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Human parvovirus B19 is a single-stranded DNA virus with a predilection for infecting rapidly dividing cell lines, such as bone marrow erythroid progenitor cells. People with defective cell-mediated immunity (eg, severe combined immunodeficiency syndrome; acquired immunodeficiency syndrome; and patients receiving immunosuppressive therapy, ie, post organ transplant) can develop pure red cell aplasia, in which suppression of erythroid precursors is permanent. Identification of parvovirus inclusions in marrow biopsies and subsequent confirmation of infection by in situ hybridization is important in the assessment of anemia in immunodeficient patients. Our objective is to provide a general overview of the parvovirus B19 infection and its characteristics in immunocompromised patients and to summarize updated information regarding the clinicopathologic features, pathobiology, and laboratory diagnosis of this subject. The pathologist should be aware of the wide spectrum of manifestations of parvovirus B19 infection depending on the patient’s hematologic and immunologic status.

Human parvovirus B19 (PV-B19) was discovered in the United Kingdom in 1975 by Cossart et al1 and has been associated with a variety of clinical manifestations, including rash, thrombocytopenia, leukopenia, fetal wastage, hypocomplementemia, autoimmune hemolytic anemia, arthritis, and vasculitis.2,3

Parvovirus B19 infection is found worldwide in persons of all ages. Most people become infected at some time during their life, up to 15% of individuals developing infection between 1 and 5 years of age, 15% to 60% between the ages of 5 and 19 years, and 30% to 60% in adulthood.4 Around 80% of the population is immune to the virus by the age of 50 years. PV-B19 acute infection occurs mainly in school-aged children and teenagers.5

Parvovirus B19 infection can be asymptomatic or can cause a broad range of diseases, including (1) diseases found among normal, nonimmunocompromised hosts (erythema infectiosum, arthropathy, hydrops fetalis); (2) hematologic diseases in immunocompromised hosts (aplastic crisis, chronic anemia, idiopathic thrombocytopenic purpura, transient erythroblastopenia of childhood, Blackfan-Diamond anemia); and (3) a heterogeneous group of diseases in which the etiologic role of PV-B19 is less clear and sometimes putative (neurologic disease, rheumatologic disease, and vasculitic and myocarditic syndromes). Less common clinical associations of PV-B19 virus infection include various skin eruptions, hematologic disorders such as neutropenia, hepatobiliary disease, neurologic disease, and rheumatic disease, including chronic fatigue syndrome.6

Symptomatic adult PV-B19 infection typically causes a brief arthritis, often with a rash. Persistent symptoms may occur, and PV-B19 has been linked with many rheumatic diseases.7 PV-B19 infection should be considered in the differential diagnosis of ill children with myocarditis and multiple organ system dysfunction.

Conditions shown to predispose to PV-B19-induced chronic anemia include Nezelof syndrome (an extremely rare immune deficiency disorder characterized by the impairment of cellular immunity against infections), acute lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Burkitt lymphoma, lymphoblastic lymphoma, myelodysplastic syndrome, astrocytoma, Wilms tumor, human immunodeficiency virus (HIV) infected patients, severe combined immunodeficiency, bone marrow (BM) transplantation, organ transplantation, systemic lupus erythematosus, immunoglobulin isotype switching defects, patients receiving cancer chemotherapy, and patients with defect immunoglobulin specificity and neutralization.8

Human PV-B19 frequently causes transient red cell aplasia in children with sickle cell disease. Although the outcome of some transient red cell aplasia episodes in children with sickle cell disease is benign, many are treated with red cell transfusions to reduce the risk of circulatory collapse from severe anemia.9

PATHOGENESIS

Human PV-B19 is a small single-stranded DNA virus classified as a member of precursors. It is the only parvovirus that has been clearly linked with disease in humans. PV-B19 virus replicates only in human cells and belongs to the family Parvoviridae, genus Erythrovirus, whose tropism is primarily for erythroid autonomous, that is, not requiring the presence of a helper virus. Specific antiviral antibody production is thought to represent the major defense against PV-B19 virus, as human normal immunoglobulin frequently clears the virus from peripheral blood and results in clinical improvement in immunosuppressed persons.6

The virus replicates in human erythroid progenitor cells of the BM and blood, inhibiting erythropoiesis. Tropism of productive PV-B19 infection is mainly due to the restrictive cellular distribution of the P blood group antigen globoside (Gb4), which is found most commonly on cells of the erythroid lineage but also on platelets; on tissues from the heart, liver, lung, kidney, and endothelium; and on synovium. Individuals who lack erythrocyte P antigens are very rare (1 in 200 000) and apparently cannot be infected by PV-B19.10

Some readers have noted that there is a significant link to the research on Avemar, reported in the recent article that I wrote about this functional food developed in Hungary (August/September, 2006) and the work of Dr. William F. Koch. His story is a significant part of the history of the therapeutic application of quinones.

Quinones have been discussed in the popular media in recent years. Researchers have speculated that the quinones in red wine are a factor possibly partly responsible for the “healthy French heart.” The rate of cardiovascular disease has been inexplicably low in France even though there is a similar level of fat consumption in the average French person’s diet. The well-known antioxidant coenzyme Q-10 (ubiquinone) is also in the quinone family and was originally developed in Japan as a medication for the treatment of heart disease. Anthraquinones and naphthoquinones are found to play important roles in a wide range of botanical medicines. Anthraquinones and naphthoquinones have been observed to have both anti-tumor and anti-microbial properties.

Quinones are carbonyl group molecules with a wide range of biological activity. One of their properties is to be able to attract and accumulate electrons in the carbon-hydrogen double bond. Benzo- and hydroquinones have anti-microbial activity. Adriamycin, daunorubicin, and mitomycin have cytostatic effects, and all of these compounds may modulate the immune system. The mechanism they share in common is suggested to be a free radical-scavenging capability.

Quinones have been discussed in the popular media in recent years. Researchers have speculated that the quinones in red wine are a factor possibly partly responsible for the “healthy French heart.” The rate of cardiovascular disease has been inexplicably low in France even though there is a similar level of fat consumption in the average French person’s diet. The well-known antioxidant coenzyme Q-10 (ubiquinone) is also in the quinone family and was originally developed in Japan as a medication for the treatment of heart disease. Anthraquinones and naphthoquinones are found to play important roles in a wide range of botanical medicines. Anthraquinones and naphthoquinones have been observed to have both anti-tumor and anti-microbial properties.

Quinones are carbonyl group molecules with a wide range of biological activity. One of their properties is to be able to attract and accumulate electrons in the carbon-hydrogen double bond. Benzo- and hydroquinones have anti-microbial activity. Adriamycin, daunorubicin, and mitomycin have cytostatic effects, and all of these compounds may modulate the immune system. The mechanism they share in common is suggested to be a free radical-scavenging capability.
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Carbonyl group molecules like quinones play an important role in tissue chemistry. There are innumerable chemical reactions that involve or produce a carbonyl group as an intermediary or as an end product. They are electron donors, and therefore hydrogen acceptors, and break up congestion from oxidative stress through hydrogen abstraction. They initiate oxidative energy production for normal function and nutrition at the cellular level. Carbonyl group molecules were first researched in the early twentieth century by Dr. William F. Koch, the nephew of Robert Koch, the famous nineteenth century microbiologist who discovered the tubercle bacillus, postulated Koch’s Law, and founded the Koch Institute.

William Koch found that carbonyl group molecules break up deposition and condensation processes, represented by tumors, degeneration, accumulation of all kinds of tissue debris, and plaque, and dissolve it because of their extremely powerful properties as electron donors (oxygen) and hydrogen acceptors. They reverse oxidative stress and initiate normal aerobic metabolism by donating negative charge. They also initiate a process of depolymerization that behaves as a type of “chain reaction,” in such a way that the therapeutic effects of the administration of a single dose can have far-reaching effects and persist for an extended period of time.

In the 1920s, a new approach to cancer treatment pioneered by Dr. Koch, who was a professor of physiology at what is now Wayne State University, took a radically different view of the disease. Koch, like the Nobel Prize winners Otto Warburg (1) and Albert Szent-Gyorgyi decades after him, believed that cancer was the result of faulty metabolism and that it might be possible to return the malignant cells to a normal state. (2) He researched and developed the carbonyl group molecules parabenzoquinone (PBQ), and Glyoxal, which were used successfully for solid tumors, leukemias, lymphomas, and chronic viral infections.

Koch did not claim that his reagents destroy cancer cells. They appear to restore the terrain by means of this antioxidant “chain reaction,” so that normal cell metabolism can resume. Koch treated hundreds of patients with phenomenal success, with long-term stability in cancer patients who were thought to be terminal, as well as with patients with a variety of neurological and metabolic disorders. (3)

Quinones similar to the ones developed by Koch are also found in pau d’arco, yew trees, and in apricot seeds and other natural sources that have been observed to have therapeutic or adjuvant properties in cancer treatment. In 1946, Dr. Willard Dow, President of the Dow Chemical Industries, said of Koch: “Koch is so far ahead of the thinking of his profession that he is not understood, and they even ridicule him at times.” But, beyond ridicule, Koch suffered legal harassment and persecution in the US and eventually relocated to Brazil where he conducted his research with government sponsorship (see www.williamfkoch.com for detailed history and publications by Koch and his colleagues). Carbonyl group remedies are still used by natural medicine doctors in South America and Europe for chronic viral infections, cancer, asthma, and many types of metabolic disorders.

The most recent chapter of the Koch carbonyl group story takes us to India where researchers have been working for over ten years using a methylglyoxal-based formulation on advanced-stage cancer patients that has had “a dramatic positive effect on the patients.” According to Manju Ray, a biochemist at the Indian Association of the Cultivation of Science (IACS), where the drug was developed under a project funded by the Department of Science and Technology and the Council of Scientific and Industrial Research, “We have what we think is a magic bullet against cancer.” The scientists have observed that methylglyoxal was successful against different types of cancer, including acute myeloid leukemia, colon cancer, non-Hodgkin’s lymphoma, and cancers of ovary, breast, liver, lung, bone, gall bladder, pancreas, and oral cavity. Administered orally, no toxic reactions were observed. We can only hope that these powerful antioxidants, which have such enormous potential for malignancy and chronic viral infections, will finally become more widely available.

In this triple analysis report the author has analyzed three major and intertwined areas of cancer R&D, Apoptopic agents, Antibodies and Vaccines in Oncology, which are all subjects to an extensive number of innovative drug candidates. This extensive 350+ pages report compiles and analyzes in parallel the progress concerning drug development and competitive situation in the three mentioned key oncology areas. The report will not only provide a framework but also a careful identification and evaluation of drug candidates, technologies and competitors.

There are today over 190 apoptopic drugs in active development for the treatment of more than 40 different cancer indications. The top five pursued cancer indications are: breast cancer, leukemia, lung cancer, lymphoma and prostate cancer. A thorough target analysis of drugs in development reveals more than 130 candidate targets for triggering apoptosis in cancer cells.

Competitive forces are reviewed, showing market leaders, active players and changes in the competitive landscape. There are only one big pharma company represented among the top 10 players in apoptopic drug development in oncology. The acquisition of Idun Pharmaceutical in 2005 by Pfizer is principal example of a further step in big pharma strategy to augment their internal research and development efforts with high-potential, externally sourced product candidates and technologies.

Apoptopic Agents Highlights

- In-depth competitive landscape assessment of the apoptopic market in oncology

- Thorough review of utilized targets in apoptopic drug development

- Thorough review of approved drugs

- Progress analysis of five major cancer indications, including players, drugs, clinical progress and pitfalls

- Among the targeted therapies for cancer, immunotherapy is probably the most versatile treatment strategy for the eradication of tumors, metastatic spread or not. Main strategies of cancer immunotherapy aim at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms (vaccines).

Immunotherapy in Highlights

- In-depth competitive landscape assessment of the cancer immunotherapy market place; Including more than 200 immunotherapy drugs and pharmaceutical companies

- Thorough review of tumor antigen discovery, immunomodulating strategies and adjuvants

- Thorough review of antibody and vaccine delivery and technologies surrounding it - The next generation

- Progress analysis of six major cancer vaccine indications and late stage antibody development projects, including players, drugs, clinical progress and pitfalls

Topics Covered

1 Executive Summary

2 Table of Contents

3 Methodology

4 Introduction to Apoptosis in Oncology

5 Apoptosis Competitive Landscape in Oncology

6 Approved Apoptopic Cancer Drugs: Performance

7 Target Analysis in Apoptosis

8 Apoptopic Drugs in Development: By Major Indications

9 Immunotherapy in Oncology

10 Competitive Landscape in Cancer Vaccines

11 Antibody Deals on the Rise

12 Tumor Antigens

13 Immunomodulators & Adjuvants in Cancer Vaccines

14 Cancer Vaccine Delivery

15 New Approaches in Antibody Delivery and Design - The Next Generation

16 Cancer Vaccines in Development: By Major Indications

17 Antibodies in Clinical Development

18 Disclaimer

19 Company Index

20 Drug Index

21 List of Boxes

22 List of Figures

23 List of Tables

BOSTON — GlycoGenesys, Inc. (NASDAQ:GLGS), a biotechnology company, today announced it has initiated Roswell Park Cancer Institute, (RPCI) Buffalo, New York as a clinical site for its Phase I/II dose escalation trial in patients with multiple myeloma, the second most common blood cancer. The trial is designed to evaluate the safety and efficacy of the Company’s drug candidate, GCS-100. RPCI was the first cancer research center in the nation and is a National Cancer Institute designated comprehensive cancer center. The Principal Investigator at this site is Asher A. Chanan-Khan, M.D. Dr. Chanan-Khan is an Attending Physician, Division of Lymphoma/Myeloma, RPCI and an Assistant Professor of Medicine, RPCI and School of Biomedical Sciences, State University of New York, Buffalo. Dr. Chanan-Khan’s research interests include novel therapies for multiple myeloma and chronic lymphocytic leukemia (CLL).

Dr. Chanan-Khan has participated in several important clinical studies in multiple myeloma, including the trials that led to regulatory approval of Velcade(R) marketed by Millennium Pharmaceuticals and Johnson and Johnson, as well as studies evaluating Celgene’s Revlimid (R) in patients with CLL.

“I’m excited to be involved as a Principal Investigator in this trial. The preclinical evidence showing GCS-100’s anti-cancer activity in multiple myeloma and CLL cell lines is compelling and suggests GCS-100 may provide therapeutic benefit in patients with these types of malignancies,” stated Dr. Chanan-Khan.

About The Clinical Trial

The primary objective of the Phase I/II dose escalation study is to evaluate the safety of GCS-100 when given to patients with relapsed or refractory multiple myeloma and to identify the recommended dose for future studies. Secondary objectives are to evaluate the response to GCS-100 as a monotherapy and in combination with dexamethasone and determine the pharmacokinetics of GCS-100 alone and with dexamethasone.

The trial was designed with the assistance of Dr. Paul Richardson and Dr. Kenneth Anderson at the Dana-Farber Cancer Institute, Boston, MA based upon pre-clinical work conducted in Dr. Anderson’s laboratory and recently published in Cancer Research 2005; 65:(18). This research shows that GCS-100:

–Induces cell death in multiple myeloma cells without significant toxicity against normal white blood cells;

–Directly targets multiple myeloma cells while in the presence of protective bone marrow cells;

–Triggers cell death in multiple myeloma cells resistant to commonly used anti-cancer agents including dexamethasone, melphalan, doxorubicin, and Velcade(R); and

–Has additive and/or synergistic effect when combined with caspase-activating agents such as dexamethasone.

About Multiple Myeloma

Multiple myeloma is a bone marrow cancer in which plasma cells, white blood cells that are normally responsible for the production of infection-fighting antibodies, become abnormal and are overproduced. The proliferation of these abnormal plasma cells, called myeloma cells, results in decreased production of normal blood cells and disease-fighting antibodies. This proliferation causes growth of tumors that spread to multiple sites - hence the term multiple myeloma. The decreased white blood cell production weakens the immune system and the decreased red blood cell production leads to fatigue and weakness, while the myeloma tumors cause bone destruction, pain and fractures.

Multiple myeloma is the second most common hematologic malignancy and although the disease is predominantly a cancer among older individuals (the average age of onset is 65 to 70 years of age), recent statistics indicate both increasing incidence and onset at a younger age. In the United States, more than 50,000 individuals have multiple myeloma and over 14,600 new cases of the disease are diagnosed each year. Worldwide, there are approximately 74,000 new cases and over 45,000 deaths due to multiple myeloma each year.

About GlycoGenesys, Inc.

GlycoGenesys, Inc. is a biotechnology company focused on carbohydrate drug development. The Company’s drug candidate GCS-100, a unique compound to treat cancer, has been evaluated in previous clinical trials at low dose levels in patients with colorectal, pancreatic and other solid tumors with stable disease and partial response documented. The Company currently is completing a Phase I dose escalation trial to evaluate higher dose levels of GCS-100LE, a low ethanol formulation of GCS-100, at Sharp Memorial Hospital, Clinical Oncology Research in San Diego, California and the Arizona Cancer Center in both Tucson and Scottsdale, Arizona. In addition, GCS-100LE is being evaluated in a Phase I/II trial for multiple myeloma at the Dana-Farber Cancer Institute in Boston, Massachusetts. Further clinical trials are planned for 2005 and 2006. Further information is available on GlycoGenesys’ web site: www.glycogenesys.com.

Safe Harbor Statement

Any statements contained in this release that relate to future plans, events or performance are forward-looking statements that involve risks and uncertainties, including, but not limited to, risks of product development (such as failure to demonstrate efficacy or safety), risk related to FDA and other regulatory procedures, market acceptance risks, the impact of competitive products and pricing, the results of current and future licensing, joint ventures and other collaborative relationships, risks relating to raising sufficient capital to fund the Company’s operations, developments regarding intellectual property rights and litigation, and other risks identified in the Company’s Securities and Exchange Commission filings. Actual results, events or performance may differ materially. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as the date hereof. The Company undertakes no obligation to publicly release the results of any revisions to these forward-looking statements that may be made to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

Context.-Splenic metastases from solid tumors, defined as parenchymal lesion, are considered exceptional. Nevertheless, the number of case reports has been increasing due to the improvement of imaging techniques and the long-term follow-up of patients with cancer. Splenic metastases occur in a context of multivisceral disseminated cancer or as a solitary lesion.

Objective.-To provide a general overview of the clini-copathologic features, differential diagnosis, and pathogenesis of splenic metastases.

Data Sources.-Relevant articles indexed in PubMed (National Library of Medicine) database. The search was based on the following terms: (metastasis or metastases) and spleen.

Conclusions.-The most common primary sources of splenic metastasis are breast, lung, colorectal, and ovarian carcinomas and melanoma in cases of multivisceral cancer and colorectal and ovarian carcinomas in cases of solitary splenic lesion. Splenectomy can be replaced by less aggressive methods such as fine-needle aspiration or percu-taneous biopsy for establishing the diagnosis of solitary splenic metastasis. The main differential diagnoses are primary lymphoma, vascular tumors, and infectious lesions of the spleen. The relative rarity of splenic metastases could be explained by anatomic factors and the inhibitory effect of the splenic microenvironment on the growth of meta-static cells. The analysis of clinical case reports suggests that solitary splenic metastases may result from the growth of an early blood-borne micrometastasis following a period of clinical latency, often several years after the diagnosis of the primary tumor.

Metastases from solid tumors to the spleen due to he-matogenous dissemination are confined to the splenic parenchyma and should not be confused with small superficial subcapsular foci associated with peritoneal dissemination observed in ovarian cancers.1 According to this definition, splenic metastases were thought to be exceptional, but the incidence of reported cases has been increasing due to the improvement of medical imaging and the long-term follow-up of patients with cancer. 2 Metastases to the spleen generally occur in a context of multivisceral metastatic cancer at terminal stage. Solitary metastases have also been reported.1-33 They are becoming a diagnostic dilemma with primary tumors of the spleen. This review outlines the clinical presentation, the diagnostic procedure, the pathologic features, the differential diagnosis, and the pathogenesis of splenic metastases.

CLINICAL PRESENTATION

The prevalence of splenic metastases in large populations with cancer was mainly obtained from autopsy series published before 1990 and ranged between 2.3% and 7.1%.34 The largest autopsy series was reported by Berge.34 He found 312 splenic metastases for 7165 autopsies performed for cancer. In his study, microscopic splenic metastases were identified in 50% of subjects who had metastases in at least 5 organs. After 1990, studies from different parts of the world brought indications about the prevalence of splenic metastases in living patients. In a Western study,35 1.3% of 1280 sequential tumors in sple-nectomy specimens were metastatic. In the same study, 9.8% of 122 splenectomies performed for diagnosis contained metastasis.35 In a Japanese study, 0.15% of 24 761 patients examined by ultrasonography had splenic metastasis. 3 A Chinese report found metastasis in 1.1% of 1743 sequential splenectomy specimens.36

Most splenic metastases are a part of multivisceral met-astatic disease. In this context, breast, lung, ovarian, colorectal, and gastric carcinomas and skin melanoma are the most common primary sources.34,36 Skin melanoma has the highest rate of splenic metastases per primary tumor because more than 30% of patients with skin melanoma have splenic metastasis at autopsy.33,34,36 Splenic metastases also occur as a solitary splenic mass, synchronous or me-tachronous to the primary tumor. To our knowledge, 93 well-documented cases of solitary splenic metastases have been reported to date (Table).3-32 The time from the diagnosis of primary tumor to the discovery of solitary splenic metastasis ranges from 0 to 264 months with a median of 28 months. Colorectal and ovarian carcinomas are the most common sources. On the other hand, solitary splenic metastases from breast carcinoma22-24 or skin melanoma33 are rare. Exceptionally, a splenic metastasis reveals a clinically occult primary tumor.17 Only 1 report described a solitary splenic metastasis from unknown primary.32

Splenic metastases are most often incidentally detected by ultrasonography or computed tomography scanning in the regular follow-up of patients with cancer or in the workup performed at the time of any event related to cancer. When isolated, more than 60% of splenic metastases are asymptomatic (Table). The increasing use of 18-fluo-rodeoxyglucose- positron emission tomography scanning has resulted in more patients with asymptomatic metastases being identified than previously found using conventional radiologic techniques.2 Splenic metastasis can also be revealed by fatigue,3 weight loss,5 fever,16 abdominal pain,* splenomegaly,5,25,32 anemia or thrombocytope-nia due to hypersplenism,14,16 and more rarely by splenic rupture.5,11,24 Serum level of tumor markers used in the follow-up of patients with cancer can predict the appearance of solitary splenic metastases before their clinical expression or radiologic detection and decreases to the normal range after splenectomy.

THOUSAND OAKS, Calif. — Amgen (Nasdaq:AMGN) today presented the results from a randomized, double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of Aranesp([R]) (darbepoetin alfa) for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy (”the 103 study”). Aranesp is not approved for use by the FDA or EMEA in these patients. These results were presented in an oral session at the 2007 American Association for Cancer Research (AACR) annual meeting in Los Angeles, Calif. (AACR Abstract #LB-3).

As reported in January, the study did not meet its primary endpoint of reducing red blood cell (RBC) transfusions in the Aranesp treatment group. Transfusion occurrences from weeks 5 to 17 favored Aranesp but were not statistically significant between the groups (hazard ratio: 0.85, p=0.32). Among those receiving Aranesp, there was a significantly higher proportion of patients with a hemoglobin response (p<0.0001), hemoglobin correction (p<0.001), and hematopoietic response (p=0.002) compared with placebo.

The adverse event rate was similar between the groups. However, the overall number of deaths was greater in the Aranesp group (48.5 percent versus 46 percent in placebo; hazard ratio: 1.29; p=0.006). In post-hoc analyses adjusting for stratification factors at randomization and sex, stage IV disease, prior chemotherapy use and prior radiotherapy use, there remained a significant difference in survival between the groups. However, hazard ratios and statistical significance diminished when the analyses were further adjusted for known prognostic factors including baseline ECOG status, tumor type, tumor stage, baseline FACT-F cutoff at median and baseline Hb (hazard ratio: 1.17, p=0.11).

“This study evaluated ESA treatment for patients with active cancer, not receiving chemotherapy or radiation, who are anemic due to the cancer itself. Unfortunately, the benefit of ESA treatment was not observed in these gravely ill patients,” said John Glaspy, M.D., professor, David Geffen School of Medicine, University of California at Los Angeles. “Since this was not designed as a survival study and statistical significance diminished when the analyses were adjusted for known prognostic factors, there is no clear explanation for the increase of deaths in the Aranesp group.”

About the Study

This Phase 3 study was designed to evaluate the efficacy and safety of Aranesp 6.75 mcg/kg administered every four weeks for the treatment of anemia in cancer patients not receiving chemotherapy or radiotherapy. The study was conducted in 21 countries, including sites in Western Europe, Central and Eastern Europe, Australia and North America. The majority of patients (60 percent) were from Central and Eastern Europe.

Patient eligibility included: eN18 years, nonmyeloid malignancy (with active disease), hemoglobin (Hb) en 11 g/dL, and no chemotherapy or radiotherapy treatment within four weeks of screening or during the study. Patients (n=985) were randomized to Aranesp 6.75 mcg/kg or placebo every four weeks, with an end of study visit at week 19, and two years of follow up to evaluate survival. Patients were stratified by screening Hb (<10 g/dL or eN 10 g/dL), geographic region (Europe versus rest of world), RBC transfusion in the prior 12 weeks, tumor type/treatment (specifically, diagnoses of chronic lymphocyctic leukemia or low grade lymphoma, ongoing hormonal or antibody therapy versus all other eligible patients), and ECOG status (0-1, 2).

Demographics were broadly similar between the groups. The mean (SD) age was 64.1 (11.6) years; the most common cancers were non-small cell lung (18 percent), breast (13 percent), and prostate (11 percent); most patients had disease stage III or IV (82 percent) and an ECOG status of 0 or 1 (72 percent); and baseline Hb was 9.5 g/dL in each group.

However, there were more men in the Aranesp group (56 percent) compared to the placebo group (47 percent) and overall survival was worse for men than women (hazard ratio: 1.38 versus 0.99, respectively). More patients received prior chemotherapy in the Aranesp group (73 percent versus 66 percent in placebo). The mean (SD) number of days between prior chemotherapy and first study drug dose was 262 (572) days for the Aranesp group compared to 315 (660) for the placebo arm.

About Aranesp

Aranesp was approved by the U.S. Food and Drug Administration (FDA) in September 2001 for the treatment of anemia associated with chronic renal failure (CRF), also known as chronic kidney disease (CKD), for patients on dialysis and patients not on dialysis. In July 2002, the FDA approved weekly dosing of Aranesp for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies and in March 2006, the FDA approved every-three-week dosing in these patients.

Important Safety Information

Use the lowest dose of Aranesp that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion (see DOSAGE and ADMINISTRATION in the prescribing information).

In October, attention often turns to Breast Cancer Awareness Month. But whatever your favorite charity is, you can support it year-round–and get some healthy exercise–by participating in a fund-raising run/walk. Whether you’ve never taken part in a run before or are used to breaking the tape at the finish line, try one of the events listed below. Check each website for upcoming dates and locations.

Money raised/
Event                  Benefits                   participants

Team in Training       The Leukemia &             $81 million/35,000
teamintraining.org     Lymphoma Society           participants in 2004
MS Challenge Walk      National Multiple          $6 million/
nationalmssociety.org  Sclerosis Society          approximately 3,500
participants in 2004
Avon Walk for          The Avon Foundation        More than $60 million/
Breast Cancer          Breast Cancer              23,000 participants in
avonwalk.org           Crusade                    2003-2004
AIDS Walk              Leading AIDS charities     $12 million/86,000
aidswalk.net           across the country         participants in 2004
in 2004-2005
March of Dimes         Research institutions      $96 million/more than
Walk America           and programs that treat    20,000 teams
walkamerica.org        or work to prevent         participated in 2004
threats to babies’ health
Komen Race for         The Komen Foundation       $68 million/1.3
the Cure               Award and Research         million participants
komen.org              Grant Program, and         in 2004
community education
about breast cancer
Revlon Run/Walk        Women’s-cancer             $62 million since
for Women              research and treatment     1993/approximately
revlonrunwalk.com      services for medically     90,000 participants in
underserved women          2005
America’s Walk         American Diabetes          $18 million/
for Diabetes           Association                approximately 200,000
walk.diabetes.org                                 participants in 2004
American Cancer        American Cancer            $1.5 billion since
Society Relay          Society                    1985/3 million
for Life                                          projected in 2005
cancer.org

Event                  Ideal for

Team in Training       Marathoners Participants of all fitness levels
teamintraining.org     are provided with training and support to help
them run a marathon (26.2 miles), half-marathon
(13.1 miles) or a triathlon in separately
sponsored events around the country.
MS Challenge Walk      Long-distance walkers The challenge is the
nationalmssociety.org  distance, not the course, which covers 20 miles
on day one, 20 more on day two and 10 miles on
day three.
Avon Walk for          Long-distance walkers Walkers can choose between
Breast Cancer          a marathon or a marathon and a half (39.3 miles)
avonwalk.org           over one weekend. The course is designed for all
fitness levels with plenty of roadside support
and a wellness village to house walkers
overnight.
AIDS Walk              Speed walkers The course is a 10k (6.2 miles)
aidswalk.net           stretch on mostly flat terrain through West
Hollywood, San Francisco’s Golden Gate Park and
New York’s Central Park and upper west side. Most
people walk or speed walk, but joggers are
welcome.
March of Dimes         Speed walkers Most routes are approximately 6
Walk America           miles and can be completed by people of all
walkamerica.org        fitness levels.
Komen Race for         Joggers The courses in this 5k (3.1 miles) run/
the Cure               walk are all roads–no cross-country running
komen.org              here–and have very little, if any, elevation.
Although most participants walk or jog, elite
runners often join in.
Revlon Run/Walk        Joggers With 5k events right outside downtown Los
for Women              Angeles and in New York City, the walks are
revlonrunwalk.com      scenic and flat.
America’s Walk         Walkers This family-friendly event offers a
for Diabetes           choice between a 2k or 5k walk.
walk.diabetes.org
American Cancer        Walkers Teams of 10-12 take turns running or
Society Relay          walking laps around a community track or field.
for Life               No athletic proficiency is required, and there is
cancer.org             no set distance or time.

LONDON — Piribo, the online destination for business intelligence for the biotech and pharmaceutical industry, has now added a new report on the cancer therapeutics market. “Cancer Therapeutics: The Worldwide Market” forecasts that the cancer therapeutics market will grow from around $46 billion in 2006 to more than $89 billion by 2011.

The potential for improved disease outcomes is vast and targeted cancer therapeutics are a very exciting prospect, offering the opportunity to improve patient survival from serious illnesses. With the market expecting more than $11 billion new therapeutics to gain approval within the next four years a global market of $89 billion may be a modest projection.

Innovation has been and remains the key to growth with the largest number of therapy approvals recorded in the US in 2006 and a further 50 therapies in Phase III or awaiting approval.

This study examines the global market for therapies for a broad range of cancers including: bladder, breast, cervical, colorectal, kidney, leukemia, liver, lung, lymphoma, melanoma, multiple myeloma, ovarian, and prostate among others. Therapy types covered in the report include chemotherapy, hormone and radiation therapy, immunotherapy and biotherapy, and adjunctive therapies.

It also includes extensive coverage of research and development pipelines, in-depth company profiles, four-region geographic breakdowns, over 160 tables and figures and more.

“Cancer Therapeutics: The Worldwide Market” is available in pdf format from Piribo. For more information, go to: http://www.piribo.com/search/results.html?k=KAL111&x=0&y=0

Piribo product ID: KAL111

About Piribo.

Piribo (http:www.piribo.com) is a UK-based independent online store supplying business information on the pharmaceutical and biotechnology industries. The website now carries over 6,000 English language titles including, market reports, studies and books and is the UK’s largest online biopharma information store. Subscribers receive a free monthly newsletter and email alerts on new titles in their areas of interest. The company was established in 2004.

Bio-Reference Laboratories, Inc (NASDAQ - “BRLI”), has announced that John M. Bennett MD, a leading authority on hematological malignancies, has agreed to serve as Chairman of the newly-formed Scientific Advisory Board at Bio-Reference Laboratories. Dr. Bennett has agreed to preside over an extremely distinguished panel of experts who will advise and assist Bio-Reference Laboratories in providing state-of-the-art testing services for cancer specialists. Dr. Bennett has long been recognized as an intellectual force in the treatment and understanding of leukemias, lymphomas and other and cancer-related diseases. He is one of the world’s leading authorities on Myelodysplasia and is founder and Chairman of the MDS Foundation as well as Editor of the “Journal Leukemia Research”. He currently sits on numerous international and national committees and chairs many leading societies seeking to understand and improve the diagnosis and treatment of cancer. Dr. Bennett has agreed to commit the necessary time and resources to work with Bio-Reference and its Scientific Advisory Board to help promote better healthcare.

Dr. Bennett is currently Professor Emeritus and former Head of the Medical Oncology Unit at the University Of Rochester Medical Center and formerly was a Professor of Oncology in Medicine, Pathology and Laboratory Medicine at the University of Rochester Medical School. For nearly four decades, Dr. Bennett has been honored by the medical community as an expert in the field of oncology as evidenced by the numerous chairs he has held in prestigious societies and committees and over 400 publications in peer review journals, the majority of which are in the area of hematologic malignancies.

In a statement, Dr. Bennett observed: “The diagnosis, monitoring and treatment of cancer patients has undergone great change in recent years. New technologies are emerging which will allow us to achieve results that were previously thought to be unattainable. The role of the clinical diagnostic laboratory has never been as critical as it is today for cancer patients. Bio-Reference seeks to bring the best clinical technology, methodologies and medical advancements to its physicians and their patients and I am pleased to assist them in that endeavor. Bio-Reference is committed to clinical laboratory excellence and I am pleased that they have asked me to work with them to maintain and improve their standards for bringing better diagnostics to the healthcare marketplace. I look forward to working with the distinguished colleagues that we have asked to join the Scientific Advisory Board and I look forward to working with the outstanding team that Bio-Reference has assembled”

Marc Grodman, M.D., Chairman and CEO of BRLI, stated, “Dr. Bennett is clearly a medical visionary who understands the role of the clinical laboratory in promoting better and more efficient healthcare. Through our cancer laboratory, GenPath, we have outlined a strategy to provide the outstanding clinical laboratory services to the cancer patient. We are excited about the tremendous value that Dr. Bennett and the Scientific Advisory Board will bring to us. We have put together an outstanding team at Bio-Reference; we have already established ourselves in the marketplace as an innovative, technologically advanced clinical laboratory dedicated to bringing value-added results to the medical community. Dr. Bennett will provide us with additional tools and a life of experience to enhance our solutions. Under Dr. Bennett’s leadership our Scientific Advisory Board will solidify our value to healthcare providers.”

About Bio-Reference Laboratories, Inc.

The Company is the largest independent regional clinical laboratory in the Northeast and has major market positions in physician offices, nursing homes and correctional institutions. The Company is a full service clinical laboratory with specialty capability, especially in the areas of oncology, hematology, gene-based testing and correctional health. PSIMedica, a business unit of the Company, is a clinical knowledge management (CKM) organization offering an array of information solutions for reducing healthcare costs and improving quality performance that are based on a flexible, scalable software analytical engine that utilizes all available source information, including claims data, enrollment data, prescription data and laboratory data. The Company provides a comprehensive connectivity solution that includes disease management, laboratory reporting and ordering, as well as claims eligibility and processing, to physicians through CareEvolve, its web-based healthcare portal.

Statements included in this release that are not historical in nature, are intended to be, and are hereby identified as “forward-looking statements”. Statements looking forward in time are included in this release pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Such statements involve known and unknown risks and uncertainties that may cause the Company’s actual results in future periods to be materially different from any future performance suggested herein.

Cyclosporine is an immunosuppressive agent that has been shown to be effective in the treatment of psoriasis. However, its serious side effects in transplant patients have hindered many dermatologists from exploiting its therapeutic capabilities. The literature contains reports of lymphomas, internal malignancies, skin cancers, and serious infections in psoriasis patients on cyclosporine therapy. However, no study has evaluated the relative risk of these side effects in relation to the general population, nor monitored the patients for years after cyclosporine was discontinued. The recently published 5-year cohort study is the most rigorous data to date on the long-term safety of cyclosporine and shows no increased risk of lymphoma or internal malignancies. The study, however, illustrates increased risk of non-melanoma skin cancers, especially squamous cell carcinoma. Review of the literature does not suggest any increased risk of opportunistic infections or tuberculosis reactivation. These data suggest that cyclosporine in dermatologic dosage (3-5 mg/kg/d) is safe and dermatologists may consider using it.

Patients with severe psoriasis often require treatment with systemic therapy to control their disease. Cyclosporine, an immunosuppressive agent that inhibits T-lymphocytes, has been widely used in transplant patients. Since cyclosporine’s initial report of clearing psoriatic lesions in 1979, many controlled studies have confirmed its efficacy in the treatment of psoriasis. (1-3) There are, however, concerns regarding its toxicity. In transplant patients, long-term treatment with cyclosporine is associated with serious side effects, including increased risk of lymphoma, internal malignancies, skin cancers, and infections. (4-7) Although the risk appears to be less in non-transplant patients, these possible long-term side effects have hindered many dermatologists from exploiting its therapeutic capabilities in treating psoriasis patients. For years, dermatologists were worried about the lack of long-term data on cyclosporine in psoriasis patients. Now, there are data available that examine the long-term safety of cyclosporine therapy in the psoriasis population. This article reviews the safety data of cyclosporine use in the past decade according to dermatologic guidelines. A review of the anecdotal studies on cyclosporine will be presented first, followed by more rigorous clinical studies of cyclosporine in dermatology patients.

Methods

A literature review of all articles in English from 1979 to 2003 was performed using Medline searching for case reports, clinical trials, epidemiological studies, cohort studies, randomized controlled trials, letters, meta-analyses, and review articles. The year 1979 was used as a starting point since that was when the first study illustrating the efficacy of cyclosporine in psoriasis was published. The literature search was performed with an emphasis on the use of cyclosporine in dermatology settings. Keywords used included cyclosporine/Neoral adverse effects, cyclosporine/Neoral therapeutic use, cyclosporine/Neoral and malignancy, lymphoma, leukemia, skin neoplasm, basal cell carcinoma, squamous cell carcinoma, melanoma, lung cancer, liver cancer, mycosis fungoides, tuberculosis reactivation, and opportunistic infections. Out of all the articles captured, only 26 provided us with relevant data. Limitations of the study include the fact that not all cases of neoplasm and infections are reported and that articles written in languages other than English were not reviewed.

Results

Anecdotal Reports

Koo et al published one of the first case reports of a psoriasis patient who developed a B-cell lymphoma 7 months after discontinuation of a 9-month course of cyclosporine. (8) Since this initial report, there have been several other case reports of lymphomas diagnosed after various latency periods following discontinuation of cyclosporine therapy. Zijlmans et al reported a case of Epstein Barr virus-associated lymphoma in a rheumatoid arthritis patient 5 months after discontinuation of cyclosporine at a dosage of less than 5 mg/kg per day. (9) Masouye, Salamon, and Saurat reported a B-cell immunoblastic lymphoma 4 months after discontinuation of a 5-month course of cyclosporine 5 mg/kg per day in a keratosis lichenoides chronica patient. (10)

In addition to cases of lymphomas occurring after cyclosporine discontinuation, there have also been several case reports of lymphomas while on cyclosporine therapy for psoriasis. Cliff et al reported a psoriasis patient with a history of methotrexate treatment who developed a B-cell lymphoma while on cyclosporine therapy. (11) The patient had been on cyclosporine therapy for 6 years, but it is not clear from the report whether the treatment was intermittent or continuous. The patient required an average dose of 4 mg/kg per day and at times required up to 10 mg/kg per day. There was no spontaneous regression after discontinuation of cyclosporine. Cockburn and Krupp reported 3 patients with autoimmune diseases who developed lymphomas with a mean latency period of 14.7 months after initiating cyclosporine therapy. (7) No information is disclosed as to the types of autoimmune diseases and lymphomas or the dosage of cyclosporine.