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Investigators at Johns Hopkins studied over 60 of these rare tumors and found that with careful examination they could accurately separate mucinous cystic tumors into two groups those that are entirely benign (the tumors never recurred) if completly resected ("mucinous cystadenomas") and those that had a malignant or cancerous potential ("mucinous cystadenocarcinomas"). This study by Dr. Robb Wilentz is reported in the November issue of the American Journal of Surgical Pathology (volume 23, pages 1320-1327). Importantly, two-thirds of the mucinous cystic tumors in Dr. Wilentzs study fell into the entirely benign group. This means that simply lumping all mucinous cystic tumors into the malignant category would have incorrectly labeled two-thirds of the patients as having cancer when they didnt!
The study is also important because it highlights the impact private donations can have on research. Dr. Wilentz conducted this research during a research fellowship year he spent in the laboratory of Dr. S. Kern and this fellowship was supported by the Helen S. Heller and Daniel Kim Memorial Funds for pancreatic cancer research at Hopkins. Without this private support, Dr. Wilentz would not have been able to do his study. Private giving makes a difference!
Reference
The Peutz-Jeghers Syndrome is a rare inherited syndrome in which affected
patients develop dark pigmented spots on their lips ("mucocutaneous
melanin macules") and polyps in their intestinal tract
("hamartomas"). These patients have an increased risk of cancer,
especially pancreatic cancer. In the June 1999 issue of the American
Journal of Pathology, Gloria Su, Ph.D. and colleagues from Johns Hopkins
explain this association.2
The STK11/LKB1 gene in chromosome 19 is responsible for the
Peutz-Jeghers Syndrome. Gloria Su and colleagues examined the status of
the STK11/LKB1 gene in a large series of pancreatic cancers and in
pancreatic cancer resected from patients with the Peutz-Jeghers Syndrome.
They found that the STK11/LKB1 gene was inactivated in 4-6% of the
pancreatic cancers. While the inactivation of this gene plays a role in
only a small percentage of pancreatic cancers, Gloria Su and colleagues
made a second, quite remarkable discovery. They found that the
inactivation of the STK11/LK1 gene in patients with the
Peutz-Jeghers Syndrome explained the development of pancreatic cancer in
these patients. Thus, a long-standing mystery was solved. The inheritance
of a defective copy of the STK11/LKB1I gene causes the
Peutz-Jeghers Syndrome and the inactivation of this gene in these patients
explains their increased risk of pancreatic cancer.
References:
In the May 1999 issue of the Annals of Surgery, Drs. Yeo,
Cameron and colleagues from Johns Hopkins report a study that may finally
help resolve this controversy. They report a randomized
single-institution trial in which patients were randomized to receive
either a standard or a radical Whipple. Of the 114 patients randomized,
56 underwent a standard Whipple and 58 a radical Whipple. Dr. Yeo and
colleagues found that the two procedures can be performed with similar
morbidity and mortality. Importantly, the one-year survival rate for both
groups was similar (~80%).
This important study will continue and the patients enrolled will
be followed to determine if there are any long-term benefits to doing a
radical Whipple. For now, part of the controversy in the radical versus
standard Whipple debate has been answered. Both can be performed with
equal morbidity and mortality, but the radical Whipple does not provide
any improvement in survival at one year.
Reference:
Yeo CJ, Cameron JL, Sohn TA, Coleman J, Sauter PK, Hruban RH, Pitt HA,
Lillemoe KD. Pancreaticoduodenectomy with or without extended
retroperitoneal lymphadenectomy for periampullary adenocarcinoma.
Comparison of morbidity and mortality and short-term outcome. Annals of
Surgery 1999; 229: 613- 624.
Reference
We continue to make progress in figuring out "What's Broke." In a study
published recently (Cancer Research 58:9329), additional clues implicate
an important tumor suppressor system. This study was led by Michael Goggins,
a postdoctoral fellow in the Kern laboratory and now a new faculty member
(see the
What's New of 2-2-99 for the establishment of his new
laboratory dedicated to developing screening techniques for the early
diagnosis of pancreatic cancer). He discovered that some pancreatic and
biliary cancers have mutations or deletions of certain genes that produce
proteins for the surface of the pancreatic cells. One of the most
well-studied proteins in cancer research is one called TGF-beta.
TGF-beta exists outside of cells, in tissue and circulating in blood,
but can
bind to receptors on a cell's surface. When this happens, the cell is
instructed to slow its growth, or to become a more mature type of cells
(called "differentiation"), or even for the cell to cease living
(called "apoptosis", from a Greek word that refers to the falling off of
leaves from trees in the fall). Cancer cells are notoriously poor in
responding normally to TGF-beta's suppressive effect, but exactly why has
been difficult to figure out. Mutations in the receptors are only rarely
found. Dr. Goggins' study was the first ever to show that cancers can
genetically inactivate both of the major types of TGF-beta receptors.
This study also provided the first concrete evidence that pancreatic
cancers arise, in part, because they acquire the ability to evade the
normal control of TGF-beta.
In a related discovery published last month (Proc Natl Acad Sci USA96:1427),
Dr. Jiale Dai, another postdoctoral fellow in the Kern laboratory, helped us
understand the role of another tumor-suppressor of pancreatic cancer. The
DPC4 gene is mutated or is deleted in just over half of pancreatic cancers.
No other tumor type has as many alterations in DPC4 as does pancreatic
cancer, suggesting that the study of DPC4 may hold some important lessons
for pancreatic cancer (see the
What's New of 11-4-98, of
July 1996, and of
2-27-96). Dr. Dai discovered that if he took cells
that made no DPC4, and then genetically engineered them so they would
produce DPC4, the cells grew much slower. This is what you might expect
for a tumor-suppressor gene. He then expanded on these findings in a
clever way. He made a special form of DPC4 where he could control its
activity at will. Upon adding a certain chemical, he could make the
DPC4 go from an inactive form to an active form within minutes.
By
doing this type of comparison, he found that active DPC4 could kill the
cancer cells, and it seemed that this may have been the major way by which
DPC4 acts as a suppressor gene. When he studied a mutant form of DPC4
found in a patient's cancer, the opposite results were found. Now instead
of suppressing growth and causing cell death, growth was stimulated and
the cancer cells were protected from death.
Due to Dr. Dai's work, we now have a clearer understanding of just how
pancreas cancer cells come to misbehave. Now that he knows the overall
effects of DPC4, Dr. Dai is currently refining his studies to understand
the exact mechanism by which DPC4 accomplishes it all.
These and future research efforts should help us to understand "What's Broke"
in pancreatic cancer. Only then will we be empowered to fix it.
Number one on the list of goals for this laboratory is to develop a
screening test for early pancreatic cancer. Screening tests for breast
cancer, colon cancer, and prostate cancer already exist and have helped
save lives. Dr. Goggins has dedicated his laboratory effort to finding the
"PSA test for pancreatic cancer."
Although we were able to raise enough funds to open this exciting new
laboratory, we have only raised approximately $100,000 of the $400,000
needed to operate the laboratory over the next three years.
Learn
how you can help support this exciting new lab.
Wilentz RE, Albores-Saavedra J, Zahurak M, Talamini MA, Yeo CJ, Cameron
JL, Hruban RH. Pathologic examination accurately predicts prognosis in
mucinous cystic neoplasms of the pancreas.
Am J Surg Pathol 23(11):1320-1327, 1999.
Peutz-Jeghers Gene Shown To Play a Role in the Development of Pancreas
Cancer
Twelve years ago doctors at Johns Hopkins reported that patients with a
rare syndrome, called "The Peutz-Jeghers Syndrome," had an
increased risk of developing pancreatic
cancer.1 The reason for this increased
risk remained a mystery until now.
June 23, 1999
Standard vs. Radical Whipple
Surgical resection is currently the most effective treatment for
cancer of the pancreas. The extent of the surgery which should be
performed is, however, controversial. Some have argued that the standard
pancreaticoduodenectomy (Whipple procedure) should be extended to include
the removal of the distal stomach (distal gastrectomy) as well as the
removal of additional lymph nodes (retroperitoneal lymphadenectomy). The
more extended surgery is called a "radical pancreaticoduodenectomy". The
controversy over standard versus radical Whipple has been difficult to
resolve, because most centers do one surgery or the other and data between
institutions may not be comparable.
May 28, 1999
Robb Wilentz Wins an Award
Robb Wilentz, one of the pancreas cancer research fellows at Johns
Hopkins, won the 1999 Gastrointestinal Pathology Society Award for best
presentation by a resident or fellow at the 1999 meetings of the United
States and Canadian Academy of Pathology. Robb won the award for his
presentation entitled "Morphology Accurately Predicts Behavior of Mucinous
Cystic Neoplasms of the Pancreas" (Modern Pathology, Volume 12, 1999, Page
169A). This work is important because it has been previously suggested
that all cystic tumors of the pancreas which produce mucin (so called
mucinous cystic neoplasms) are malignant (cancerous). Robb showed that a
careful microscopic examination of these tumors can be used to separate
them into two groups: those patients who are completely cured if their
tumors are removed surgically and those patients who need additional
therapy. Using the techniques Robb outlined a group of patients with these
tumors can be told that they are cured while other patients will receive
the benefit of additional therapies. Our congratulations go out to Robb
for a job well done.
March 26, 1999
Wilentz et al. Morphology Accurately Predicts Behavior of Mucinous Cystic
Neoplasms of the Pancreas. Modern Pathol 12(1):169A, 1999.
More on "What's Broke in Pancreatic Cancer?"
A few months ago here in the What's New pages, we introduced an analogy.
We noted that we get televisions fixed when only a single small part breaks.
The same holds for cars, houses, and bicycles. Maybe if we knew just what
was broken in a cancer cell, we could fix it.
March 1, 1999
New Laboratory Established at Hopkins for the Early
Detection of Pancreatic Cancer
All too often patients with pancreas cancer do not come for medical
attention until after the disease has spread beyond the pancreas. We
urgently need a new test for the early diagnosis of pancreatic cancer, so
that these cancers can be detected at their earliest stages while they are
still curable. Johns Hopkins is therefore pleased to announce that on
February 1, 1999 we opened a new laboratory dedicated to finding new
methods to detect early pancreatic cancer. Dr. Michael Goggins will head
this laboratory. Remarkably, the creation of this lab was made possible by
funds raised from the November 8th, 1998 Pancreatic Cancer Fundraiser held
in California, and by generosity of users of this Web page! The creation
of this lab shows what "people power" can accomplish.
February 2, 1999
Left to right: Mike Goggins, Jessa Jones, Gloria Su, Judy
M., Ralph Hruban, Marsha G.