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Gregory R. Pacheco Castleman Disease Research Laboratory. Opening The Way To Novel Therapies for Castleman Disease. What is Castleman Disease?. Discovered by Dr. Benjamin Castleman in 1956 “Benign” enlargement of lymph nodes (not cancer)

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Gregory R. Pacheco

Castleman Disease

Research Laboratory

Opening The Way To Novel Therapies for Castleman Disease


What is castleman disease
What is Castleman Disease?

  • Discovered by Dr. Benjamin Castleman in 1956

  • “Benign” enlargement of lymph nodes (not cancer)

  • Debilitating symptoms may be controlled with life-long therapy


What is castleman disease1
What is Castleman Disease?

  • Causes of Castleman Disease are unknown

    • Virus

    • Auto-immune Disease

    • Uncontrolled Inflammation

  • Parallels to:

    • Hodgkin Disease

      • Excessive host response to rare tumor cells

    • Rheumatoid Arthritis


Castleman s original publications
Castleman’s Original Publications

  • Benjamin Castleman 1906-1982Pathologist, Massachusetts General Hospital, Boston MAEditor, Clinical-Pathological Case Presentations, NEJM

  • Castleman B and Towne VW: Case Records of Massachusetts General Hospital, Case 40001. NEJM,1954; 26: 250

  • Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph-node hyperplasia resembling thymoma. Cancer, 1956; 9: 822-830


Castleman disease concerns
Castleman Disease: Concerns

  • Some patients do not respond well to therapy

  • Multicentric Castleman Disease may progress to non-Hodgkin’s lymphoma or other malignancies

  • Often misdiagnosed

  • Constitutional symptoms can be debilitating

  • There is no standardized therapy and patients can succumb to CD


Classification of castleman disease
Classification of Castleman Disease

  • Clinical: Unicentric vs. Multicentric

  • Histology Hyaline Vascular vs. Plasmacytic

    (microscopy) vs. Mixed Cellularity type

  • HIV Status Positive vs. Negative

  • HHV8 Status Positive vs. Negative

  • Interleukin 6 Excess vs. no excess


Unicentric castleman disease
Unicentric Castleman Disease

  • Single slow-growing lymph node mass, e.g. neck, chest, abdomen, or groin

  • Symptoms, if any, caused by pressure effect of the enlarging lymph nodes

  • Usually Hyaline Vascular type, usually HIV and HHV8 negative

  • Usually no progression to, or association with other tumors


Symptoms and signs of multicentric castleman disease
Symptoms and signs ofMulticentricCastleman Disease

  • Enlarged lymph nodes in multiple areas

  • Enlargement of liver and spleen

  • Fever and night sweats

  • Loss of appetite

  • Tiredness

  • Edema: swelling of legs, fluid in abdomen, fluid behind lungs


Typical laboratory findings in multicentric castleman disease
Typical Laboratory Findings inMulticentricCastleman Disease

  • Anemia

  • Low blood protein levels (albumin)

  • Laboratory signs of “inflammation” caused by increased interleukin 6 production

    • Increased sedimentation rate (ESR)

    • Increased C-reactive protein (CRP)

    • Increased fibrinogen (clotting factor)


Castleman disease and interleukin 6
Castleman Disease and Interleukin 6

  • Interleukin 6 (IL6) is made by cells in the Castleman nodes

  • IL6 stimulates Castleman nodes to grow

  • IL6 overproduction is found in all types of multicentric Castleman Disease

  • IL6 makes patients sick: loss of appetite, weight loss, night sweats, tiredness


The interleukin 6 connection
The Interleukin 6 Connection

  • Dysregulated interleukin-6 expression produces a syndrome resembling Castleman disease in mice.

Brandt et al, JCI 86, 1990


Anti interleukin 6 receptor antibody therapy controls multicentric cd
Anti-Interleukin 6 Receptor Antibody Therapy Controls Multicentric CD

Before therapy After 2 months After 6 months


How to standardize therapy
How To Standardize Therapy Multicentric CD

  • Central Pathology Review

  • Imaging Guidelines

  • Establish Castleman Disease Consortium (CDC)

    For diagnosis, research, therapy, and long-term follow-up

  • Molecular Diagnosis & Targeted Therapy


Current research
Current Research Multicentric CD

  • Castleman Disease research has been limited

  • The Pacheco Castleman Disease Research Lab is investigating:

    • disease etiology

    • why some patients exhibit increased interleukin 6 levels and others do not

  • SNPs in the interleukin 6 genes may be the cause of its overproduction

    • Subtle genetic differences seen among individuals

    • SNPs have been linked to other related diseases and disorders, including some malignancies.


Seed funding will lead to improved patient outcomes
Seed funding will lead to improved patient outcomes Multicentric CD

No

laboratory

research

Seed

funding

Federal

grants

Clinical

trials

Limited

therapies

Early

studies

Larger

studies

Novel

therapies

Preliminary

data

Awareness

Etiology revealed

Improved

outcomes

Misdiagnosis


The gregory r pacheco castleman disease research laboratory

Gregory R. Pacheco Multicentric CD

The Gregory R. Pacheco Castleman Disease Research Laboratory

Studies the etiology of Castleman Disease, with the goal of shedding light on its cause and leading to more efficacious treatments and the possibility of a cure.


Flow cytometer
Flow Cytometer Multicentric CD

This powerful instrument is used for the identification and characterization of individual cells in a mixed population.


Tissue bank tissue culture pcr
Tissue Bank, Tissue Culture, PCR Multicentric CD

The Pacheco Lab houses the largest bank of Castleman Disease patient samples in the world, and a suite of equipment for tissue culture and molecular studies.


Additional questions
Additional Questions Multicentric CD

  • Does truly unicentric CD really exist?

  • Hyaline-vascular vs. plasma-cell variants: what drives the difference?

  • Viral/self-sustaining inflammatory disease process?

  • Gene expression profiling/tissue array: lymph nodes, blood lymphocytes, dendritic cells, endothelial cells

  • Proteomics

  • Perform serial sampling from multiple sites after therapy


How to advance research
How to Advance Research Multicentric CD

  • Concerted International Effort

    First CD conference in Santa Fe, New Mexico

  • Scientific/Clinical Infrastructure

    Tissue/Serum Bank, consensus for methods of procurement, triaging, studies to be performed

  • Funding Mechanisms

    NIH (Orphan Disease), IMF, MMRF, LLS, Pharma

  • Patient Advocates


Thank you
Thank You Multicentric CD

  • The Pacheco Family

  • The George Hoag Family Foundation

  • Castleman Disease patients for entrusting us with their care and for participating in the research

  • MIRT clinical faculty, research faculty, and support staff


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