In children with the rare disease Pfeiffer syndrome, craniofacial surgery to correct skull defects is followed by a distinct pattern of increases in body temperature, reports a study in the January Journal of Craniofacial Surgery. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health, a leading provider of information and business intelligence for students, professionals, and institutions in medicine, nursing, allied health, pharmacy and the pharmaceutical industry.

Together with previous studies, the results suggest that the postoperative temperature spikes are normal after surgery to correct craniosynostosis even when the skull defect is the only abnormality, and not part of a larger syndrome like Pfeiffer syndrome. The study was performed by Dr. Ikkei Tamada and colleagues of the Australian Craniofacial Unit at Women’s and Children’s Hospital, Adelaide, Australia.

‘Bimodal’ Pattern Is Normal after Craniosynostosis Surgery

The researchers analyzed temperature changes after skull surgery in 21 infants and children with Pfeiffer syndrome: a rare genetic condition affecting about 1 in 100,000 people. Infants with Pfeiffer syndrome develop craniosynostosis, in which the joints (sutures) between the bones of the skull close prematurely, resulting in abnormal growth of the skull and brain. Craniofacial surgeons, in concert with other professionals, design effective treatments to correct the skull deformity, prevent complications, and promote good long-term functioning.

Patients with Pfeiffer syndrome may have other abnormalities as well, such as hearing loss and defects of the fingers and toes. This is in contrast to the more common “nonsyndromic” forms of craniosynostosis, in which the skull defect is the only abnormality.

In the children with Pfeiffer syndrome, temperature changes followed a “bimodal” pattern, with two spikes in body temperature occurring within the first 48 hours after surgery. The temperature spikes were higher and longer lasting in children with more complex procedures for example, those whose surgery took longer.

The swings in body temperature were also more pronounced, and more complicated, in children whose surgery was complicated by leakage of cerebrospinal fluid (fluid that helps to cushion the brain and spinal cord). In contrast, the temperature spikes were less prolonged in infants less than six months old.

In a previous study, Dr. Tamada and colleagues found an almost identical pattern of temperature spikes in children undergoing surgery for simple, nonsyndromic craniosynostosis. As in Pfeiffer syndrome patients, the temperature changes resolved by 48 hours after surgery, remaining normal thereafter.

The causes of the temperature changes after surgery for skull defects aren’t clear. A similar bimodal pattern has been found in patients undergoing heart surgery, but not other types of procedures.

Fever is one of the most important signs of complications after surgery, especially infection. However, the new results suggest that increases in body temperature after craniofacial surgery for craniosynostosis alone or as part of a syndrome like Pfeiffer syndrome are normal and apparently not related to infection.

Surgeons and others caring for children with craniosynostosis should be aware of the normal bimodal pattern of temperature spikes in the first 48 hours after corrective skull surgery, according to the researchers. Other patterns, especially if more complex, should lead to further evaluation for infection or other complications.

Source: Lippincott Williams & Wilkins

A recent clinical trial - led by Goshen Center for Cancer Care - has yielded promising results for the future use of a cancer vaccine. One of the first studies to prove vaccines might have a medical benefit against cancer, study results found the new cancer vaccine doubled the response rate for tumor shrinkage as well as delayed the progression of cancer in patients with metastatic melanoma.

These results were announced May 30 during the American Society of Clinical Oncology annual meeting in Orlando, Fla. As lead author and principle investigator of the trial, Goshen Center for Cancer Care Medical Director Dr. Doug Schwartzentruber presented the results at the ASCO meeting for the first time.

Goshen acted as the coordinating center - and only site in Indiana - for this multi-institute, national research trial that evaluated a novel cancer vaccine for the treatment of metastatic melanoma - a form of skin cancer that has spread to other parts of the body.

The vaccine, sponsored by the National Cancer Institute, is a synthetic fragment from a specific protein found on the surface of melanoma cells. This protein, the gp100 protein, acts as a marker for melanoma cells in the body. The vaccine primes a patient’s immune system to find and attack the cancer by locating the gp100 protein. Preliminary findings found the new cancer vaccine doubles the response rates and extends progression free survival in patients with metastatic melanoma.

“This study is one of the first to show positive, promising results for a cancer vaccine. That’s how we make cancer progress - one step at a time,” said Schwartzentruber, who brought the trial to Goshen from the National Cancer Institute 5 years ago.

The 8-year trial tested the benefit of combining the vaccine with the high-dose Interleuken-2. IL-2 is a biological therapy that boosts the immune system. Goshen Center for Cancer Care is one of only about 60 sites that offer high-dose IL-2 therapy to patients.

Involving 21 sites and 185 patients, the study investigated whether IL-2 given with the vaccine would create positive responses for more patients, making the body’s immune response even stronger than with IL-2 alone.

“Metastatic melanoma is a difficult disease to treat successfully and is resistant to most therapies,” said Schwartzentruber. “These results will give patients and the oncology community hope that we are making progress against the disease.”

Before the vaccine could be introduced as treatment for melanoma, said Schwartzentruber, the next step would be to conduct a larger clinical trial to demonstrate the vaccine improves overall survival.

“We are just now processing the findings of this trial but we are in discussions about a larger trial. This trial took 8 years - for a larger trial we would enlist more centers and conduct the trial in a shorter time,” Schwartzentruber said. “Not only did this study show a trend toward overall survival, it demonstrated a doubling of response rate to treatment and a delay in the progression of the cancer. It is one of the first times we’ve been able to prove that vaccines have a medical benefit in the fight against cancer.”

Clinical trials have contributed to major medical breakthroughs in cancer treatments and Goshen Center for Cancer Care is committed to cancer research - involved in and sponsoring a number of clinical trials in addition to prevention, screening, diagnostic, treatment and quality of life trials.

“We continue to be very committed to research, recognizing that it is what will move us forward in the treatment of all cancers as we look for ways to improve established therapies,” Schwartzentruber said. “The only way we will find better treatments is through clinical trials. Our research also involves looking for new diagnostics because if we find cancer better, we can treat it better.”

About Goshen Center for Cancer Care

Goshen Center for Cancer Care is a leader in innovative cancer treatment. They were among the first to adopt a comprehensive, multidisciplinary approach to cancer treatment. They offer holistic programs for strengthening minds as well as bodies, place a premium on family involvement and spiritual needs, and encourage patients to play a decision-making role in treatment selection. Through this integrative team approach, the center provides medical, radiation, nuclear and surgical oncology as well as naturopathic medicine.

Goshen Center for Cancer Care is involved in, and sponsors, a number of clinical trials. Additionally, prevention, screening, diagnostic and treatment trials are conducted at the Goshen Center for Cancer Care, as well as quality of life trials. Clinical trials offered include treatments for breast cancer, colon cancer, Non-Hodgkin’s Lymphoma, lung cancer, esophageal cancer, head and neck cancer, liver cancer, melanoma, myeloma, prostate cancer and pancreatic cancer. To find out more about the Goshen Center for Cancer Care or Goshen Health System, call 866-561-HOPE or visit http://www.goshencancer.org.

Source
Goshen Health System

Bristol-Myers Squibb Company (NYSE: BMY) and
Medarex, Inc. (NASDAQ: MEDX) today announced updated survival results from follow-up
extensions of three Phase 2 ipilimumab studies of patients with advanced metastatic melanoma
(Stage III or IV). The two-year survival rate ranged from 29.8 to 41.8 percent in patients who
received ipilimumab (10 mg/kg). Results of the survival data were presented at the 45th Annual
Meeting of the American Society of Clinical Oncology in Orlando, FL., May 29 - June 2, 2009.
The results are based on follow-up of up to 37.5 months (median follow-up ranging from 10.1 to
16.3 months) of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of
ipilimumab (induction and maintenance) and, specifically, showed:

- Two-year survival rate of 32.8 percent (95% CI: 25.37%- 40.49%) in patients who had
progressed while on or after receiving standard treatment (Study 008, Abstract #9033);

- Two-year survival rate of 29.8 percent (95% CI: 19.13%- 41.14%) in patients who were
previously treated, relapsed or failed to respond to experimental treatment or were unable to
tolerate currently approved therapies (Study 022, Abstract #9033);

- Two-year survival rate of 40.6 percent (95% CI: 27.12%- 54.37%) and 41.8 percent (95%
CI: 28.30%- 55.46%) in patients receiving ipilimumab plus budesonide or ipilimumab plus
placebo, respectively, which included treatment-naïve patients and patients previously
treated with therapy other than ipilimumab (Study 007, Abstract #9033).

Historical melanoma survival rates from previous clinical trials have been estimated by a recent
meta-analysis of 42 Phase 2 trials of over 2,100 patients with Stage III or IV metastatic melanoma
indicating that, at one year, approximately 25 percent of patients were alive.1 Results from three
separately published randomized Phase 3 studies using dacarbazine as the control arm reported that,
at two years, approximately 8 to 12 percent of metastatic melanoma patients were alive.2,3,4
The updated survival analyses did not include additional safety data. As previously reported, safety
results include follow-up of up to 16.3 months with a median follow-up ranging from 4.7 to 5.65
months. The most common immune-related adverse events were rash, diarrhea and hepatitis. Grade
3 and 4 immune-related adverse event rates were approximately 20 to 29 percent and zero to 12
percent, respectively, in patients who received 10 mg/kg of ipilimumab. Adverse events were
managed with the use of supportive care and systemic steroids using established treatment
guidelines in the majority of patients. Additionally, the use of systemic steroids to manage adverse
events does not appear to diminish or impact the clinical effect of ipilimumab (Abstract #9037).
“The ongoing survival data observed with ipilimumab are encouraging, particularly because the
advanced melanoma patient population currently has limited treatment options,” said Steven J.
O’Day, M.D., Chief of Research and Director of the Melanoma Program at The Angeles Clinic and
Research Institute, California. “The potential of ipilimumab is also underscored by the fact that we
can report two-year survival results from these studies involving a significant number of metastatic
melanoma patients.”

Candidate Biomarkers of Ipilimumab

Researchers also presented an exploratory analysis from four Phase 2 ipilimumab studies (008,
022, 007 and 004) that looked at the association between clinical activity and multiple potential
biomarkers, including the change in absolute lymphocyte count (ALC) in melanoma patients after
they received ipilimumab (Abstracts #9008 and #3020). ALC is a measure of the number of
immune cells in circulation.

In a combined analysis of studies 007, 008 and 022, clinical activity was associated with an increase
in the rate of change in ALC. Patients with clinical activity had a higher average increase in ALC
over time than did patients without clinical activity (P=0.0013) and no patient with a decrease in
ALC over time had clinical activity. This association was separately confirmed in Study 004.
Increases in ALC following administration of ipilimumab were also significantly associated with
dose (studies 007, 008, 022: P<0.0001; study 004: P=0.0015), favoring the 10 mg/kg
regimen. Based on these early biomarker findings, further research to explore the implication of
ALC and other potential biomarkers of clinical activity of ipilimumab continues.

About Studies 008, 022 and 007

The three studies enrolled a total of 487 patients across North America, Europe, South America,
Africa and Australia with Stage III or Stage IV metastatic melanoma treated with ipilimumab
therapy (0.3 mg/kg, 3.0 mg/kg or 10 mg/kg every three weeks for up to four doses, followed by
maintenance dosing every 12 weeks). Specifically, the three Phase 2 monotherapy trials include:

- A Phase 2 open-label, single-arm trial (008) evaluating overall response rate in 155 patients
who progressed while on or after receiving standard treatment;

- A Phase 2 randomized, double-blind trial (022) evaluating the efficacy of three dose levels
of ipilimumab in 217 patients who were previously treated, relapsed or failed to respond to
experimental treatment or were unable to tolerate currently approved therapies; and

- A Phase 2 randomized, double-blind trial (007) evaluating the rate of Grade 2+ diarrhea in
115 patients receiving ipilimumab with or without prophylactic oral budesonide.
The primary endpoint of studies 008 and 022 was best overall response rate and the primary
endpoint of study 007 was to compare the rate of Grade 2+ diarrhea in patients receiving
ipilimumab with or without prophylactic oral budesonide. Overall survival, one-year survival rates,
disease control rate, stable disease, and other measurements of anti-tumor activity and patterns of
responses were secondary endpoints in studies 008, 022 and 007. The two-year survival data
reported are current (through March, 2009) for all subjects followed: 93.6% from study 008, 91.7%
from study 022 and 84.2% and 82.8% from the two subgroups of study 007 (placebo and
budesonide, respectively).

About Study 004

Study 004 is a Phase 2 randomized, double-blind biomarker trial. The study enrolled 82 patients
with advanced melanoma who were previously treated with therapy other than ipilimumab or who
received no prior therapy. All patients received ipilimumab therapy (3.0 mg/kg or 10 mg/kg). Preand
post-treatment (week four) tumor biopsies were performed to assess associations between
tumor biomarkers and clinical activity of ipilimumab. Clinical activity was defined as complete or
partial response or stable disease at ?24 weeks using modified World Health Organization criteria.

About Ipilimumab

Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated
antigen 4), a molecule on T-cells that plays a critical role in regulating natural immune responses.
The absence or presence of CTLA-4 can augment or suppress the immune system’s T-cell response
in fighting disease.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing
cells (melanocytes) located in the skin.5 As with many cancers, it is more difficult to treat once the
disease has spread beyond the skin to other parts of the body by way of the bloodstream or the
lymphatic system (metastatic disease).6,7 Melanoma accounts for about three percent of skin cancer
cases,8 but it causes most skin cancer deaths.9 The American Cancer Society estimates that in 2009,
there will be 68,720 new cases of melanoma in the U.S.9

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and
enhance human life. For more information, visit http://www.bms.com.

This press release contains “forward-looking statements” as that term is defined in the Private
Securities Litigation Reform Act of 1995, regarding the research and development of ipilimumab.

Such forward-looking statements are based on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change any of them, and could cause
actual outcomes and results to differ materially from current expectations. No forward-looking
statement can be guaranteed. Among other risks, there can be no guarantee that the development of
ipilimumab will be successful or that the clinical studies described in this release will support the
filing of a Biological License Application (BLA) with the U.S. Food and Drug Administration
(FDA). Furthermore, there can be no assurances that if a BLA is filed with the FDA, that it will be
filed in the timeframe developed by the parties or that such BLA will receive regulatory approval.

There can be no assurances that if approved, ipilimumab will be commercially successful.
Forward-looking statements in the press release should be evaluated together with the many
uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the
cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year
ended December 31, 2008, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K.
Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement,
whether as a result of new information, future events, or otherwise.

References

1. Korn, E. “Meta-analysis of Phase 2 Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and
Overall Survival Benchmarks for Future Phase 2 Trials.” Journal of Clinical Oncology.2008; 26 (4):526-534.

2. Middleton M.R., Grob J.J, Aaronson N et al. “Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of
Patients With Advanced Metastatic Malignant Melanoma.” Journal of Clinical Oncology.2000; 18(1): 158-166.

3. Chapman P, Einhorn L, Myers M et al. “Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in
Patients With Metastatic Melanoma.” Journal of Clinical Oncology. 1999; 17(9): 2745-2751.

4. Bedikian AY, et al. “Bcl-2 antisense (oblimersen sodium) Plus Dacarbazine in Patients with Advanced Melanoma: The Oblimersen
Melanoma Study Group.” Journal of Clinical Oncology. 2006; 24(29):4738-45.

5. National Cancer Institute Web site. “Melanoma.” http://www.cancer.gov/cancertopics/types/melanoma. Accessed on May 27, 2009.

6 American Cancer Society Web site. “Detailed Guide: Advanced Cancer What Is Metastatic Cancer?”
See here Accessed on May 27, 2009.

7 American Cancer Society Web site. “New Treatments On Horizon For Melanoma.”
See here. Accessed on May 27,
2009.

8 American Cancer Society Web site. Overview: Skin Cancer - Melanoma How Many People Get Melanoma Skin Cancer?
See here.
Accessed on May 27 2009

9 American Cancer Society Web site. Cancer Facts & Figures 2009. http://www.cancer.org/downloads/STT/500809web.pdf. Accessed
May 27, 20009.

Source
Bristol-Myers Squibb