodenectomies (Whipple procedures) are safest when they are performed at hospitals with extensive experience with this procedure, and which perform a large number of Whipples every year. Furthermore, the data suggest that as the health care market is restructured, that regionalization of health care services should result in optimization of outcomes for complex, high risk elective surgeries.

Reference

1. Gordon TA; Bowman HM; Tielsch JM; Bass EB; Burleyson GP;Cameron JL. Statewide regionalization of pancreaticoduodenectomy and its effect on in-hospital mortality. Annals of Surgery 228: July 1998, pages 71-78.

When is an accelerator used as a brake?

When it's a new type of tumor-suppressor gene, apparently.

Cancer cells could be said to be hyperactive. They make new cells faster than is appropriate, and invade neighboring areas when they should stay still. Cancer cells have two major types of changes in their genes that cause this. Some of the normal growth-promoting genes become overactive, and these genes are termed oncogenes. In the classic automotive metaphor, they correspond to the cell's accelerator pedal. A separate set of genes normally suppresses the cell, and are called tumor-suppressive genes. These are the brakes. When oncogenes are activated, or tumor-suppressor genes are turned off, tumors can grow and spread. Thus in a cancer cell, genetic changes are easy to interpret. If a change appears to activate a gene, the gene is an oncogene. If it inhibits or deleted a gene, the gene is a tumor-suppressor gene. Easy.

The process by which one cell becomes two is called "mitosis". Some of the substances that a cell encounters in its environment act to stimulate the cell to undergo mitosis. These are called, "mitogens". Once a cell encounters a mitogen, a number of proteins in the cell relay the signal down to the nucleus of the cells where it is interpreted as a command to grow and divide, forming new cells. These proteins are the subject of a great deal of scientific interest, and are in a category of proteins called, "mitogen-activated protein kinases", or simply "MAP kinases". In a cancer cell, MAP kinases were initially expected to be activated - certainly not inactivated. MAP kinases were interesting in part because they are suspected of acting as oncogenes.

Eyebrows were raised when the first genetic changes were found in a human MAPK gene. Myriad Genetics reported finding occasional alterations in a gene called MKK4, or "MAP kinase kinase 4". The mutations were rare, affecting only a few percent of a very large panel of samples that consisted of multiple tumor types. Mutations were found in two pancreatic cancers, as well as some tumors of testis, breast, and colon. And the mutations included inactivating mutations and total deletions of the gene, clearly suggesting that MKK4 was a tumor-suppressor, not an oncogene! Perhaps because this was a very confusing set of findings, the discovery did not seem to generate the excitement that some felt was due.

Dr. Gloria Su, as postdoctoral fellow of the Kern laboratory at Johns Hopkins, has now published the first study that confirms these findings. MKK4 indeed harbors the classic mutations of a tumor-suppressor gene. In her recent study, published in the June 1 issue of the journal Cancer Research, mutations were found to affect about 4% of pancreatic cancers, some biliary cancers, and 15% of breast cancers. This makes MKK4 the seventh tumor-suppressor gene found to involve pancreatic cancer, and one of the more common tumor-suppressor genes mutated in breast cancer. Her study also determined for the first time that the mutations indeed occurred during the growth of the tumors.

A closer look at MKK4 shows that it is much more than a simple mitogenic gene. For the pathways regulated by MKK4 are also activated by stresses, such as exposure to chemotherapy. The MKK4 pathway appears to be responsible for a number of consequences, such as cell death and differentiation (moving the cell toward a more mature, functioning state), that indeed do make sense for a tumor-suppressor gene to participate in.

The low percentage of mutations raises a number of questions. Are there other important genes of the MKK4 pathway that are mutated at a high frequency, but that have been simply overlooked? Can we find a way to use the pathway in diagnosis? If the pathway is important enough to be mutated in some patients, but still remains intact in most cancers, can it be harnessed for therapy of the disease? What exactly does the pathway do in pancreatic cells? How soon until we understand why it is important in tumorigenesis?

The discoveries will come in time. The pursuit for these answers is what keeps pancreatic cancer research so exciting.

Reference:

1. Cancer Research 1998; 58:2339-2342

      The question often comes up, "How old is too old to have a Whipple?" In this month's issue of the Journal of Gastrointestinal Surgery (J Gastroentest Surg 1998;2:207-216) Drs. Sohn, Yeo, and colleagues, from Johns Hopkins, try to answer this question. They studied forty-six patients over the age of eighty who had a pancreaticoduodenectomy (Whipple resection) at Johns Hopkins. They then compared the outcome of these forty-six patients to the outcome of six hundred eighty-one patients who had a Whipple at Hopkins but were younger than eighty years of age. Interestingly, patients eighty years of age or older had a shorter operative time (6.4 hours versus 7 hours) but a longer post-operative length of stay (median fifteen days versus thirteen days). There were slightly more complications in the older patients than in the younger patients, but the mortality from the surgery was the same. Importantly, long-term survival was good for patients eighty years of age or older. The patients in the eighty years or older age group had an average survival of thirty-two months, and a five-year-survival rate of 19%. This compared to an average survival of twenty months and a five-year-survival rate of 27% in the patients younger than eighty years.

      These data demonstrate that Whipple procedures (pancreaticoduodenectomies) can be performed safely in selected patients eighty years of age or older, with morbidity and mortality rates approaching those observed in younger patients. Based on these data, Dr. Sohn and colleagues suggest that age alone should not be a contraindication to pancreaticoduodenectomy.

Reference

1. Sohn TA, Yeo CJ, Cameron JL, Talamini MA, Hruban RH, Sauter PA, Coleman J, Ord SE, Grochow LB, Abrams RA, Pitt HA. Should pancreaticoduodenectomy be performed in octogenarians? J. Gastroentest Surg 1998;2:207-216.

      The question often comes up, "How old is too old to have a Whipple?" In this month's issue of the Journal of Gastrointestinal Surgery (J Gastroentest Surg 1998;2:207-216) Drs. Sohn, Yeo, and colleagues, from Johns Hopkins, try to answer this question. They studied forty-six patients over the age of eighty who had a pancreaticoduodenectomy (Whipple resection) at Johns Hopkins. They then compared the outcome of these forty-six patients to the outcome of six hundred eighty-one patients who had a Whipple at Hopkins but were younger than eighty years of age. Interestingly, patients eighty years of age or older had a shorter operative time (6.4 hours versus 7 hours) but a longer post-operative length of stay (median fifteen days versus thirteen days). There were slightly more complications in the older patients than in the younger patients, but the mortality from the surgery was the same. Importantly, long-term survival was good for patients eighty years of age or older. The patients in the eighty years or older age group had an average survival of thirty-two months, and a five-year-survival rate of 19%. This compared to an average survival of twenty months and a five-year-survival rate of 27% in the patients younger than eighty years.

      These data demonstrate that Whipple procedures (pancreaticoduodenectomies) can be performed safely in selected patients eighty years of age or older, with morbidity and mortality rates approaching those observed in younger patients. Based on these data, Dr. Sohn and colleagues suggest that age alone should not be a contraindication to pancreaticoduodenectomy.

Reference

1. Sohn TA, Yeo CJ, Cameron JL, Talamini MA, Hruban RH, Sauter PA, Coleman J, Ord SE, Grochow LB, Abrams RA, Pitt HA. Should pancreaticoduodenectomy be performed in octogenarians? J. Gastroentest Surg 1998;2:207-216.

What's New
5/6/98

         The National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins is now 4 years old and over 300 families have joined this Registry. We periodically update the registrants with the latest development in pancreatic cancer research and I wanted to take this opportunity to share the letter we are sending out to the participants in NFPTR with you. Below is our spring 1998 letter.

Dear Friends of The NFPTR:

        The last several years have witnessed dramatic advances in our understanding of the genetic basis for the development of pancreatic cancer and I wanted to update everyone who has helped our efforts with The National Familial Pancreas Tumor Registry (NFPTR).

        The NFPTR has enrolled over 300 families (called kindreds). Slightly more than 130 of these kindreds are families in which two or more first-degree relatives have been diagnosed with pancreatic cancer, called "familial" cases. The remaining 170 families have only one family member with pancreatic cancer; these are called "sporadic" cases. Our initial analysis of the first 212 families (80 familial, 132 sporadic) enrolled in The NFPTR revealed that the increased risk of pancreatic cancer seen in familial cases of pancreatic cancer may also extend to involve the second-degree relatives (aunts, uncles, cousins, etc.) of patients with pancreatic cancer. Twelve (3.7%) of the 324 second-degree relatives of the familial cases developed pancreatic carcinoma compared to only four (0.6%) of the 702 second-degree relatives of sporadic pancreatic cancer cases (See reference #1). Furthermore, this increased risk of cancer in second-degree relatives of familial pancreatic cancer cases was also seen in other cancer types (27.2% vs. 12.1%). The most common other cancers to occur in relatives of pancreatic cancer patients in this study were breast cancer, lung cancer, and colon cancer. These exciting preliminary results help establish that pancreatic cancer does indeed aggregate in some families. It is our hope that an understanding of the genetics pancreatic cancer will help define the causes of this aggregation. We have therefore concentrated our research efforts on understanding the genetics of pancreatic cancer. These genetic studies have been very fruitful and I wanted to update you on a few of our recent discoveries. We have:

(1)        Discovered the Deleted in Pancreas Cancer 4 gene (DPC4 ) (reference #2) and showed that this gene is inactivated in approximately 50% of cancers of the pancreas. The identification of this gene may lead to novel therapeutic strategies to treat pancreas cancer.

(2)        Helped in the discovery of the second breast cancer gene (BRCA2) (reference #3) and showed that this gene plays a role in the development of carcinoma of the pancreas (reference #4). Furthermore, it appears that patients who inherit a defective copy of this gene are at increased risk for developing pancreatic cancer. Our findings therefore suggest that patients with inherited BRCA2 gene mutations may benefit from screening both for breast cancer and for pancreatic cancer.

(3)       Demonstrated that the p16 gene is frequently inactivated in pancreatic cancer (reference #5) and that some cases of familial pancreatic cancer are caused by inherited mutations (changes in the DNA sequence) in this gene (reference #6). Again, this finding has important implications for screening for early pancreatic cancers in patients with inherited p16 mutations.

(4)        Described a new variant of pancreatic cancer. This new form can be recognized by routine microscopic examination. It is also associated with a specific genetic alteration called "microsatellite instability" (reference #7). This variant may have a better prognosis and may respond differently to chemotherapy and it is therefore important to recognize.

(5)        Identified hundreds of genes overexpressed in pancreas cancer using a revolutionary new technique developed here at Johns Hopkins called SAGE (reference #8). We then demonstrated that these overexpressed genes can be used to develop new blood markers that are increased in persons with pancreatic cancer (reference #9). It is our belief that this approach might lead to the development of a new blood test that would enable the earlier diagnosis of pancreatic cancer.

(6)       Demonstrated that many infiltrating carcinomas of the pancreas arise from microscopically identifiable precursor lesions in the pancreas (reference #10). This finding suggests that if these early lesions can be detected, patients can be treated before the cancer has spread beyond the pancreas.

(7)       Characterized the genetic alterations in pancreatic cancer at the chromosome level and at the DNA level (references #11 and 12).

(8)       Demonstrated that genetic alterations in pancreatic cancers can be detected in various other specimens such as duodenal fluid (reference #13) and in the stool (reference #14) of patients with pancreatic cancer. These studies established that an improved understanding of the genetic alterations of cancer of the pancreas may lead to new techniques to detect these tumors earlier.

(9)       Demonstrated that the p53 tumor suppressor gene is frequently inactivated in pancreatic cancer (reference #15).

(10)       We established a World Wide Web page on carcinoma of the pancreas. The Web address is http://pathology.jhu.edu/pancreas We are particularly proud of this Web page and we feel that it has provided an invaluable resource to patients, family members, and friends battling pancreatic cancer. For example, there have already been close to 1 million accesses to the Web page and over 15,000 messages have been posted in the chat room section of this Web page. These numbers are quite remarkable considering that approximately 27,000 Americans are diagnosed every year with pancreatic cancer. We continually update this Web page. For example, there is a section of this Web page entitled, "What's New" in which we post our latest discoveries. Those of you who have not visited this Web page are encouraged to do so.

(11)       In addition, Dr. E. Jaffee here at Johns Hopkins has developed a pancreas cancer vaccine. This is a way to help a patient's own immune system battle against the cancer. Dr. Jaffee tells us that this vaccine has just completed its phase I clinical trials. She is in the process of analyzing the data and hopes to begin the phase II trial shortly. If successful, this vaccine will open up an entire new way to treat pancreatic cancer.

These are just some of our accomplishments over the last three to four years. A more complete list can be found in the References section of our Web page (http.//pathology.jhu.edu/pancreas).

        As you can tell from this summary, our work centers on the realization that cancer is a genetic disease. We believe that by studying families in which there is an aggregation of pancreas cancer and by studying the genetic alterations found in the cancers of the pancreas, we will better understand what causes it. Once we identify the causes we can develop new strategies to prevent this disease. Furthermore, once we identify the genes involved in the development of cancer of the pancreas, we can develop new gene-based screening tests to screen family members at risk for the disease. The goal of this would be to detect clinically early cancers while they are still surgically treatable. Finally, as we come to a better understanding of the genetics of cancer of the pancreas we can develop rational therapeutic strategies to treat this disease.

         Finally, before I close, I wanted to let everyone know about an exciting fund raiser that Michael Landon Jr., (the son of the late TV actor) and Pam Acosta (one of the more active participants in our Web page) are organizing to raise awareness of carcinoma of the pancreas and to support our research efforts here at Johns Hopkins. This exciting dinner will take place on November 8, 1998 at The Beverly Hills Hotel in Beverly Hills California. Those of you wishing to find out more about this may contact Pam Acosta (909) 983-0655 or Deb Barbara at (410) 955-9485.

         I sincerely wish everyone well and I hope that you find this information helpful.

With warm regards,

Ralph H. Hruban, M.D.
Associate Professor of Pathology
Associate Professor of Oncology
Director, National Familial Pancreas Tumor Registry

P.S. A number of you have asked about the results of any research that may have been done on your blood sample. These analyses take many years and in most cases we have not found any changes. Nonetheless, I wanted to assure you that we will contact you if we do find something that we feel may benefit your family.

References

1. Hruban RH, Petersen GM, Kern SE. Genetics of Pancreatic Cancer. From Genes to Families. Surgical Oncology Clinics of North America 7:1-23, 1998.

2. Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor-suppressor gene at human chromosome 18q21.1. Science 271:350-353, 1996.

3. Schutte M, da Costa LT, Hahn SA, Moskaluk C, Hoque ATMS, Rozenblum E, Weinstein CL, Bittner M, Meltzer PS, Trent JM, Yeo CJ, Hruban RH, Kern SE. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci USA 92:5950-5954, 1995.

4. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein C, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Research 56:5360-5364, 1996.

5. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schmiegel W, Baylin SB, Kern SE, Herman JG. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Research 57:3126-3130, 1997.

6. Moskaluk CA, Hruban RH, Lietman A, Jackson C, Yeo CJ, Lynch HT, Kern SE. Novel germline p16INK4 mutations in familial pancreatic carcinoma. Human Mutation (in press, 1998).

7. Goggins M, Griffin CA, Turnacioglu K, Hilgers W, Hahn SA, Shekher M, Tang D, Song T, Offerhaus J, Yeo, CJ, Kern SE, Hruban RH. Adenocarcinomas of the pancreas with DNA replication errors (RER+) are associated with a characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol., June 1998

8. Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR, Vogelstein B, Kinzler KW. Gene expression profiles in normal cancer cells. Science 276:1268-1272, 1997.

9. Zhou W, Sokoll LJ, Bruzek DJ, Zhang L, Velculescu VE, Goldin SB, Hruban RH, Kern SE, Hamilton SR, Chan DW, Vogelstein B, Kinzler KW. Identifying markers for pancreatic cancer by gene expression analysis. Cancer Epidemiology, Biomarkers and Prevention 7:109-112, 1998.

10. Brat DJ, Lillimoe KD, Yeo CJ, Warfield PB, Hruban RH. Progression of pancreatic intraductal lesions (High grade PanIN) to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol. 22:163-169, 1998.

11. Griffin CA, Hruban RH, Morsberger LA, Ellingham T, Long PP, Jaffee EM, Hauda KM, Bohlander SK, Yeo CJ. Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res 55:2394-2399, 1995.

12. Hahn SA, Seymour AB, Hoque ATMS, Schutte M, da Costa LT, Reston MS, Caldas C, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. Alleotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res 55:4670-4675, 1995.

13. Wilentz RE, Chung CH, Strum PDJ, Musler A, Sohn TA, Offerhaus GJA, Yeo CJ, Hruban RH, Slebos RJC. K-ras mutations in duodenal fluid from patients with pancreas cancer. Cancer 82(1):96-103, 1998.

14. Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SE. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54:3568-3573, 1994.

15. Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Can Res 54:3025-3033, 1994.

A new type of pancreatic cancer has been discovered by scientists at Johns Hopkins. this cancer was discovered based on a unique type of genetic change preent in the DNA from this cancer.
4/1/98

Reference

1. Michael Goggins, G. Johan A. Offerhaus, Werner Hilgers, Constance A.Griffin, Manu Shekher, David Tang, Taylor A. Sohn, Charles J. Yeo, Scott E. Kern, Ralph H. Hruban. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. American Journal of Pathology 1998: 152: 150101507.

Risks of Cancer in Families with Pancreatic Cancer
3/24/98

New Markers for Pancreatic Cancer
Whats New 2/18/98