Four Cases of the Rare Skin Manifestation: Monoclonal-Proteinemia / 罕见病研究

The skin manifestations of monoclonal(M)-proteinemia are rare and present in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering plasma cell myeloma (SMM) and multiple myeloma (MM). In this study, we reported 4 cases with M-proteinemia-related rare skin lesions, including pyoderma gangrenosum (PG), erythema elevatum diutinum (EED), cutis laxa (CL) and lichen myxedematosus(LM). These skin lesions are specific, where the potential mechanism was immune-mediated paraneoplastic syndrome rather than direct plasma cell infiltration. Anti-plasma cell treatment was effective in treating skin lesions. The clinical outcome of MM-related skin changes was correlated to tumor control, whereas the prognosis of MGUS or SMM related skin lesions was favorable. Skin involvement in M-proteinemia is extremely rare and less well-known, which greatly impairs quality of life. The diagnosis and treatment of these 4 cases support the need for futher study.

The 492nd case: recurrent thrombosis, thrombocytopenia / 中华内科杂志

A 43-year-old female patient was admitted with recurrent thrombosis for more than 2 years and thrombocytopenia for more than 1 year. Both arterial and venous thromboses developed especially at rare sites even during anticoagulation therapy such as cerebral venous sinus thrombosis. Antinuclear antibody, anti-ENA antibody and antiphospholipid antibody were all negative. Platelet count elevated to normal after high dose glucocorticoid and intravenous immunoglobulin (IVIG). Immune thrombocytopenia was suspected. When 4 grade thrombocytopenia recurred, intravenous heparin, rituximab 600 mg, IVIG and eltrombopag were administrated. After 3 weeks, thrombocytopenia did not improve, and new thrombosis developed instead. Screening of thrombophilia related genes revealed PROS1 gene heterozygous mutation and MTHFR TT genotype. Low amount of serum IgG κ monoclonal protein was detected. Heparin-induced thrombocytopenia was differentiated and excluded. Finally, serum negative antiphospholipid syndrome was considered the most likely diagnosis. Dexamethasone 20 mg/day × 4 days combined with sirolimus 2 mg/day was prescribed. The patient was discharged with low molecular weight heparin. At one month, her headache was greatly relieved. The platelet count raised to 20-30×10 9/L, and no new thrombosis or bleeding was reported.

Overlap or mimic: Castleman disease and connective tissue disease / 中华风湿病学杂志

Objective:To investigate the relationship of Castleman disease (CD) and connective tissue disease (CTD).Methods:Clinical records and laboratory data of 11 patientsdiagnosed with CD and CTD were collected and retrospectively analyzed. All patients were diagnosed at Peking Union Medical College Hospital.Results:① The proportion of CD associated with or mimicking CTD was 5.67% (11/194) in all CD patients during the same period. The average age of these cases at the diagnosis was (51±17) years and the ratio of male to female was 6∶5. ② Lymphadenopathy (10/11), fever (8/11), serosal effusion (6/11), arthralgia (5/11), alopecia (2/11), Raynaud phenomenon (1/11) and photosensitivity (1/11) were the common clinical manifest- ations that could mimic CTD. ③ Elevated ESR (11/11), hypoalbuminemia (11/11), elevated CRP (10/11), elevated IgG (7/11), proteinuria (5/11), hematuria (5/11) and positive ANA(5/11) were commonly found in the patients' laboratory tests. ④ CD was inclined to mimic systemic lupus erythematosus(SLE)(5/11), IgG4-related disease(IgG4-RD)(2/11) and adult onset Still's disease(AOSD)(2/11), as well as 2 cases were associated with Sj?gren's Syndrome(SS)(2/11). ⑤All cases were ultimately diagnosed as multicentric CD, the pathologic subtypes were plasma cell variant (10/11) and mixed(1/11) respectively.Conclusion:CD maybe overlapped with or mimic a variety of clinical manifestations, such as fever, serosal effusion, arthralgia and proteinuria which could mimic CTD. Early biopsy is helpful for the diagnosis and to avoid misdiagnosis and mistreatment.

Lymphomatoid gastropathy: one case report and literatures review / 中华血液学杂志

Objective@#To report the first case of lymphomatoid gastropathy in China, and to demonstrate the clinical characteristics, diagnostic approach, treatment and prognosis in this kind of patients.@*Methods@#One patient was diagnosed as lymphomatoid gastropathy at Peking Union Medical College Hospital, and her clinical characteristics, lab data, treatment and follow-up outcomes were reviewed.@*Results@#A case of a 51-year-old female was presented, who underwent esophagogastroduodenoscopy (EGD) due to slight epigastric discomfort. EGD revealed multiple ulcers and erosions. Biopsies showed atypical lymphocytes infiltration with CD3(+), CD56(+), CD20(-), CD8(-), TIA(+), Granzyme B(-) and Ki-67 (75%). Epstein-Barr virus-encoded RNA in situ hybridization was negative. Four months later, repeated EGD examination showed regression of the lesions without specific treatment.@*Conclusion@#Lymphomatoid gastropathy was a unique disease entity mimicking NK/T-cell lymphomas in pathology, with the quite different profile of treatment and prognosis. It’s important to consider this issue during the differential diagnosis to avoid any excessive treatment.

Purpura fulminans related to paroxysmal nocturnal haemoglobinuria: a case report and literatures review / 中华血液学杂志

Objective@#To improve the understanding of the rare clinical presentation and management of purpura fulminans (PF) in patients with paroxysmal nocturnal haemoglobinuria (PNH).@*Methods@#A case of PF occurring in PNH is reported, while the related literature review is conducted.@*Results@#A 49-year-old male patient suffered from one-week history of fever, greenish-brown colour urine, multiple well demarcated and painful purpura of the head and neck. He had been reported to have two thromboembolic events during the 22-year course of PNH. Skin biopsy displayed classic PF features. Laboratory testing showed a high PNH clone, intravascular hemolysis and coagulation system changes. After sufficient anticoagulation and short course of glucocorticoid therapy, the clinical conditions were improved correspondingly. During a follow-up period of 6 month, there was no recurrence of thrombosis.@*Conclusion@#PF should be considered in PNH patients with unexplained, quickly developed painful purpura. Extensive work-up should be performed to find out other potential thrombophilic risk factors after diagnosis of PF. Early diagnosis, adequate anticoagulation therapy and control hemolysis were essential to PF treatment occurring in PNH. The survival of patients and the qualities of life can be improved. The PNH clone detection is needed to evaluate the status of procoagulation and predict the risk of recurrent thrombosis.

Clinical characteristics of intravascular large B cell lymphoma: a single-center retrospective study / 中华血液学杂志

Objective@#To investigate clinic-pathological characteristics, diagnosis, treatment and prognosis of intravascular large B cell lymphoma (IVLBCL) in China.@*Methods@#Clinical and pathological records were analyzed from 12 IVLBCL patients diagnosed between Jan 2010 to Jun 2016. Kaplan-Meier method was used to estimate overall survival (OS), and univariate analysis was performed to identify prognostic factors.@*Results@#A series of 12 patients with IVLBCL (median age, 53.8 years; range, 32-76 years; 6 males and 6 females) was reviewed. Fever was the most common symptom (10/12), respiratory symptoms (cough, pleural effusion, dyspnea, 50%) and hemophagocytic lymphohistiocytosis (50%) were frequently observed, and only 12 patients had neurological symptom. All patients had elevated lactic dehydrogenase and serum ferritin. International Prognostic Index score was high in 75% of total patients. All patients had extra-nodal involved, pulmonary (6/12) and bone marrow (4/12) were frequently involved. Large lymphoid cells within vessel lumina or sinuses were observed in all patients. These cells were large, with scant cytoplasm, vesicular nuclei, and one or more nucleoli, and the structures of vessels and sinus were reserved. CD20 and CD79a were positive in all cases. 11patients received rituximab combined CHOP regimen chemotherapies, overall response rate (ORR) was 90.1%, and complete response rate was 66.7%. Median survival time and median progression time were not reached after a median follow-up of 20 months. Univariate analysis revealed that no clinical characters were associated with OS.@*Conclusion@#As a rare variant of DLBCL, IVLBCL presented with pulmonary involved frequently, and trans-bronchial lung biopsy had good positive rates. Rituximab contained chemotherapy was the backbone for IVLBCL.

Posaconazole as primary prevention of fungal infection in intensive immunosuppressive therapy for severe aplastic anemia / 中华血液学杂志

Objective@#To Evaluate the efficacy and safety of posaconazole as primary prevention of invasive fungal disease (IFD) in patients with severe aplastic anemia (SAA) treated with anti-thymus/lymphocyte immunoglobulin (ATG/ALG) combined with cyclosporine intensive immunosuppressive therapy (IST).@*Methods@#A retrospective analysis of clinical data of 58 SAA patients who received IST of anti-thymocyte immunoglobulin combining cyclosporine and antifungal prophylaxis during April 2013 to May 2017 in Peking Union Medical College Hospital was performed. The patients were divided into posaconazole prophylaxis group and the control group (itraconazole or fluconazole). The disease characteristics, IFD prevention effect and adverse drug reaction, curative effect and prognosis of the two groups were compared.@*Results@#Posaconazole was used to prevent fungal infection in 20 patients. The other 38 patients were used as the control group. Retrospective analysis showed comparable characteristics (gender, age, disease severity, etiology, interval between the onset of disease to treatment, ATG/ALG type) of both groups. The incidence of IFD were 0 and 15.8% in posaconazole prophylaxis group and the control group, respectively (P=0.084). In the control group, there were 6 cases diagnosed as IFD. Of them, 2 were confirmed, 2 suspected and 2 not identified. Five of the 6 cases were pulmonary infection, 1 bloodstream infections. Of the 6 IFD cases, 5 were very severe aplastic anemia (VSAA). There was no obvious adverse reaction in posaconazole prophylaxis group.@*Conclusion@#Posaconazole is safe and effective for primary prevention of fungal infection of SAA patients receiving IST, especially for the VSAA.

Changes of microparticle levels before and after daunorubicin-based chemotherapy in patients with acute leukemia / 白血病·淋巴瘤

Objective To observe the serum levels of endothelial microparticles (EMP) and tissue factor-bearing microparticles (TF+MP) in patients with acute leukemia before and after daunorubicin-based chemotherapy. Methods From July 2012 to February 2013, 15 patients with newly diagnosed acute leukemia in Peking Union Medical College Hospital received DA (daunorubicin + cytarabine) regimen or VDCLP (vincristine + daunorubicin + cyclophosphamide + L-asparaginase + prednisone) regimen chemotherapy. There were 8 males and 7 females, and the median age of patients was 44 years old. Eleven patients were acute myeloid leukemia (M01 case, M11 case, M29 cases), and 4 were acute lymphocytic leukemia. The peripheral blood samples were taken before induction chemotherapy and after 3 days of daunorubicin. Levels of EMP and TF+MP were assessed using flow cytometry. Results The serum EMP and TF+MP levels were significantly higher after 3-day daunorubicin infusions than those before induction chemotherapy (28.94/μl vs. 10.74/μl, P= 0.001; 64.24/μl vs. 43.80/μl, P= 0.02). Conclusion Daunorubicin-based chemotherapy may cause increased numbers of EMP and TF+MP in patients with acute leukemia.

Efficacy and safety of Hyper-CVAD regimen for treatment of aggressive T-cell lymphoma / 白血病·淋巴瘤

Objective To evaluate the safety and efficacy of Hyper-CVAD intensive chemotherapy regimen in patients with newly diagnosed aggressive T-cell lymphoma. Methods The efficacy, side effects and survival status were retrospectively analyzed in 34 patients with newly diagnosed aggressive T-cell lymphoma who received Hyper-CVAD regimen as induction therapy in Peking Union Medical College Hospital from September 2009 to December 2010. Results Of 34 patients, 28 cases (82.4 ％) showed treatment response, including 10 cases (29.4 ％) of complete response (CR). Eleven patients underwent stem cell transplantation, including 1 case of human leukocyte antigen-identical siblings allogeneic stem cell transplantation. The median follow-up was 16 months (1-82 months), and the overall survival (OS) rate of 1 or 3-year was 70.2 ％ and 41.1 ％ respectively, and progression-free survival (PFS) rate of 1 or 3-year was 49.3 ％ and 31.6 ％ respectively. The major adverse reaction was myelosuppresion, including 18 cases (52.9％) of myelosuppresion with grade Ⅳ. Three patients died of serious infection. Cox regression multifactor analysis showed CR was the only influencing factor for PFS (HR=6.118, 95％CI 1.327-28.206, P=0.020). Marrow involvement (HR= 0.270, 95 ％CI 0.101-0.722, P= 0.009) and CR (HR= 6.669, 95 ％CI 1.754-25.354, P= 0.005) were independent influencing factors for OS. Conclusions Hyper-CVAD regimen has a high response rate for aggressive T-cell lymphoma, but the lasting effectiveness and the short-term efficacy show unfavorable performances. Meanwhile, myelosuppression is serious and infection incidence is high. Autologous hematopoietic stem-cell transplantation after remission may improve the outcome.

Evaluation of clinical characteristics, MYD88L265P mutation, CXCR4WHIM mutation and prognosis in Waldenström macroglobulinemia: A single center retrospective study of 93 patients / 中华血液学杂志

Objective@#To evaluate the clinical characteristics, MYD88L265P mutation, CXCR4WHIM mutation and prognosis in patients with Waldenström macroglobulinemia (WM).@*Methods@#The clinical characteristics, International Prognostic Scoring System for symptomatic WM (WPSS) , and overall survival (OS) were retrospectively assayed in 93 patients with newly diagnosed WM at Peking Union Medical College Hospital during January 2000 to August 2016. The MYD88L265P mutation and CXCR4WHIM mutation were tested among 34 patients.@*Results@#The median age of the 93 patients was 64 years (range, 33-85 years) with a male-to-female ratio of 2.44. According to WPSS, we included 16 (17.2%) low-risk, 44 (47.3%) intermediate-risk and 33 (35.5%) high-risk patients. Eight patients had secondary amyloidosis. With a median follow-up of 44 (1-201) months, the median OS was 84 months. Cox regression multifactor analysis showed WPSS risk group (HR=2.342, 95% CI 1.111-4.950, P=0.025) , whether patients had secondary amyloidosis (HR=5.538, 95% CI 1.958-15.662, P=0.001) and whether patients received new drugs (HR=3.392, 95% CI 1.531-7.513, P=0.003) were independent factors associated with OS. We have investigated the presence of the MYD88L265P and CXCR4WHIM mutation in 34 patients and found that MYD88L265P mutation was occurred in 32 patients (94.1%) and CXCR4WHIM mutation was occurred in 8 patients (23.5%). Seven of 8 patients who harbored CXCR4WHIM-mutated also exhibited the MYD88L265P mutation. Patients with MYD88L265PCXCR4WHIM vs MYD88L265PCXCR4WT presented with more severe anemia, lower platelet level, higher M protein level and more hyper-viscosity syndrome.@*Conclusion@#WPSS risk group, whether patients had secondary amyloidosis or received new drugs are independent factors for OS in WM. MYD88L265P and CXCR4WHIM mutation, the most common somatic variants in WM, often occur together and impact the clinical presentation.

The 455th case:swollen leg, jaundice and mental disturbance / 中华内科杂志

A 17-year-old young man with a history of swollen leg and intermittent jaundice was presented to Peking Union Medical College Hospital with acute fever and mental disturbance.He developed deep venous thrombosis,acute myocardial infarction and plantar skin necrosis during the past four years,and was presented with an acute episode of fever,thrombocytopenia,acute kidney injury,acute myocardial infarction,mental disturbance,and obstructive jaundice.Laboratory tests showed schistocytes on peripheral blood smear.High titer of antiphospholipid antibodies was detected.Strikingly,the activity of a disintegrin and metalloprotease with a thrombospondin type 1 motif,member 13 (ADAMTS13)was significantly decreased without the production of inhibitors.Images indicated stenosis of the common bile duct,common hepatic duct,and cystic duct,which caused dilation of bile ducts and the gall bladder.Corticosteroids and anticoagulation therapy were effective at first,but the disease relapsedonce the corticosteroids tapered down.Plasma exchange was administrated for 17 times,which was effective temporarily during this episode.Methylprednisolone pulse therapy,intravenous immunoglobulin,rituximab,anticoagulation therapy,and bile drainage,were all tried but still could not control the disease.The patient's family agreed to withdraw treatment after he developed septic shock.

Safety of polyethylene glycol conjugated L-asparaginase in patients with acute lymphoblastic leukemia and T cell non-Hodgkin lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the safety of polyethylene glycol conjugated L-asparaginase (PEG-Asp) for patients with adult acute lymphoblastic leukemia (ALL) and T cell non-Hodgkin lymphoma (T-NHL).</p><p><b>METHODS</b>A retrospective analysis was conducted on the clinical data of 101 young patients (≤40 years old) with ALL and T-NHL, diagnosed at Peking Union Medical College Hospital between January 2012 and June 2014.</p><p><b>RESULTS</b>A total of 480 doses of PEG-Asp were administered in 44 cases with ALL and 57 patients with T-NHL. Only one patient (0.2%) experienced mild allergic reaction. Other grade 3 or 4 toxicities of non-hematologic effects included low level of fibrogen (6.4%), elevated ALT (4.4%), blood glucose (2.3%), and triglyceridemia (2.3%), decreased albumin (0.8%) and elevated amylase (0.2%). Furthermore, 5 cases (1.0%) developed venous thrombosis, 9 cases (1.9%) hemorrage, 1 patient (0.2%) non-necrosis pancretitis.</p><p><b>CONCLUSION</b>The risk of allergic reaction incurred by PEG-Asp is very low. It can be used safely in ALL and T-NHL. Coagulation status should be monitored during the treatment.</p>

Clinical characteristics and outcome of patients with primary central nervous system lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the characteristics, treatment and outcome of patients with primary central nervous system lymphoma （PCNSL）.</p><p><b>METHODS</b>A total of 37 patients with PCNSL treated in Peking Union Medical College Hospital from June 1999 to June 2012 were enrolled into this retrospective study. The clinical characteristics, results of treatment and prognostic factors were analyzed.</p><p><b>RESULTS</b>The median age of 37 patients with PCNSL at diagnosis was 57 years（range 17 to 78 years） with a male to female ratio of 2.7:1. The symptoms or signs of elevated intracranial pressure and cognitive dysfunction were the most common initial manifestations. The median time period between onset of symptoms and diagnosis was 1.5 months. The majority of lesions were located in the cerebral hemisphere. At a median follow-up of 50 months, the median overall survival for all treated patients was 36.0 months （95% CI 21.7-50.3 months）, with a progression-free survival of 18.0 months（95% CI 9.1-26.9 months）. The 3-year cumulative survival rate was 46.9%. Compared to chemotherapy alone, combined-modality regimens which did not improve outcome were associated with a greater risk of neurotoxicity.</p><p><b>CONCLUSION</b>The prognosis of PCNSL was still poor, and the optimal treatment strategy for these patients should be explored in the future clinical trials.</p>

Clinical analysis of 14 cases with primary breast lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinical features, prognostic factors, diagnostic methods and treatment outcomes of primary breast lymphoma (PBL).</p><p><b>METHODS</b>The clinical data of 14 patients diagnosed with PBL between 2000.1 and 2013.6 were analyzed retrospectively.</p><p><b>RESULTS</b>The 14 patients were diagnosed with PBL, which comprised 0.24% and 0.54% of all breast malignancies and lymphoma, respectively. The median age was 43(20-77) years. All but one was female. The median course before diagnosis was 1(0.17-12) month. There were 9 patients with international prognostic index (IPI) 0 and 5 with IPI 1. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) with total 11 cases (78.6%), there was 1 case (7.1%) in each of extranodal margin zone lymphoma, peripheral T cell lymphoma(PTCL) and small lymphocytic lymphoma (SLL), respectively. Patients treated with radical operation versus local mass removing or needle biopsy were 6(42.9%) and 8(57.1%), respectively, there were 2 relapses in each group. Patients treated with or without rituxinmab combined with chemotherapy were 6(42.9%) and 7(50.0%), respectively, there were 3 and 1 relapses in each group, respectively. Three (21.4%) patients received intrathecal injection (IT). There were 3(21.4%) cases of central nervous system (CNS) relapse, who were not received IT. After the median follow-up of 45.2 (10.7-116.1) months, two patients died of disease progression. The median overall survival did not reach and median progression free survival was 73 (11- 116) months.</p><p><b>CONCLUSION</b>The most common histological subtype in patients with PBL was DLBCL, the role of rituxinmab in the treatment was not sure, CNS relapse should be monitored closely.</p>

The clinical analysis of 14 cases of systemic lupus erythematosus complicated by thrombotic thrombocytopenic purpura / 中华内科杂志

Objective To analyze the clinical features,diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in patients with systemic lupus erythematosus (SLE).Methods Clinical manifestations,laboratory findings,diagnosis,treatment and prognosis of 14 SLE patients with TTP were retrospectively analyzed.Results Of the 14 patients diagnosed with SLE and TTP,4 were men and 10 were women.The median age at diagnosis was 23 (17-69) years old.In five patients,the onset of SLE preceded TTP,and in nine patients SLE and TTP occurred simultaneouslv.All the 14 patients had thrombocytopenia and hemolytic anemia,12 had fever,11 had neurologic abnormalities,and 11 had renal dysfunction.Eight patients presented with the classic pentad of symptoms.Six patients were given steroids (alone or in combination with intravenous immunoglobulin and cyclophosphamide),and eight patients were treated with steroids in combination with plasmapheresis,with response rates of 2/6 and 6/8,respectively.Six patients died,with overall mortality rate of 6/14.No patients relapsed during the follow-up period.Conclusions SLE and TTP share some similar clinical symptoms.As a result,repeated examinations of peripheral blood smears are very important for early diagnosis.The renal damage in patients of co-existing diseases is more serious than those with TTP alone or SLE alone.Early diagnosis and prompt treatment with plasma exchange and steroids may improve the prognosis in SLE patients with TTP.

The prophylactic effect of ceftazidime on early bacterial infection after autologous peripheral blood stem cell transplantation: a prospective randomized controlled trial / 中华内科杂志

Objective To evaluate the efficacy and safety of prophylactic cefiazidime on early bacterial infection in APBSCT recipients during neutropenia.Methods APBSCT recipients were prospectively randomly assigned to intravenous ceftazidime treatment group and control group (no prophylaxis of antibiotics).The treatment started from the first day until resolution of neutropenia or the appearance of early bacterial infection.Results From March 2010 to January 2013,70 APBSCT recipients were enrolled in the study with 36 in treatment and 34 in control group.Overall,29 (41.4％) patients developed early bacterial infection,among which,9(25.0％) in the treatment group and 20(58.8％) in the control group (P =0.004).The median infection free survival (IFS) was not reached in the treatment group and was 8 days in the control group (P =0.005).Despite whether patients received single high dose melphalan or other conditioning regimes,the early bacterial infection rate was lower in the treatment group than in the control group,and the median IFS was longer in the treatment group than that in the control group.The mean courses of antibiotic administration were (8.08 ± 2.03) days and (3.68 ± 3.56) days respectively in the treatment and control groups (P ＜ 0.001).However,the duration of empirical carbapenems were (1.67 ±3.03) days and (3.68 ±3.56) days respectively (P =0.013).There was no significant difference of antibiotics cost per patient between the two groups.Four patients in the treatment group had a transient elevated serum creatinine.Overall,no infection related mortality was observed in either group.Conclusions Prophylaxis of intravenous ceftazidime for APBSCT recipients is effective in preventing early bacterial infection with an acceptable toxicity and cost profile.However,it doesn't have effect on infection related mortality.Therefore,our results do not support the use of antibiotic prophylaxis for patients undergoing APBSCT.

Clinical manifestations and diagnosis of POEMS syndrome / 基础医学与临床

Objective To analyze the clinical manifestations and the criteria for the diagnosis of POEMS syndrome.Methods The clinical characteristics of 36 cases of POEMS syndrome were retrospectively reviewed and compared with the cases reported in literature.Results In addition to the typical characteristics of polyneuropathy(100%),organomegaly(92%),endocrinopathy(86%),monoclonal plasmaproliferative disorder(100%) and skin changes(86%),the patients of POEMS syndrome also have other important features including extravascular volume overload(97%),papilledema(57%) and bone lesions(25%).Furthermore,25% of POEMS syndrome patients have co-existent Castleman disease.Conclusion To make the diagnosis of POEMS syndrome,both major and minor criteria are required.The former includes polyneuropathy and monoclonal plasmaproliferative disorder and the latter includes osteosclerotic bone lesions,Castleman disease,papilledema,organomegaly,edema or serous cavity effusion,endocrinopathy and skin changes.