Archive for the ‘Pancreatic’ Category

Study Provides Insight Into Pancreatic Cancer Progression, New Target for Treatment

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Posted 12 Jun 2012 — by James Street
Category Immune System, Pancreatic
Released: 6/11/2012 12:10 PM EDT
Source: NYU Langone Medical Center

Mystery of How Pancreatic Cancer Escapes Immune Detection is Unraveled,
Offering Hope for Treatment

Newswise — NEW YORK, June 11, 2012 – Researchers at NYU School of Medicine have made a key discovery that could help doctors treat one of the deadliest cancers.

A new study reveals a strategy used by pancreatic cancer cells to tinker with the immune system in a way that enables them to escape destruction by specialized immune cells.

The study, funded by the National Institutes of Health, The Pancreatic Cancer Action Network and by The Irvington Institute Postdoctoral Fellowship Program of the Cancer Research Institute, appears in the June 12 issue of Cancer Cell.

Pancreatic cancer is known for its aggressive nature. Only four percent of patients survive past five years from the time of diagnosis, and currently available therapies are largely ineffective.

“It is extremely important that we learn how the advancement of pancreatic cancer is being regulated in an effort to interrupt the progression of the disease,” said senior author Dafna Bar-Sagi, PhD, senior vice president and vice dean for Science and chief scientific officer at NYU School of Medicine.

Using mouse models of pancreatic cancer, Dr. Bar-Sagi and colleagues found that a mutation of the KRAS gene, present in 95 percent of all pancreatic cancers, triggers the expression of a protein called GM-CSF. The tumor-derived GM-CSF then directs accumulation of myeloid-derived suppressor cells in the area surrounding the tumor. These cells suppress the body’s natural immune defense reaction to growing tumor cells. In this way, pancreatic cancer cells escape being seen by the body’s immune system and are free to grow and divide. Establishment of an immunosuppressive environment around pancreatic cancer cells, therefore, prevents their prompt rejection by the immune system.

By blocking production of GM-CSF in pancreatic cancer cells, the researchers found that they were able to disrupt accumulation of myeloid-derived suppressor cells, liberating the tumor-killing immune response. “Our study suggests a therapeutic strategy for harnessing the anti-tumor potential of the immune system,” Dr. Bar-Sagi explained.

“Our findings should be applicable to a significant proportion of human pancreatic cancer cases, as the vast majority of human pancreatic cancer samples that we tested express the GM-CSF protein prominently,” Dr. Bar-Sagi added. The researchers are hopeful that their findings will open new doors in therapeutic research, eventually leading to new drug therapies that block the production or function of the GM-CSF protein to allow anti-tumor immune cells to attack the cancer cells and halt tumor development.

Although the study focuses on pancreatic cancer, KRAS mutations are prevalent in a number of other cancers, including colon and lung cancer. “From a research standpoint, the contribution of KRAS mutation to the production of GM-CSF is a very exciting find, as it may have important implications for the therapeutic management of other cancers, as well,” Dr. Bar-Sagi said.

Co-authors on the study include first author Yuliya Pylayeva-Gupta, PhD, Kyoung Eun Lee, PhD, Cristina H. Hajdu, MD, and George Miller, MD, all of NYU School of Medicine.

About NYU School of Medicine:
NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/.

Proteomic Analysis Reveals Warburg Effect and Anomalous Metabolism of Glutamine in Pancreatic Cancer Cells

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Posted 22 Mar 2012 — by James Street
Category pancreatic ductal adenocarcinoma, Vitamins and Supplements, Warburg Hypothesis
Weidong Zhou*†, Michela Capello‡§, Claudia Fredolini†‡§, Leda Racanicchi, Lorenzo Piemonti, Lance A. Liotta†, Francesco Novelli‡§, and Emanuel F. Petricoin†
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Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia 20110, United States
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, Turin 10126, Italy
§ Department of Medicine and Experimental Oncology, University of Turin, Turin 10125, Italy
Diabetes Research Institute, San Raffaele Scientific Institute, Milano 20132, Italy
J. Proteome Res., 2012, 11 (2), pp 554–563
DOI: 10.1021/pr2009274
Publication Date (Web): November 3, 2011
Copyright © 2011 American Chemical Society
*Dr. Weidong Zhou, Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd, MS 1A9, Manassas, VA 20110. Phone: 703-993-9492. Fax: 703-993-4288. E-mail: wzhou@gmu.edu.

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Proteomic Analysis Reveals Warburg Effect and Anomalous Metabolism of Glutamine in Pancreatic Cancer Cells

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Weidong Zhou*†, Michela Capello‡§, Claudia Fredolini†‡§, Leda Racanicchi, Lorenzo Piemonti, Lance A. Liotta†, Francesco Novelli‡§, and Emanuel F. Petricoin†
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia 20110, United States
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, Turin 10126, Italy
§ Department of Medicine and Experimental Oncology, University of Turin, Turin 10125, Italy
Diabetes Research Institute, San Raffaele Scientific Institute, Milano 20132, Italy
J. Proteome Res., 2012, 11 (2), pp 554–563
DOI: 10.1021/pr2009274
Publication Date (Web): November 3, 2011
Copyright © 2011 American Chemical Society
*Dr. Weidong Zhou, Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd, MS 1A9, Manassas, VA 20110. Phone: 703-993-9492. Fax: 703-993-4288. E-mail: wzhou@gmu.edu.

Abstract

Abstract Image

In this present work, we characterized the proteomes of pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and normal pancreatic duct cells by mass spectrometry using LTQ-Orbitrap and identified more than 1700 proteins from each sample. On the basis of the spectra count label-free quantification approach, we identified a large number of differentially expressed metabolic enzymes and proteins involved in cytoskeleton, cell adhesion, transport, transcription, translation, and cell proliferation as well. The data demonstrated that metabolic pathways were altered in PANC-1, consistent with the Warburg effect. In addition, the comparative MS analysis unveiled anomalous metabolism of glutamine, suggesting that glutamine was largely consumed as a nitrogen donor in nucleotide and amino acid biosynthesis in PANC-1. Our analysis provides a potentially comprehensive picture of metabolism in PANC-1, which may serve as the basis of new diagnostics and treatment of PDAC.

Keywords:

mass spectrometry; proteomics; pancreatic ductal adenocarcinoma; metabolism; Warburg effect; glutamine

Scientists Break Through Pancreas Cancer Treatment Barrier

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Posted 19 Mar 2012 — by James Street
Category Gemcitabine, Pancreatic
Released: 3/14/2012 11:15 AM EDT
Embargo expired: 3/19/2012 12:00 PM EDT
Source: Fred Hutchinson Cancer Research Center

Research study reports extending survival in mice by 70 percent; initial studies in humans are under way

Newswise — SEATTLE – Pancreas cancer tumors spread quickly and are notoriously resistant to treatment, making them among the deadliest of malignancies. Their resistance to chemotherapy stems in part from a unique biological barrier the tumor builds around itself. Now scientists at Fred Hutchinson Cancer Research Center have found a way to break through that defense, and their research represents a potential breakthrough in the treatment of pancreas cancer.

In a paper to be published in the March 20 issue of Cancer Cell, senior author Sunil Hingorani, M.D., Ph.D., an associate member of the Hutchinson Center’s Clinical Research and Public Health Sciences divisions, and colleagues describe the biological mechanisms of how the tumor barrier is formed and detail a newly discovered way to break it down. Their research significantly increased the length of survival in a genetically engineered mouse model of the disease. Early clinical trials in humans are under way at a few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the Hutchinson Center’s patient treatment arm. Details about the open clinical trial can be found here: http://clinicaltrials.gov/show/NCT01453153

Using a mouse model developed by Hingorani, the scientists combined gemcitabine, the current standard chemotherapy used to treat pancreatic ductal adenocarcinomas, with an enzyme called PEGPH20. When they infused the combination into specially engineered mice whose pancreas tumors mimic those of human pancreas cancer, the combination broke down the matrix barrier within the tumors and allowed the chemotherapy to permeate freely and spread throughout the cancerous tissue. The result was a 70 percent increase in survival time of the mice after the start of treatment, from 55 to 92 days.

“This represents the largest survival increase we’ve seen in any of the studies done in a preclinical model, and it rivals the very best results reported in humans,” Hingorani said.

Unlike most solid tumors, pancreas tumors use a two-pronged defense to keep small molecules, such as those contained in chemotherapy, from entering: a vastly reduced blood supply and the creation of a strong fibroinflammatory response. The latter includes the production of fibroblasts, immune cells and endothelial cells that become embedded within a dense and complex extracellular matrix throughout the tumor. One major component of this matrix is a substance called hyaluronan, or hyaluronic acid (HA). HA is a glycosaminoglycan, a complex sugar that occurs naturally in the body and is secreted at extremely high levels by pancreas cancer cells.

Hingorani and colleagues discovered that the fibroinflammatory response creates unusually high interstitial fluid pressures that collapse the tumor’s blood vessels. This in turn prevents chemotherapy agents from entering the tumors. The researchers found that HA is the main biological cause of the elevated pressures that leads to blood vessel collapse.

“That’s the primary reason pancreas cancers are resistant to everything we’ve thrown at them: because none of the drugs get into the tumor. It’s physics first, before we even get to the intrinsic biology,” Hingorani said.

Administering the enzyme/gemcitabine combination degrades HA in the tumor barrier and results in rapid reduction of the interstitial fluid pressure. This in turn opens the blood vessels and permits high concentrations of chemotherapy to reach the tumor.

“Being able to deliver the drugs effectively into the tumor resulted in improved survival as well as the realization that pancreas cancer may be more sensitive to conventional chemotherapy than we previously thought,” Hingorani said.

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Overall five-year survival is less than 5 percent with a median survival of four to six months.

Grants from the National Cancer Institute, the Giles W. and Elise G. Mead Foundation, Safeway and several individuals supported the research. Collaborators from the University of Washington and the Translational Genomics Research Institute in Scottsdale, Ariz., contributed to the study.

Note for media only: Please contact Dean Forbes to schedule interviews with Hingorani. He is available on Friday, March 16 and next Monday and Tuesday, March 19 and 20. Please contact the Cell Press office at 617-397-2802 or moleary@cell.com to obtain a copy of the Cancer Cell paper, “Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma.”

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit fhcrc.org.

MD ANDERSON: MUTATED KRAS SPINS A MOLECULAR LOOP THAT LAUNCHES PANCREATIC CANCER

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Posted 31 Jan 2012 — by James Street
Category genetic research, Kras, Pancreatic
tct main 2010
MD ANDERSON: MUTATED KRAS SPINS A MOLECULAR LOOP THAT LAUNCHES PANCREATIC CANCER
Published 01/28/2012 – 2:17 p.m. CST
UT MD Anderson-led team identifies new potential treatment avenue to block an elusive target

HOUSTON — Scientists have connected two signature characteristics of pancreatic cancer, identifying a self-perpetuating “vicious cycle” of molecular activity and a new potential target for drugs to treat one of the most lethal forms of cancer.

The research, reported in the journal Cancer Cell and led by scientists at The University of Texas MD Anderson Cancer Center, connected the molecular dots between:

Mutated versions of Kras, a gene that acts as a molecular on-off switch but gets stuck in the “on” position when mutated.
Heightened activity of a protein complex called NF-?B that controls activation of genes.

“Kras is mutated in 80 to 95 percent of pancreatic ductal adenocarcinomas, and is the most frequent mutation among all cancers,” said senior author Paul Chiao, Ph.D., professor in MD Anderson’s Department of Molecular and Cellular Oncology.

About 42,000 new cases of pancreatic ductal adenocarcinoma are diagnosed in the United States each year. Estimates vary, but the 5-year survival rate has been 1 to 3 percent for decades and median survival after diagnosis is six months, the researchers note.

Interleukin-1a is a new potential drug target
“There have been many attempts to inhibit mutated Kras, but it’s an elusive target that so far has defied treatment,” Chiao said. “So if we can’t hit Kras, maybe we can target one of its downstream genes. This research identifies some of those genes and suggests that interleukin-1apha (IL-1a) is a potential therapeutic target.”

Chiao and colleagues identified IL-1a as a crucial player in a feed-forward loop that:

Begins with mutationally activated Kras triggering a chain reaction that induces IL-1a expression;
This in turn activates NF-?B via the protein kinase IKK2/ß, which blocks the inhibitor of NF-?B.
In the cell nucleus, NF-?B oversees gene transcription and regulates a number of inflammation-promoting genes, including IL-1a.
IL-1a and another protein called p62 activate NF-?B which in turn cycles back to perpetuate the loop by activating its activators.

“It’s a vicious cycle,” Chiao said. The overactive NF-?B fuels pancreatic cancer by activating genes that promote inflammation, the growth of new blood vessels and block programmed cell death.

Chiao has three research grants from the National Cancer Institute to study pancreatic cancer. “We study signaling transduction pathways to try to find out why it’s such a bad disease and to find a weak point for targeted therapy,” he said.

In the Cancer Cell paper, the authors conclude: “Our findings suggest that the prime mover responsible for cancer-related inflammatory response and the development of pancreatic intraepithelial neoplasia (precancerous lesions) and pancreatic ductal adenocarcinoma is the mutant Kras-initiated constitutive activation of NF-?B.”

This process, they further noted, creates a pro-tumor microenvironment by promoting inflammation, creation of new blood vessels and tissue repair that is similar to conditions found in inherited pancreatitis, inflammation of the pancreas that is linked to the development of cancer.

Kras mutation, IL-1a, NF-?B go together with poor survival
The team analyzed mouse and human tumors and mouse strains with mutated Kras expressed in their pancreases. In a series of experiments they found:

Active IKK2/ß – the activator of NF-?B – was required for the Kras-mutated mice to develop either pancreatic cancer or precancerous legions.
Deletion of IKK2/ß interrupted Kras-stimulated inflammation and cell proliferation, suggesting that chronic inflammation is a key factor in promoting pancreatic cancer development.
Microarray profiles of gene expression showed that several NF-?B-regulated inflammatory genes were present in high levels in mice with mutated Kras and active IKK2/ß but only found at lower levels in mice with IKK2/ß knocked out.
In human pancreatic tumors, high expression of the same inflammatory genes in the mutated Kras mice were associated with positive lymph node status, high-risk, late tumor stage and poor survival.
Expression of several genes regulated by NF-?B progressed from low levels in normal pancreases to higher levels in precancerous lesions and tumors, including IL-1a.
IL-1a was known to be both a target of and an inducer of NF-?B, but its expression had not previously been connected to mutated Kras. The team found that downstream targets of Kras, including IL-1a, are interrupted when IKK2/ß is inactivated.
Analysis of 14 human pancreatic cancer tumor samples showed that overexpression of IL-1a, the presence of Kras mutation and the activation of NF-?B are correlated and are associated with poor survival.
Continued activation of NF-?B and its gene transcription activity are sustained by IL-1a and p62.

Co-authors with Chiao are Jianhua Ling, Ph.D., Rulying Zhao, M.D., Ph.D., Qianghua Xia, Ph.D., Zhe Chang, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson’s Department of Molecular and Cellular Oncology; Ya’an Kang, M.D., Ph.D., and Jason Fleming, M.D., of MD Anderson’s Department of Surgical Oncology; Huamin Wang, M.D., Ph.D., and Jinsong Liu, M.D., Ph.D., of MD Anderson’s Department of Pathology; Dung-Fang Lee, Ph.D., and Ihor Lemischka, Ph.D., of the Black Family Stem Cell Institute of Mount Sinai School of Medicine; Jin Li, Ph.D., of the Center for Applied Genomics of the Children’s Hospital of Philadelphia; and Bailu Peng, Ph.D. of the Guangdong Entomological Institute, Guangdong, China.

The team’s research was funded by grants from the National Cancer Institute, including MD Anderson’s Cancer Center Core Support Grant.

Trace Elements Linked to Pancreatic Cancer

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Posted 20 Dec 2011 — by James Street
Category Carcinogens, Pancreatic, Prevention
Higher levels of cadmium, arsenic, and lead in the body appear to be associated with an increased risk of pancreatic cancer, according to results from an analysis of toenail clippings from the 1990s.Significantly increased risks of exocrine pancreatic cancer (EPC) were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88, P=5X10-6), arsenic (OR 2.02, 95% CI 1.08 to 3.78, P=0.009), and lead (OR 6.26, 95% CI 2.71 to 14.47; P=3X10-5) were in the highest quartile, reported Núria Malats, MD, PhD, of the Spanish National Cancer Center in Madrid, and colleagues in Gut.

The scientists analyzed toenail clippings obtained from 118 EPC case patients during the PANKRAS 2 Study, conducted in 1992-1995. The 118 patients represented 63.8% of the 185 pancreatic cancer patients recruited for the study; the remainder did not have toenail clippings available.

For their control group, they obtained toenail clippings from 399 patients during the Spanish Bladder Cancer/EPICURO Study in 1998-2001. The control group patients were selected from hospitals in the same regions as those participating in the PANKRAS 2 Study, the researchers reported.

The toenail clippings, which had been stored at room temperature until analysis, had their trace elements quantified using inductively coupled plasma mass spectrometry. Samples also underwent acid digestion and gravimetric recording for assay purposes. A Mann-Whitney U test was performed to assess median concentrations of trace elements between cases and controls.

Covariates for each trace element model included age at interview, gender, patient’s geographic region, and smoking status. The model was further adjusted for educational level (low versus high), diabetes status, and pack years and duration of cigarette smoking.

“The toenail concentrations of cadmium and lead were significantly higher in cases than in controls (P<0.001),” the authors wrote.

They also found that EPC case patients had lower concentrations of nickel and selenium than the control group. “By contrast, levels of nickel (adjusted OR 0.27, 95% CI 0.12 to 0.59, P=2X10-4) and selenium (adjusted OR 0.05, 95% CI 0.02 to 0.15, P=8X10-11) were inversely associated with EPC risk,” they observed. The authors noted that no statistically significant associations were observed for the other trace elements.

Limitations of the study were its small sample size, exclusion of 36% of patients due to absence of toenail clippings, its retrospective design, and a slight difference in the recruitment period among cases and controls. The study was not designed to identify the environmental sources of the trace elements that were found, nor was it possible to adjust for diet or occupation, according to the researchers.

The authors also emphasized the study’s strengths, including matching area of residence, similar age distributions among cases and controls, and the simultaneous quantification of trace elements from the toenail clippings in the same laboratory and under the same quality control procedures.

“Furthermore, toenails are not altered with long-term storage and they are reliable matrices to assess past exposures,” they wrote.

Procedure targets inoperable tumors

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Posted 29 Nov 2011 — by James Street
Category Pancreatic

Posted: Nov 28, 2011 4:56 AM PST Updated: Nov 28, 2011 4:56 AM PST

MIAMI (WTVJ/NBC) – A new procedure gives hope to pancreatic cancer patients.

Dominga Ungaro was diagnosed with Stage 3 inoperable pancreatic cancer in January 2010.

“I never was afraid. It was just: ‘We’ll accept whatever comes this way,’” Ungaro said.

With five children and 16 grandchildren, she had many reasons to fight for her life.

She started with chemo.

“That was the first thing and I went through that I had over 25 treatments. In the middle of that they started me with radiation,” she said.

Surgery was not an option because the tumor was wrapped around major blood vessels.

Then in November 2010 at UM Sylvester Comprehensive Cancer Center, she became the first pancreatic cancer patient in Florida to have a NanoKnife procedure.

Using CT scan imaging for guidance, Dr. Govindarajan Narayanan inserted several long needles into her Ungaro’s pancreas.

“We placed four needles to bracket the tumor, on the top and the bottom” Narayanan said.

Then high voltage electrical currents run between the needles.

“That creates holes in the cell membranes and then kills the tumor cells, but it does not damage to the blood vessels,” Narayanan said.

“I woke up didn’t know a thing had happened and everything has been really good,” Ungaro said.

Five months later she was able to have surgery to remove part of the pancreas.

“He was able to do lab tests right there samples, and there was no sign of cancer at different levels,” she said.

Ungaro says she recently had a scan and there is still no sign of cancer.

Tumor markers in the blood are also at good levels.

Eleven inoperable pancreatic patients have been treated with NanoKnife at Sylvester.

So far two patients have gone on to have successful surgeries.

“This is very early stage, and we’ve done a very small sample but what we’ve seen so far is that’s it’s safe, it can be done without opening the patient and early results are promising” Narayanan said.

He has proposed doing a larger study at UM Sylvester.

This treatment is keeping hope alive for Ungaro and her family.

Earlier in November they took part in a fundraising walk for the Pancreatic Cancer Action Network.

NanoKnife is also being used to treat inoperable tumors in the liver, kidney and lungs.

Steve Jobs Regretted Wasting Time on Alternative Medicine

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Posted 21 Oct 2011 — by James Street
Category Complementary and Alternative Medicine, experimental treatments, Nutrition and Cancer, Pancreatic

Steve Jobs Regretted Wasting Time on Alternative MedicineEveryone else wanted Steve Jobs to move quickly against his tumor. His friends wanted him to get an operation. His wife wanted him to get an operation. But the Apple CEO, so used to swimming against the tide of popular opinion, insisted on trying alternative therapies for nine crucial months. Before he died, Jobs resolved to let the world know he deeply regretted the critical decision, biographer Walter Isaacson has told 60 Minutes.

“We talked about this a lot,” Isaacson told 60 Minutes of Jobs’s decision to treat a neuroendocrine tumor in his pancreas with an alternative diet rather than medically recommended surgery. “He wanted to talk about it, how he regretted it….I think he felt he should have been operated on sooner… He said, ‘I didn’t want my body to be opened…I didn’t want to be violated in that way.’”

The account lends credence to a Harvard cancer researcher we quoted in a controversial post last week.

Ramzi Amri, a Fullbright scholar researching neuroendocrine tumors at the Harvard Medical School and at Massachusetts General Hospital, said the tumors of the subtype Jobs is believed to have contracted are “relatively mild” and very survivable if detected early. But Jobs delayed surgery for at least nine months, making it “sound to assume that Mr. Jobs’ choice for alternative medicine has eventually led to an unnecessarily early death.”

Says Isaacson:

He’s regretful about it… Soon everybody is telling him, ‘Don’t try and treat it with these roots and vegetables and these kinds of things…’ By the time they operate on him they notice it has spread to the tissues around the pancreas.

To understand Jobs’s prognosis, it is necessary to appreciate the precise type of cancer he had, and the subtype he is believed to have had. First, Jobs’s neuroendocrine tumor, also called an islet cell tumor, put him outside the 95 percent of pancreatic cancer victims who have highly fatal adenocarcinoma.

Second, Jobs is believed to have contracted one of the more survivable neuroendocrine tumors. It had several characters weighing the initial prognosis favorably, had Jobs acted as doctors recommended:

  • It was apparently functional, meaning it produced hormones, hence the “hormone imbalance” that Apple eventually acknowledged. These sorts of tumors are more “differentiated” from other cells and are thus considered less progressed and easier to treat.
  • Jobs’s tumor did not initially appear to have metastasized, as there were no outward signs of chemotherapy, though after being left untreated it did become metastatic and spread to his liver.
  • The tumor was in Jobs’s pancreas, among the more survivable locations a neuroendocrine tumor can appear.
  • Insulinoma, the type of tumor Jobs was most often reported and speculated to have had is also among the more survivable types.

The five-year survival rates on this chart give a good indication of the prognosis for insulinoma (88.7 percent) and tumors located in the pancreas (78.1). It also shows how much less survivable metastasic and non-function tumors—of the type Jobs is believed NOT to have had, at diagnosis—can be.

If you want more details, we’ve included some notes Amri sent us by email below. But suffice it to say, Jobs’s instinct for defiant iconoclasm and his insistence on unconventional approaches did not, in the end, serve him as well as it served Apple’s customers and shareholders. And it seems clear Jobs knew this, and wanted the rest of us to know it, too.


 


Additional Medical Details

Here’s how Amri explained things when we asked him on email about a particular type of neuroendocrine tumor with a lower survival rate (“non-functioning metastatic islet cell tumors,” whose survival rate is only around five years):

That number could very well be true, but there are two reasons it doesn’t apply to Jobs (and again, we’re on the border of speculation but it’s based on hard number and what Jobs said):

The metastatic part: Metastasis means the tumor spread outside its original site. His tumor probably wasn’t metastatic until when Jobs spoke of that “hormonal imbalance”, I believe in ’08 (source is easy to google). That was also the reason for his liver transplant: his liver was probably invaded by metastatic disease. If he had mets before, he certainly didn’t treat them as we’d have seen the obvious signs of chemotherapy appear.

The nonfunctional part, nonfunctional in those tumors means the cells degenerated to the point that they cannot carry out their original function, in this case, as I said in my first point, Jobs spoke about a “hormonal imbalance” when the disease recurred somewhere as late as ’08/’09. This means the tumor was -even then- clearly still producing hormones, proving it was a functional one, which is far less deadly than the nonfunctional ones.

This so-called called loss of differentiation is actually a strong predictor of how bad the tumor is in many cancers. The less differentiated it is, the more reckless it will be in its growth pattern and its tendency to spread.

For instance, in my colon cancer patients, they’re about 8 times as likely to develop or already have metastasis if their tumor is poorly differentiated as compared to well or even moderately differentiated tumor.

The subtype: so Jobs didn’t have a nonfunctioning one, but from what I read (please google to double-check) he even had an insulinoma, which is actually the most common and best treatable type.

He also had it in the pancreas, which is known to have one of the best prognosis averages.

Combine the two in this table comparing the different kinds of neuroendocrine tumors, add up the extraordinary level of care a man like Jobs can access and afford and you can see what I mean about his considerable chance of cure, hope it helps.

Amri also fielded questions (in italics) about this Slate piece:

1. “Islet-cell cancer, like Jobs and I had, is usually curable when
caught early” – this seems to fit with what you wrote. Is “curable”
the right word, i.e. it’s gone and you don’t die from it?

1 – Absolutely. If you’re on time, you can resect the tumor (depending on the site) without even needing to remove the pancreas or any other organ.

And since you’re early, the chances of it coming back as a recurrence from the original tumor are small.

There could always be an independent recurrence, if you have a familial disease that makes you at risk of developing these nasties (google MEN-1 for the most common example) but there’s no indication this was the case for Jobs and -one again- seen the level of care he can afford, I’m pretty sure that has been checked on him. It you do not have a familial disease, it’s like lightning striking twice at the same place. It happens, but with these tumors, that’s really, really unusual.

2. “After I was diagnosed, I was told that modern medicine doesn’t
have chemotherapy or radiation to use against islet cells. (“We’ve got
nothing that works” went the refrain.) ” I noticed in your piece you
mentioned Jobs seemed to eschew chemo; would he have had a choice?

2 – I think that was specific to his own case and his own subtype of islet-cell tumor.

In general, and especially if Jobs had a well-differentiated insulinoma, there are many treatment options, but when you’re early and the tumor is small enough, surgery is by far the best, in most cases you take the tumor out locally, check the local lymph nodes and if there is no spread in the nodes, you can confidently release the patient without any lasting side-effects, a low risk of recurrence and only a checkup consisting of a scan an labs every year or so as long as symptoms don’t come back.

- Chemo doesn’t always work and works in only about 10-20% of cases if the tumor is in the intestines or the stomach, but if it’s in the pancreas, some agents have been FDA approved and can help much more often.

Also, these numbers might appear worse than they really are because only the worst cases actually get chemo because most won’t need it at all. If you treat only the bottom, the average success will of course be low.

- There’s also radiotherapy with special isotopes that will be absorbed by the endocrine tumor cells that helps a lot if the tumor is metastatic.

- If that doesn’t help there’s the option of partial resection of the liver instead of removing the whole thing. The liver has the amazing faculty to partially regrow so a lot of the liver can be resected before the patient actually has a problem. This option is only available to those cases where the tumor is confined to either the right or left lobe, or in milder cases, only one of its eight so called Couinaud Segments.

All of that is usually tried before one refers to a liver transplant. If only because livers are very scarce organs and transplants to cancer patients are not always a good idea because of the immune-system suppressing drugs used to prevent rejection. They also partly suppress the body’s own immune reaction to any cancer growths, making the cancer more prone to spread.

Pancreatic Cancer Killed Steve Jobs, the Truth About How You Can Prevent It

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Posted 15 Oct 2011 — by James Street
Category Alternative Therapies, CURCUMIN, curcumin, Pancreatic
Friday, October 14, 2011 04:16 PM

By: Sylvia Booth Hubbard

The death of Steve Jobs from pancreatic cancer last week added yet another name to the list of celebrities who have died as a result of that type of cancer, a stellar group which includes Patrick Swayze, Michael Landon, Luciano Pavarotti, and Jack Benny. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and has the highest mortality rate of all cancers, killing 95 percent of its victims, according to the American Cancer Society.

“It’s a dismal, deadly disease,” surgical oncologist Dr. Robert Wascher tells Newsmax Health. “But like other forms of cancer, up to 65 percent can be prevented by relatively modest diet and lifestyle changes,” says Wascher, author of “A Cancer Prevention Guide for the Human Race.”

One simple preventative step to lower the risk of pancreatic cancer is to take the spice turmeric, which is a strong cancer fighter, says Wascher.

Pancreatic Cancer took Steve Jobs in the prime of his life.Steve Jobs lived for seven years after he announced he was suffering from pancreatic cancer. Most victims aren’t nearly so fortunate as Steve Jobs was and often live less than a year after their diagnosis. But Steve Jobs had a rare type of pancreatic cancer called neuroendocrine. “Only 5 to 8 percent of pancreatic cancers are this type, and its biology is different from the more common garden variety called adenocarcinoma that most people get,” says Wascher. “The form Jobs had is less aggressive and patients tend to live longer.”

One reason for the poor survival statistics is that pancreatic cancer usually causes no symptoms until it is advanced and has metastasized to other organs. The fortunate few who survive, including Supreme Court Justice Ruth Bader Ginsburg, are diagnosed early, when the disease is treatable by surgery — and usually as a result of a CT scan or MRI conducted for another reason.

Treatment options are few, says Wascher: “The only cure comes with very radical surgery. No one is cured by chemotherapy or radiation without surgery. If pancreatic tumors can’t be removed surgically, they tend to be quite resistant to chemotherapy and radiation therapy.

“Conventional medical and surgical procedures obviously do not cure pancreatic cancer for the vast majority of patients,” he says. “So, I think it’s reasonable to be a little more open-minded about complementary and alternative therapies when you have tried conventional therapies and have no other options. Both laboratory and clinical studies suggest there are some nutritional therapies that might have an effect on pancreatic cancer.”

Turmeric. Turmeric has a cancer-fighting component called curcumin. “Laboratory tests and some animal studies show it has potential activity against pancreatic cancer.” But, he warns, “What works in a laboratory environment doesn’t necessarily work in humans.” Wascher himself takes 1,000 mg of turmeric twice a day. “I don’t know for sure that it will help me, but I’m pretty sure it won’t hurt.” There is no established dosage, but most experts recommend taking between 500 mg and 2,000 mg daily.

A Phase II clinical trial at MD Anderson Center involved 25 patients with pancreatic cancer who were given 8 grams of turmeric a day for two months. Tumor growth stopped in two patients, one for eight months and another for two-and-a-half years. Another patient’s tumor temporarily regressed by 73 percent. Since the only two drugs approved by the FDA are effective in no more than 10 percent of patients, turmeric’s effectiveness was similar with no side effects.

In another study, turmeric reduced tumor growth in mice with pancreatic cancer by 43 percent. When combined with fish oil, tumor growth was reduced by 70 percent.

Since turmeric is poorly absorbed by the body, experts advise mixing it with olive oil or a combination of olive oil and black pepper to increase absorption.

Metformin. Metformin is a drug used to treat Type 2 diabetes. University of Texas MD Anderson Center researchers found that diabetics who took metformin had a 60 percent lower risk of developing pancreatic cancer compared to diabetics who didn’t use the drug. “In clinical studies, we’ve found that people who take metformin tend to survive longer,” Wascher says. “Based on that data, I tend to put patients who have pancreatic cancer on metformin even if they have very mild diabetes. It’s such a lethal disease that it’s worth the hope of even a small benefit.”

By far the best option is to avoid pancreatic cancer, and as in the prevention of other cancers, changes in diet and lifestyle offer you your best chances of living a long and healthy life. Steps to lower risk include:

Quit smoking. Approximately 27 percent of pancreatic cancers are linked with smoking. One study in Los Angeles County found that smoking a pack or more of cigarettes a day was associated with a fivefold to sixfold increase in the risk. Research at Jefferson Medical College of Thomas Jefferson University found that a protein in the body which makes cancer cells more likely to spread is much higher in the pancreas of smokers who have pancreatic cancer.

Lose weight. About 25 percent of pancreatic cancer is associated with obesity. Women who are severely obese have a 45 percent higher risk of developing pancreatic cancer, according to a study published in the American Journal of Epidemiology. And a study published in the Journal of the American Medical Association found that adults who were overweight as teens had a 60 percent higher risk of developing pancreatic cancer as adults.

Eat fresh vegetables and whole grains. A study published in the journal Cancer Epidemiology, Biomarkers & Prevention found that people who ate the most vegetables lowered their risk of pancreatic cancer by 55 percent when compared to those who ate the least. A study published in the American Journal of Epidemiology found that people with the highest fiber intake lowered their risk of pancreatic cancer up to 48 percent when compared with those with the lowest fiber intake.

Keep sugar levels in check. Studies have found that 1 percent of patients diagnosed with Type 2 diabetes after the age of 50 will be diagnosed with pancreatic cancer within three years.

Avoid sugary drinks. The Georgetown University Medical Center found that people who drank as few as two soft drinks a week doubled their risk of pancreatic cancer.

Shun processed meats and red meat. Research from the Cancer Research Center at the University of Hawaii found that people who ate the highest amount of processed meats increased their risk of pancreatic cancer by 67 percent. Diets high in red meats upped cancer risk by about 50 percent.

“When it comes to cancer prevention,” says Wascher, “the old adage about an ounce of prevention being worth a pound of cure should probably be revised to ‘An ounce of cancer prevention is worth a ton of cancer cure.’”

Harvard Cancer Expert: Steve Jobs Probably Doomed Himself With Alternative Medicine

Steve Jobs had a mild form of cancer that is not usually fatal, but seems to have ushered along his own death by delaying conventional treatment in favor of alternative remedies, a Harvard Medical School researcher and faculty member says. Jobs’s intractability, so often his greatest asset, may have been his undoing.

“Let me cut to the chase: Mr. Jobs allegedly chose to undergo all sorts of alternative treatment options before opting for conventional medicine,” Ramzi Amri wrote in an extraordinarily detailed post to Quora, an online Q&A forum popular among Silicon Valley executives. “Given the circumstances, it seems sound to assume that Mr. Jobs’ choice for alternative medicine has eventually led to an unnecessarily early death.”

Amri went on to say that, even after entering conventional medical care, the Apple CEO seemed to eschew the most practical forms of treatment. Addressing the period when Jobs began to visibly shed weight, Amri wrote, “it seems that even during this recurrent phase, Mr. Jobs opted to dedicate his time to Apple as the disease progressed, instead of opting for chemotherapy or any other conventional treatment.”

When we contacted Amri at his Harvard Medical School email address to verify the post was his—he’s a researcher in the department of surgery at the medical school and research fellow at Massachusetts General Hospital—Amri emphasized, “I wrote that on a PERSONAL title and it’s my PERSONAL opinion.” On Quora, Amri expressed his “profoundest respect” for Jobs and that “I do not pretend to know anything about the case on a personal level and I never participated in the care of Mr. Jobs. I base all my cancer figures on my own research or sources from biomedical research known to me… I have done 1.5 years of research on the type of tumor that affected Steve Jobs and have some strong opinions on his case.”

According to a 2008 Fortune article, Jobs for nine months pursued “alternative methods to treat his pancreatic cancer, hoping to avoid [an] operation through a special diet.” The Buddhist vegetarian took this approach from the time he was diagnosed in October 2003 until at least the end of July 2004, when he underwent surgery at Stanford University Medical Center.

Harvard Cancer Expert: Steve Jobs Probably Doomed Himself With Alternative MedicineBy then the cancer was so far along Jobs had to lose his pancreas and duodenum in a “Whipple procedure.” The cancer also spread to all the major parts of his liver. “The only reason he’d have a transplant,” wrote Amri, “would be that the tumor invaded all major parts of the liver, which takes a considerable amount of time.” Amri said the Whipple procedure and liver transplant were clear signs the cancer was out of control and should have been stopped earlier.

The condition might have been nipped in the bud if Jobs had acted right away. Jobs’s cancer manifest in neuroendocrine tumors, which are typically far less lethal than the “pancreatic adenocarcinoma” that make up 95 percent of pancreatic cancer cases. Amrit said neuroendocrine tumors are so “mild” that…

“In my series of patients, for many subtypes, the survival rate was as high as 100% over a decade… As many as 10% of autopsied persons in the general population have been reported to have one of these without ever having had any symptoms during their life. Up to 30% of detected GEP-NETs are so well differentiated they’re strictly not cancers.”

But even “the most innocent cancer” needs to be removed quickly, which is why older men are always being lectured about colon cancer screenings; colon cancer tumors are thought to begin as removable polyps. In Jobs’s case, surgical removal may well have saved him if performed early enough, Amrit implies. He wrote:

“In many cases, a simple enucleation (just cutting out the tumor with a safe margin around it) is enough and leaves no residual side-effects.”

The cancer researcher made his comments about Jobs because he was looking for a lesson in his case. Doctors routinely face the ethical conundrum of being unable to treat patients because they’ve exercised their freedom to reject sound medical science.

But there is also, thankfully, a much clearer and easier lesson for patients in Jobs’s experience: Do not waste time. Don’t waste time by ignoring advice to get screened; don’t waste time by drowning yourself in research about your condition; and don’t waste time by delaying medically recommended treatment in the hops that something else will work.

Harvard Cancer Expert: Steve Jobs Probably Doomed Himself With Alternative Medicine“We saw the tumor slowly draining the life out him,” Amrit wrote of Jobs. “It was a horrible thing to see him lose weight and slowly turn into a skin and bones form of himself.”

That, in the end, may prove the most compelling reason to forgive the brilliant CEO his many faults: Of all the people who suffered on the dark side of his headstrong, iconoclastic decisionmaking, it was Jobs himself who appears to have paid the biggest price.

Did Cancer Pain Killers Cause Steve Jobs’ Respiratory Arrest?

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Posted 12 Oct 2011 — by James Street
Category Life Death and Dying, Pancreatic

By Amrutha Gayathri | October 11, 2011 3:19 AM EDT

Steve Jobs died of respiratory arrest caused by pancreatic tumor at about 3 p.m. on Oct. 5 at his home in Palo Alto, Calif., his death certificate revealed. His occupation was filed as “entrepreneur” in “high tech” business.

In the document issued by the Santa Clara County Public Health Department in San Jose and obtained by Bloomberg, “respiratory arrest” was listed as the immediate cause of death, with “metastatic pancreas neuroendocrine tumor” as the underlying cause. No autopsy was performed.

Respiratory arrest in cancer patients isn’t uncommon, even though in many cases it is not the cancer, but the medication used in relieving the cancer pain that results in the cessation of breathing.

Palliative care or pain management involving potentially harmful drugs such as opioids often exhibit side effects of hastening death by causing respiratory depression, according to a paper published by the International Association for Hospice and Palliative Care.

“Respiratory depression is potentially life threatening, and it is considered the most serious opioid side effect and is of great concern to physicians and nurses. Opioids can depress both the rate and depth of respiration,” says the paper.

However, opioids, including morphine, are used extensively in managing the unbearable pain that is common in cancer patients even when studies have shown that these pain relievers hasten death.

“The principle of double effect is used to justify the administration of medication to relieve pain even though it may lead to the unintended, although foreseen, consequence of hastening death by causing respiratory depression,” the paper explains the ethical and moral feasibility of pain medication.

Conversely, a considerable number of cancer patients are undertreated for pain, due to the ethically questionable status of the standard pain-killing procedure using opiates.

Walter Issacson, author of Jobs’ authorized biography, had said that Jobs was in severe pain weeks prior to his death and was unable to climb the stairs of his house.

Palliative care medication is a comfort mechanism and enables terminally ill patients to spend their last hours with their family and loved ones and ensures a painless death.

None of Jobs’ family members or Apple representatives have issued a statement regarding the cause of Jobs’ death.