1. Castle-POES disease successfully treated with Rituximab Nezam Torok, MD PGY2

2. History : A 42 year old African American Man A 42 year old African American Man CC : Back pain, for 1 week CC : Back pain, for 1 week

3. PMH : Nov 2008 : Pericardial effusion Nov 2008 : Pericardial effusion Dec 2008 : Suspecion of sarcoidosis Dec 2008 : Suspecion of sarcoidosis

4. Social history Smoker 30 PPY Smoker 30 PPY sexual dysfunction sexual dysfunction

7. Neurological : Motor function : power 4/5 lower limb –leg flexor and extensors as well as foot, bilaterally with diminished DTR and decreased sensation to touch, pain, and position, otherwise negative. Neurological : Motor function : power 4/5 lower limb –leg flexor and extensors as well as foot, bilaterally with diminished DTR and decreased sensation to touch, pain, and position, otherwise negative.

11. More lab tests : HIV, HHV 8 negative HIV, HHV 8 negative Normal or negative tests include : TFT, LH, FSH, testosterone,ANA, ANCA, ACE,RF, SS-A, SS-B, C3, C4, Hep B, Hep C,PSA, vit B12, APA. Normal or negative tests include : TFT, LH, FSH, testosterone,ANA, ANCA, ACE,RF, SS-A, SS-B, C3, C4, Hep B, Hep C,PSA, vit B12, APA.

12. SPE : SPE : increase in IgG 1950 mg/dL(normal 590-1540 mg/dL) increase in IgG 1950 mg/dL(normal 590-1540 mg/dL) mild increase in IgA 498 (normal 50-413mg/dL ) mild increase in IgA 498 (normal 50-413mg/dL ) serum immunofixation polyclonal hypergammaglobulinemia with slightly excess lambda chains, kappa chains 1040 mg/dL ( normal 539 -1320 mg/dL), and Lambda chains 690mg/dL (normal 285-673mg/dL ) with kappa /lambda ratio of 1,5. serum immunofixation polyclonal hypergammaglobulinemia with slightly excess lambda chains, kappa chains 1040 mg/dL ( normal 539 -1320 mg/dL), and Lambda chains 690mg/dL (normal 285-673mg/dL ) with kappa /lambda ratio of 1,5.

13. Normal architecture

14. Effaced architecture of the LN in castlemans disease, HE stain 4 X Normal architecture of LN

15. Atrophic germinal centers, HE stain 40X Normal germinal center, containing larger lymphocytes undergoing activation

16. Atrophic germinal center and effaced architercture

17. Vascular proliferation,10 X

18. Vascular proliferation 20 X

19. Vascular proliferation 40 X

20. interleukin 6 level: 6 pg/ml (normal 0-5pg/ml) interleukin 6 level: 6 pg/ml (normal 0-5pg/ml) plasma Vascular Endothelial Growth factor level (VEGF): 130 pg/ml (normal 6-86 pg/ml) plasma Vascular Endothelial Growth factor level (VEGF): 130 pg/ml (normal 6-86 pg/ml) normal interleukin 1. normal interleukin 1.

21. Summary of findings Osteosclerotic lesions Osteosclerotic lesions Neuropathy motor and sensory Neuropathy motor and sensory Skin changes Skin changes Lymphadenopathy Lymphadenopathy History of pericardial effusion History of pericardial effusion Castlemans disease Castlemans disease High IL-6 and VEGF High IL-6 and VEGF

22. Diagnosis is Multicentric Castleman’s disease with features of POEMS syndrome (Castle- POES)!

24. Treatment There is no standard treatment for this disorder and no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome exist in the available literature* There is no standard treatment for this disorder and no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome exist in the available literature* * Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M- protein, and skin changes) syndrome. Kuwabara S; Dispenzieri A; Arimura K; Misawa S Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006828 * Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M- protein, and skin changes) syndrome. Kuwabara S; Dispenzieri A; Arimura K; Misawa S Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006828

25. How did we treat the patient Rituximab Rituximab 375/m2, weekly for 4 weeks, then once every 2-3 months

26. How did the patient respond Remarkable improvement in muscle power, able to function again Remarkable improvement in muscle power, able to function again Fatigue resolved Fatigue resolved Sexual function improved. Sexual function improved. Dec PET scan activity at the scerotic bone lesions Dec PET scan activity at the scerotic bone lesions No lymphadenopathy No lymphadenopathy

27. BUT VEGF was still at the same level. VEGF was still at the same level. no change in skin lesions. no change in skin lesions. SPEP and immunofixation the same pattern SPEP and immunofixation the same pattern

28. Investigational model differential scanning calorimeter (DSC)

29. differential scanning calorimeter (DSC Our Patient Control

30. The DST shows abnormal thermogram, which means there is abnomal molecular species present in the serum of the serum sample that interact in a significant way with one or more of the proteins in the serum The DST shows abnormal thermogram, which means there is abnomal molecular species present in the serum of the serum sample that interact in a significant way with one or more of the proteins in the serum it is different from electrophoresis technique that are sensitive to size and charge it is different from electrophoresis technique that are sensitive to size and charge What kind of protein, whats is the relation to immunofixation ? What kind of protein, whats is the relation to immunofixation ?

31. “Thinking is more interesting than knowing, but less interesting than looking ”. “Thinking is more interesting than knowing, but less interesting than looking ”.Thinking is more interesting than knowing, but less interesting than lookingThinking is more interesting than knowing, but less interesting than looking

32. References Bradwick PA, Zvaifler NJ, Gill GN, et al. Plasma celldyscrasia with polyneuropathy, organomegaly,endocrinopathy, M protein and skin changes: the POEMSsyndrome. Medicine 1980; 59: 311–322 Bradwick PA, Zvaifler NJ, Gill GN, et al. Plasma celldyscrasia with polyneuropathy, organomegaly,endocrinopathy, M protein and skin changes: the POEMSsyndrome. Medicine 1980; 59: 311–322 Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 2003;101:2496–506 Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 2003;101:2496–506 Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 1984;34:712-20. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 1984;34:712-20. Shikama N, Isono A, Otsuka Y, Terano T, Hirai A.a case of POEMS syndrome with high concentration of IL-6 in pericardial fluid. J Intern Med. 2001 Aug;250(2):170-3 Shikama N, Isono A, Otsuka Y, Terano T, Hirai A.a case of POEMS syndrome with high concentration of IL-6 in pericardial fluid. J Intern Med. 2001 Aug;250(2):170-3 Hashiguchi T, Arimura K, Matsumuro K, et al. Highly concentrated vascular endothelial growth factor in plateletsin Crow-Fukase syndrome. Muscle Nerve. 2000;23:1051-1056. Hashiguchi T, Arimura K, Matsumuro K, et al. Highly concentrated vascular endothelial growth factor in plateletsin Crow-Fukase syndrome. Muscle Nerve. 2000;23:1051-1056. Soubrier M, Dubost JJ, Serre AF, et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum. 1997;40:786-787 Soubrier M, Dubost JJ, Serre AF, et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum. 1997;40:786-787 Joanne Shirine Allam, Cassie C. Kennedy, Timothy R. Aksamit and Angela Dispenzieri. Pulmonary Manifestations in Patients With POEMS Syndrome. Chest 2008;133;969- 974 Joanne Shirine Allam, Cassie C. Kennedy, Timothy R. Aksamit and Angela Dispenzieri. Pulmonary Manifestations in Patients With POEMS Syndrome. Chest 2008;133;969- 974