Pfizer, Novartis Get Nod From FDA Panel On Pancreatic Cancer Drug

 

 

 

A Food and Drug Administration panel has voted to recommend for approval drugs from Pfizer and Novartis.

GoogleNews.com, FORBES.com, April 13, 2011 –  A Food and Drug Administration panel has voted to recommend for approval drugs from Pfizer and Novartis that treat a rare form of pancreatic cancer.

Both drugs are under consideration to treat unresectable pancreatic neuroendocrine tumors.

Pfizer ( PFEnews people ) said the panel voted 8-2 that its drug Sutent provides a favorable benefit-risk profile to treat this kind of cancer.

Pfizer noted that the approval would be a major advancement in the treatment of patients with pancreatic neuroendocrine tumors, for which, it said, there is a significant unmet need in the US Sutent is approved to treat this type of cancer in Europe. It is currently approved to treat gastrointestinal stromal tumors and advanced renal cell carcinoma in the US

Novartis ( NVSnews people ) cancer treatment Afinitor was unanimously recommended for approval. It is already approved to treat renal cancer.

The FDA will take the panel recommendations into consideration when it makes a final determination of the supplemental New Drug Applications on the new uses for the treatments.

 

 

The Pancreas has Two Major Functions:

 

 

 

The pancreas is a 6-inch-long spongy, tube-shaped organ located in the back of the abdomen, behind the stomach. It has two major jobs in the body:

  • It makes digestive juices (enzymes) that help the intestines break down food.
  • It produces hormones — including insulin — that regulate the body’s use of sugars and starches.

Pancreatic cancer has been brought to the forefront by the diagnoses of several prominent figures, including the late actor Patrick Swayze, who died of pancreatic cancer in September 2009, Apple cofounder and CEO Steve Jobs, and U.S. Supreme Court justice Ruth Bader Ginsburg.

 

The American Cancer Society estimated that 37,680 people in the U.S. were diagnosed with pancreatic cancer during 2008. Of those diagnosed, 34,290 will die of the disease, making this type of cancer the fourth leading cause of cancer death overall.

Additional tests that may be used to diagnose pancreatic cancer?

Besides the known diagnostic tests, here are other tests that may be performed:

  • Angiogram: special X-ray of blood vessels.
  • CT scans: X-rays that give detailed pictures of a cross section of the pancreas.
  • Transabdominal ultrasound: high-frequency sound waves that form a picture of the pancreas.
  • ERCP (endoscopic retrograde cholangiopancreatogram): a special X-ray of the common bile duct.
  • Endoscopic ultrasound: a relatively new procedure in which an endoscope containing an ultrasound probe scans the pancreas for cancers.

 

 

 

 

Surgery may be necessary to treat pancreatic cancer.

Surgery may be done to remove all or part of the pancreas. Sometimes it is also necessary to remove a portion of the stomach, the duodenum, and other nearby tissues. This operation is called a Whipple procedure. In cases where the cancer in the pancreas cannot be removed, the surgeon may be able to create a bypass around the common bile duct or the duodenum if either is blocked.

 

What are the side effects of pancreatic cancer surgery?

The side effects of surgery depend on the extent of the operation, the person’s general health, and other factors. Most patients have pain for the first few days after surgery that can be controlled with medicine. Removal of part or all of the pancreas may make it hard for a patient to digest foods. At first, a patient may have only liquids and may receive extra nourishment intravenously or by a feeding tube. Solid foods are added to the diet gradually. The health-care team can suggest a diet plan and medicines to help relieve diarrhea, pain, cramping, or feelings of fullness. Patients may not have enough pancreatic enzymes or hormones after surgery. Those who do not have enough insulin may develop diabetes. The doctor can give the patient insulin, other hormones, and enzymes.

 

 

 

 

How is cancer of the pancreas treated?

Cancer of the pancreas is curable only when it is found in its earliest stages, before it has spread. Otherwise, it is very difficult to cure. However, it can be treated, symptoms can be relieved, and the quality of the patient’s life can be improved.

Treatment for pancreatic cancer depends on a number of factors. Among these are the type, size, and extent of the tumor as well as the patient’s age and general health. Treatment can consist of surgery, radiation therapy, chemotherapy, or possibly biological therapy.

Radiation therapy may be used to treat pancreatic cancer.

Radiation therapy (also called radiotherapy) uses high-powered radiation to damage cancer cells and stop them from growing. Radiation is usually given five days a week for five to six weeks. This schedule helps to protect normal tissue by spreading out the total dose of radiation. The patient doesn’t need to stay in the hospital for radiation therapy.

Radiation is also being studied as a way to kill cancer cells that remain in the area after surgery. In addition, radiation therapy can help relieve pain or digestive problems when the common bile duct or duodenum is blocked.

 

What are the side effects of pancreatic cancer radiation therapy?

Radiation therapy may cause patients to become very tired as treatment continues. Resting is important, but doctors usually advise patients to try to stay as active as they can be. In addition, when patients receive radiation therapy, the skin in the treated area may sometimes become red, dry, and tender.

 

 

 

 

Chemotherapy may be used to treat pancreatic cancer

Chemotherapy uses drugs to kill cancer cells. When cancer occurs, cells in the body that are not normal keep dividing and forming more cells without control. Chemotherapy destroys cancer cells by stopping them from growing or multiplying. However, healthy cells can also be harmed, causing side effects. These cells usually repair themselves after chemotherapy.

Treatment may consist of just one drug or a combination of drugs. It may be given by mouth or by injection into a muscle or vein. The drugs enter the bloodstream and travel through the body. Chemotherapy is usually given in cycles; a treatment period is followed by a recovery period, then another treatment period, and so on.

What are the side effects of pancreatic cancer chemotherapy?

Systemic chemotherapy affects rapidly dividing cells throughout the body, including blood cells. When anticancer drugs damage healthy blood cells, patients are more likely to get infections, may bruise or bleed easily, and may have less energy. Cells in hair roots and cells that line the digestive tract also divide rapidly. As a result, patients may lose their hair and may have other side effects such as poor appetite, nausea and vomiting, diarrhea, or mouth sores. Usually, these side effects go away gradually during the recovery periods between treatments or after treatment is over.

Biological therapy may be used to treat pancreatic cancer

Biological therapy is treatment designed to stimulate or restore the ability of the body’s immune system (natural internal defense) to fight infection and disease. Biological therapy is also called biotherapy or immunotherapy. This form of treatment uses portions of the body’s natural immune system to treat a disease. Biological therapy is also used to protect the body from some of the side effects of certain treatments.

 

Biological therapy often involves the use of substances called biological response modifiers (BRMs). The body normally produces these substances in small amounts in response to infection and disease. Using modern laboratory techniques, scientists can produce BRMs in large amounts for use in the treatment of the cancer.

 

What are the side effects of pancreatic cancer biological therapy?

The side effects of biological therapy depend on the type of treatment. Side effects include flu-like symptoms such as chills, fever, muscle aches, weakness, loss of appetite, nausea, vomiting, and diarrhea. Some patients develop a rash, and some bleed or bruise easily. Depending on how severe these problems are, for some patients, hospitalization during treatment may be required. Side effects are usually short-term and gradually subside after treatment ends.

 

What does the future hold for pancreatic cancer?

Laboratory scientists are studying the pancreas to learn more about it. They are studying the possible causes of pancreatic cancer and are researching new ways to detect tumors. They also are looking for new therapies that may kill cancer cells. In trials with people who have pancreatic cancer, doctors are studying new drugs, new combinations of chemotherapy, and combinations of chemotherapy and radiation before and after surgery. Biological therapy (discussed earlier) is under investigation as well as the study of several cancer vaccines to help the immune system fight cancer. Other studies use monoclonal antibodies to slow or stop the growth of cancer.

 

 

 

Pancreatic cancer

 

 

Cancer that starts in the pancreas is called pancreatic cancer. This picture of the pancreas shows its location in the back of the abdomen, behind the stomach.

 

 

Pancreatic cancer is a malignant neoplasm of the pancreas. It is estimated that in 2010 more than 43,000 individuals in the United States have been diagnosed with this condition, and 36,800 have died from the disease. The prognosis is poor, with fewer than 5% of those diagnosed still alive five years after diagnosis. Complete remission is still rare.

About 95% of exocrine pancreatic cancers are adenocarcinomas (M8140/3). The remaining 5% include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Exocrine pancreatic tumors are far more common than pancreatic endocrine tumors, which make up about 1% of total cases.

 

 

 

Front View of the Pancreas
The pancreas is about 6 inches long and sits across the back of the abdomen, behind the stomach. The head of the pancreas is on the right side of the abdomen and is connected to the duodenum (the first section of the small intestine) through a small tube called the pancreatic duct. The narrow end of the pancreas, called the tail, extends to the left side of the body.

 

 

Signs and symptoms

Presentation

Pancreatic cancer is sometimes called a “silent killer” because early pancreatic cancer often does not cause symptoms, and the later symptoms are usually nonspecific and varied. Therefore, pancreatic cancer is often not diagnosed until it is advanced. Common symptoms include:

  • Pain in the upper abdomen that typically radiates to the back (seen in carcinoma of the body or tail of the pancreas)
  • Loss of appetite and/or nausea and vomiting
  • Significant weight loss
  • Painless jaundice (yellow tint to whites of eyes and/or yellowish skin in serious cases, possibly in combination with darkened urine) when a cancer of the head of the pancreas (about 60% of cases) obstructs the common bile duct as it runs through the pancreas. This may also cause pale-colored stool and steatorrhea. The jaundice may be associated with itching as the salt from excess bile can cause skin irritation.
  • Trousseau sign, in which blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, is sometimes associated with pancreatic cancer.
  • Diabetes mellitus, or elevated blood sugar levels. Many patients with pancreatic cancer develop diabetes months to even years before they are diagnosed with pancreatic cancer, suggesting new onset diabetes in an elderly individual may be an early warning sign of pancreatic cancer.
  • Clinical depression has been reported in association with pancreatic cancer, sometimes presenting before the cancer is diagnosed. However, the mechanism for this association is not known.

Causes

Risk factors for pancreatic cancer include:

  • Age (particularly over 60)
  • Male sex (likelihood up to 30% greater than females)
  • Smoking. Cigarette smoking has a risk ratio of 1.74 with regard to pancreatic cancer; a decade of nonsmoking after heavy smoking is associated with a risk ratio of 1.2.
  • Diets low in vegetables and fruits
  • Diets high in red meat
  • Diets high in sugar-sweetened drinks (soft drinks) – risk ratio 1.87. In particular, the common soft drink sweetener fructose has been linked to growth of pancreatic cancer cells.
  • Obesity
  • Diabetes mellitus is both risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.
  • Chronic pancreatitis has been linked, but is not known to be causal. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
  • Helicobacter pylori infection
  • Family history, 5–10% of pancreatic cancer patients have a family history of pancreatic cancer. The genes responsible for most of this clustering in families have yet to be identified. Pancreatic cancer has been associated with the following syndromes; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, hereditary non-polyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, and the familial atypical multiple mole melanoma-pancreatic cancer syndrome (FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene.
  • Gingivitis or periodontal disease

Alcohol

It is controversial whether alcohol consumption is a risk factor for pancreatic cancer. Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer. However, chronic pancreatitis associated with alcohol consumption does not increase risk of pancreatic cancer as much as other types of chronic pancreatitis. Overall, the association is consistently weak and the majority of studies have found no association.

Some studies suggest a relationship with risk increasing with increasing amount of alcohol intake. Risk is greatest in heavy drinkers mostly on the order of four or more drinks per day. But there appears to be no increased risk for people consuming up to 30g of alcohol a day, so most of the U.S. consumes alcohol at a level that “is probably not a risk factor for pancreatic cancer”.

Several studies caution that their findings could be due to confounding factors. Even if a link exists, it “could be due to the contents of some alcoholic beverages” other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.

A pooled analysis concluded, “Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day”.

Diagnosis

 

 

Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head.

 

 

Most patients with pancreatic cancer experience pain, weight loss, or jaundice.

Pain is present in 80% to 85% of patients with locally advanced or advanced metastatic disease. The pain is usually felt in the upper abdomen as a dull ache that radiates straight through to the back. It may be intermittent and made worse by eating. Weight loss can be profound; it can be associated with anorexia, early satiety, diarrhea, or steatorrhea. Jaundice is often accompanied by pruritus and dark urine. Painful jaundice is present in approximately one-half of patients with locally unresectable disease, while painless jaundice is present in approximately one-half of patients with a potentially resectable and curable lesion.

The initial presentation varies according to location of the cancer. Malignancies in the pancreatic body or tail usually present with pain and weight loss, while those in the head of the gland typically present with steatorrhea, weight loss, and jaundice. The recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis are sometimes noted. Courvoisier sign defines the presence of jaundice and a painlessly distended gallbladder as strongly indicative of pancreatic cancer, and may be used to distinguish pancreatic cancer from gallstones. Tiredness, irritability and difficulty eating because of pain also exist. Pancreatic cancer is often discovered during the course of the evaluation of aforementioned symptoms.

Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, γ-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity. When a cutoff above 37 U/mL is used, this marker has a sensitivity of 77% and specificity of 87% in discerning benign from malignant disease. CA 19-9 might be normal early in the course, and could be elevated because of benign causes of biliary obstruction.[36] Imaging studies, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) can be used to identify the location and form of the cancer.

 

 

Pathology

 

 

Micrograph of pancreatic ductal adenocarinoma (the most common type of pancreatic cancer). H&E stain.

 

 

The definitive diagnosis is made by an endoscopic needle biopsy or surgical excision of the radiologically suspicious tissue. Endoscopic ultrasound is often used to visually guide the needle biopsy procedure.

The most common form of pancreatic cancer (ductal adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. Pancreatic cancer has an immunohistochemical profile that is similar to hepatobiliary cancers (e.g. cholangiocarcinoma) and some stomach cancers; thus, it may not always be possible to be certain that a tumour found in the pancreas arose from it.

 

 

Micrographs of normal pancreas, pancreatic intraepithelial neoplasia (precursors to pancreatic carcinoma) and pancreatic carcinoma. H&E stain.

 

 

Like colorectal carcinoma, pancreatic carcinoma is thought to arise, typically, from nonmalignant precursor lesions; i.e., it is thought to follow a preneoplasm-neoplasmcarcinoma sequence. In the prototypical colorectal cancer, the lesion has arisen from a tubular adenoma, which developed from colorectal mucosa with an adenomatosis polyposis coli gene mutation. In pancreatic adenocarcinoma, the preneoplastic lesion is pancreatic intraepithelial neoplasia 1a (PanIN1a) and pancreatic intraepithelial neoplasia 1b (PanIN1b) the neoplastic lesions pancreatic intraepithelial neoplasia 2 (PanIN2) and pancreatic intraepithelial neoplasia 3 (PanIN3).

 

Screening

 

Patients with high risk of pancreatic cancer (hereditary) can be followed, however the method to do this is continuously debated in scientific circles. Several very small underpowered studies have shown promising results in new biomarkers, but so far nothing has been validated in a larger scale.

 

Prevention

 

According to the American Cancer Society, there are no established guidelines for preventing pancreatic cancer, although cigarette smoking has been reported as responsible for 20–30% of pancreatic cancers.

The ACS recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing red meat intake, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. In 2006, a large prospective cohort study of over 80,000 subjects failed to prove a definite association. The evidence in support of this lies mostly in small case-control studies.

In September 2006, a long-term study concluded taking vitamin D can substantially reduce the risk of pancreatic cancer (as well as other cancers) by up to 50%, but this study needs to evaluate fully the risks, costs and potential benefits of taking vitamin D.

Several studies, including one published on 1 June 2007, indicate B vitamins, such as B12, B6, and folate, can reduce the risk of pancreatic cancer when consumed in food, but not when ingested in vitamin tablet form.

 

Treatment

 

Surgery

 

Treatment of pancreatic cancer depends on the stage of the cancer. The Whipple procedure is the most common surgical treatment for cancers involving the head of the pancreas. This procedure involves removing the pancreatic head and the curve of the duodenum together (pancreato-duodenectomy), making a bypass for food from stomach to jejunum (gastro-jejunostomy) and attaching a loop of jejunum to the cystic duct to drain bile (cholecysto-jejunostomy). It can be performed only if the patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed in only the minority of cases.

Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy. Recently, localized cancers of the pancreas have been resected using minimally invasive (laparoscopic) approaches.

After surgery, adjuvant chemotherapy with gemcitabine has been shown in several large randomized studies to significantly increase the 5-year survival (from approximately 10 to 20%), and should be offered if the patient is fit after surgery (Oettle et al. JAMA 2007, Neoptolemos et al. NEJM 2004, Oettle et al. ASCO proc 2007). Addition of radiation therapy is a hotly debated topic, with groups in the US often favoring the use of adjuvant radiation therapy, while groups in Europe do not, due to the lack of any large randomized studies to show any survival benefit of this strategy.

Surgery can be performed for palliation, if the malignancy is invading or compressing the duodenum or colon. In that case, bypass surgery might overcome the obstruction and improve quality of life, but it is not intended as a cure.

 

Chemotherapy

 

In patients not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. Gemcitabine was approved by the United States Food and Drug Administration in 1998, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in patients with advanced pancreatic cancer. This marked the first FDA approval of a chemotherapy drug primarily for a nonsurvival clinical trial endpoint. Gemcitabine is administered intravenously on a weekly basis.

2005: On the basis of a Canadian-led Phase III randomized controlled trial involving 569 patients with advanced pancreatic cancer, the US FDA in 2005 licensed the use of erlotinib (Tarceva) in combination with gemcitabine as a palliative regimen for pancreatic cancer. This trial compared the action of gemcitabine/erlotinib to gemcitabine/placebo, and demonstrated improved survival rates, improved tumor response and improved progression-free survival rates (Moore et al. JCO 2005). New trials are now investigating the effect of the above combination in the adjuvant (post surgery) and neoadjuvant (pre-surgery) setting.

Addition of oxaliplatin to Gemcitabine (Gem/Ox) was shown to confer benefit in small trials, but is not yet standard therapy.

 

Prognosis

 

Patients diagnosed with pancreatic cancer typically have a poor prognosis, partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis. Median survival from diagnosis is around 3 to 6 months; 5-year survival is less than 5%. With 37,170 cases diagnosed in the United States in 2007, and 33,700 deaths, pancreatic cancer has one of the highest fatality rates of all cancers, and is the fourth-highest cancer killer in the United States among both men and women. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.

Pancreatic cancer may occasionally result in diabetes. Insulin production is hampered, and it has been suggested the cancer can also prompt the onset of diabetes and vice versa.

Prominent Recent Pancreatic Cancer Survivors

 

 

Ruth Bader Ginsberg

 

 

Supreme Court Justice of the United States

August 10, 1993 to present
Nominated by Bill Clinton
Judge of the Court of Appeals for the District of Columbia Circuit
In office from June 30, 1980 – August 10, 1993
Nominated by Jimmy Carter
Born March 15, 1933 (1933-03-15) (age 78)
Brooklyn, New York
Spouse(s) Martin Ginsburg (1954–2010)
Children Jane Ginsburg
James Steven Ginsburg
Alma mater Cornell University
Harvard Law School
Columbia Law School

 

Illness

 

Ginsburg was diagnosed with colon cancer in 1999 and underwent surgery followed by chemotherapy and radiation therapy. During the process, she did not miss a day on the bench. On February 5, 2009, she again underwent surgery related to pancreatic cancer. Ginsburg’s tumor was discovered at an early stage. Ginsburg was released from a New York hospital, eight days after the surgery and heard oral arguments again four days later. On September 24, 2009, Ginsburg was hospitalized for lightheadedness following an outpatient treatment for iron deficiency and was released the following day.

 

Future plans

 

With the retirement of John Paul Stevens in 2010, Ginsburg became, at 77 years of age, the eldest justice on the Court. Despite rumors she would retire as a result of old age, poor health, and the death of her husband, she denied she was planning to step down. In an August 2010 interview, Ginsburg stated that the Court’s work was helping her cope with the death of her husband and suggested she would serve until at least 2012 when a painting that used to hang in her office is due to be returned to her. She also expressed a wish to emulate Justice Louis Brandeis, who retired at 82, an age that Ginsburg would attain in 2015.

 

 

Steve Jobs

 

 

 

Jobs holding a white iPhone 4 at Worldwide Developers Conference 2010

Born Steven Paul Jobs
February 24, 1955 (1955-02-24) (age 56)[1]
San Francisco, California, U.S.
Residence Palo Alto, California, U.S.
Alma mater Reed College (dropped out in 1972)
Occupation Chairman and CEO, Apple Inc.
Salary $1
Net worth $8.3 billion (2011)
Board member of The Walt Disney Company[
Spouse Laurene Powell
Children 4

 

 

Health concerns

 

In mid-2004, Jobs announced to his employees that he had been diagnosed with a cancerous tumor in his pancreas. The prognosis for pancreatic cancer is usually very grim; Jobs, however, stated that he had a rare, far less aggressive type known as islet cell neuroendocrine tumor. After initially resisting the idea of conventional medical intervention and embarking on a special diet to thwart the disease, Jobs underwent a pancreaticoduodenectomy (or “Whipple procedure”) in July 2004 that appeared to successfully remove the tumor.  Jobs apparently did not require nor receive chemotherapy or radiation therapy. During Jobs’ absence, Timothy D. Cook, head of worldwide sales and operations at Apple, ran the company.

In early August 2006, Jobs delivered the keynote for Apple’s annual Worldwide Developers Conference. His “thin, almost gaunt” appearance and unusually “listless” delivery, together with his choice to delegate significant portions of his keynote to other presenters, inspired a flurry of media and internet speculation about his health. In contrast, according to an Ars Technica journal report, WWDC attendees who saw Jobs in person said he “looked fine”; following the keynote, an Apple spokesperson said that “Steve’s health is robust.”

Two years later, similar concerns followed Jobs’ 2008 WWDC keynote address; Apple officials stated Jobs was victim to a “common bug” and that he was taking antibiotics, while others surmised his cachectic appearance was due to the Whipple procedure. During a July conference call discussing Apple earnings, participants responded to repeated questions about Steve Jobs’ health by insisting that it was a “private matter.” Others, however, voiced the opinion that shareholders had a right to know more, given Jobs’ hands-on approach to running his company. The New York Times published an article based on an off-the-record phone conversation with Jobs, noting that “while his health issues have amounted to a good deal more than ‘a common bug,’ they weren’t life-threatening and he doesn’t have a recurrence of cancer.”[

On August 28, 2008, Bloomberg mistakenly published a 2500-word obituary of Jobs in its corporate news service, containing blank spaces for his age and cause of death. (News carriers customarily stockpile up-to-date obituaries to facilitate news delivery in the event of a well-known figure’s untimely death.) Although the error was promptly rectified, many news carriers and blogs reported on it, intensifying rumors concerning Jobs’ health. Jobs responded at Apple’s September 2008 Let’s Rock keynote by quoting Mark Twain: “Reports of my death are greatly exaggerated”; at a subsequent media event, Jobs concluded his presentation with a slide reading “110/70”, referring to his blood pressure, stating he would not address further questions about his health.

On December 16, 2008, Apple announced that marketing vice-president Phil Schiller would deliver the company’s final keynote address at the Macworld Conference and Expo 2009, again reviving questions about Jobs’ health.  In a statement given on January 5, 2009 on Apple.com, Jobs said that he had been suffering from a “hormone imbalance” for several months. On January 14, 2009, in an internal Apple memo, Jobs wrote that in the previous week he had “learned that my health-related issues are more complex than I originally thought” and announced a six-month leave of absence until the end of June 2009 to allow him to better focus on his health. Tim Cook, who had previously acted as CEO in Jobs’ 2004 absence, became acting CEO of Apple, with Jobs still involved with “major strategic decisions.”

In April 2009, Jobs underwent a liver transplant at Methodist University Hospital Transplant Institute in Memphis, Tennessee. Jobs’ prognosis was “excellent.”

On January 17, 2011, one and a half years after Jobs returned from his liver transplant, Apple announced that he had been granted a medical leave of absence. Jobs announced his leave in a letter to employees, stating his decision was made “so he could focus on his health.” As during his 2009 medical leave, Apple announced that Tim Cook would run day-to-day operations and that Jobs would continue to be involved in major strategic decisions at the company.

On March 2, 2011 Steve Jobs made an appearance at the iPad 2 launch event.