Bence-Jones Research Articles

A case of bilateral pleural effusion as the first sign of multiple myeloma

Multiple myeloma (MM) is a type of hematological malignancy that can affect all types of tissues in human. However, it is extremely rare that pleural effusion presents as the first sign in MM patients. A 54-year-old male patient attended our department of respiratory medicine complaining of shortness of breath for the past 3 months. A chest computer tomography (CT) radiograph revealed a bilateral pleural effusion, which was further assessed as exudative type. Sinus spiral CT scan demonstrated diffuse bone destruction of craniofacial bone. A broad reduction of the lumbar bone signal was confirmed by MRI. Furthermore, pleural biopsy showed abnormal proliferation of plasmocytes whereas bone marrow biopsy showed active hyperplasia of plasmacytoid cells. Interestingly, Bence-Jones protein in urine and serum protein electrophoresis was negative. The patient was diagnosed as non-secretory MM. He then underwent chemotherapy with vincristine, adriamycin and dexamethasone. Partial regression of the pleural effusion was achieved after two rounds of chemotherapy, and the patient has been followed for more than one year.

Carbamazepine and Multiple Myeloma: Possible Interaction

To the Editor Epilepsy is the most common chronic neurological disease and patients are treated by various classes of antiepileptic drugs [1]. In addition to their acute side effects, there are long-term adverse effects of antiepileptic drugs [2]. Hemopoietic neoplasias such as lymphoma, multiple myeloma, and some solid cancers including lung, liver, pancreas, and gastrointestinal cancers are the malignant disorders most frequently discussed in relation to use of antiepileptic drugs [3,4]. The carcinogenic effect of carbamazepine is very limited. However, there are some case reports and series containing a limited number of cases of hypogammaglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma [3,4,5,6,7,8,9,10,11]. We present here a 54-year-old woman with multiple myeloma with long exposure to carbamazepine. Vertebral fracture was detected and vertebroplasty was done urgently. There was no evidence of neurologic deficit. She had a history of 400 mg carbamazepine usage for more than 20 years due to idiopathic epilepsy. Laboratory examination showed total protein/albumin of 8.85/3.41 g/dL and calcium of 10.77 mg/dL (8.4-9.2); she had macrocytic anemia. Bence-Jones protein in the urine was not demonstrated. Protein electrophoresis showed an M-peak (Figure 1) with an elevated serum level of immunoglobulin G (IgG) of 2740 mg/dL. Immunoelectrophoresis revealed M-protein composed with a kappa chain. Bone marrow aspiration and biopsy showed 90% plasma cell infiltration and CD38 and kappa were positive. Cytogenetic analysis of bone marrow showed 17 p deletion (+), 13 q deletion (+), t (11;14), t (4;14). Histopathological examination of a vertebroplasty specimen revealed plasma infiltration. Carbamazepine usage was stopped and treatment was continued with valproic acid. A regimen containing bortezomib (1.3 g/m2), dexamethasone (40 mg), and zoledronic acid was prescribed. After 4 courses of chemotherapy, blood and bone marrow exams were normal. Stem cell transplantation was planned for consolidation. Carbamazepine-related multiple myeloma has been reported in a few case reports. It has been suggested that carbamazepine may cause the IgG type of M-protein multiple myeloma, MGUS, and hypogammaglobulinemia [5,6,9,11,12]. Our patient was younger than is usual for multiple myeloma. We can speculate that the exposure to an extrinsic factor may be associated with younger age in this case. The relationships among the duration of use of antiepileptic drugs, cumulative dose of antiepileptic drugs, and development of multiple myeloma are not known completely. In our case, multiple myeloma developed after 20 years of carbamazepine use. In conclusion, carbamazepine may be a potential drug in the development of multiple myeloma. For this reason, periodical evaluation of serum levels of immunoglobulin is necessary in patients receiving carbamazepine. Figure 1 Abnormal serum protein electrophoresis pattern in a patient with multiple myeloma. Note the large spike in the early gamma region. Conflict of Interest Statement The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.

Extramedullary plasmacytoma of the orbit: A rare case

Solitary orbital plasma cell neoplasm in the absence of multiple myeloma is very rare. We present here a case report of extramedullary plasmacytoma of the right orbital soft tissue in a 50-year-old Indian woman whose thorough diagnostic workup was negative for multiple myeloma. The patient presented with gradually increasing proptosis, swelling, and visual disturbances of the right eye for past one and half years. Computed tomography (CT) scan of the orbit revealed lobulated, mildly enhancing soft tissue lesion in the supero-lateral aspect of right orbit without intracranial extension. Pathological report revealed a plasma cell neoplasm and immunohistochemistry was positive for CD138, CD20, CD 79a, PAX-5. Complete skeletal survey and bone marrow examination report were normal. So, normal skeletal survey, absence of bone marrow involvement, absence of Bence-Jones protein, no anemia, no hypercalcemia, no renal disease, normal level of immunoglobulins all exclude the diagnosis of multiple myeloma. Since the visual acuity of the patient is well-preserved, so we have planned to treat her with local radiotherapy alone with 50 Gy over 5 weeks.

A case of plasmacytoma of scalp in pediatric thalassemia human immunodeficiency virus positive child

A 9-year-old female child, known case of beta thalassemia major and human immunodeficiency virus seropositive, presented with two slowly growing masses in the temporoparietal region of the skull on both sides. Irregular bony erosion at left parietal area with underlying scalp hematoma with similar change at the right side to a lesser degree were found. Fine needle aspiration cytology from masses showed abundant plasmacytoid cells some of which are binucleated along with free erythroblasts. Cytological features were suggestive of plasmacytoma. Serum protein electrophoresis showed no M-band. Urine was negative for Bence-Jones protein. Bone marrow biopsy showed no plasma cell neoplasm. Diagnosed as first reported case of primary multiple solitary plasmacyomas affecting bilateral temporoparietal bones in a pediatric patient, the child was treated with external beam radiation therapy to scalp lesions showing excellent results and on further follow-up showed no evidence of progressive disease.

An Intact Immunoglobulin IgAλ Multiple Myeloma Patient Exhibiting Light Chain Escape

AbstractAbstract 5008A 48 year old man was referred to the Institute of Hematology and Transfusion Medicine, Warsaw, Poland in April 2008 with anemia (Hemoglobin; 10. 4 g/dl) and mild renal impairment (eGFR; 75. 4 mL/min/1. 73m2). An initial diagnostic monoclonal protein screen (serum protein electrophoresis (SPE), serum immunofixation electrophoresis (IFE) and serum free light chain (FLC) analysis) revealed an IgAλ monoclonal protein (0. 8g/dL) with monoclonal serum FLC and an abnormal serum FLC κ/λ ratio (0. 0001; RI, 0. 26–1. 65). A bone marrow biopsy at that time confirmed 60% involvement of monoclonal λ - restricted plasma cells; a bone survey did not detect any osteolysis. The patient was diagnosed with multiple myeloma (MM) (ISS stage I, Durie and Salmon stage IA) and was initially treated with 6 cycles of vincristin, doxorubicin and dexamethasone (VAD). The patient responded well to the induction treatment and subsequently underwent a successful autologous stem cell transplantation (ASCT).The patient was monitored for 3 years subsequent to the ASCT with both serum and urine electrophoresis, serum FLC analysis (Freelite) and heavy chain/light chain (HLC) immunoassays (Hevylite). Sixteen months following the ASCT the dFLC (involved λ FLC– uninvolved κ FLC) concentration began to increase, the FLC κ/λ ratio became abnormal with a trace of λ Bence Jones protein (BJP) detected by urine IFE. However, both SPE and IFE were normal and the HLC ratio (IgAλ/IgAκ) was within the normal range. During the next 9 months the dFLC continued to increase and a λ BJP could now be clearly detected on the urine IFE. 27 months following the ASCT the patient sustained a pathological fracture of the tibiae and was referred to our centre 4 months later. At this point, the dFLC concentration was highly elevated (3168 mg/L) with a λ BJP detectable by both serum and urine IFE. However, there was no detectable monoclonal intact immunoglobulin by serum IFE or HLC analysis, indicating disease relapse by a separate FLC clone; referred to as light chain escape (LCE). A bone marrow biopsy revealed 15% involvement of λ restricted plasma cells; this time a bone survey identified osteolysis. The patient was diagnosed with progression of multiple myeloma and received 6 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD regimen). He responded well to treatment and 3 years following the ASCT achieved a CR as indicated by a normalized κ/λ FLC ratio, negative immunofixation with 1–3% bone marrow plasma cells. The patient is now well and able to continue with normal life.In this case study the increase in the dFLC levels was the first indication of disease progression and highlights the importance of monitoring intact immunoglobulin MM patients with serum FLC immunoassays for early detection of LCE. Disclosures:Endean:The Binding Site Group Ltd: Employment. Harding:Binding Site: Employment.

Discovery Research On the Effects of Continuous Administration of Bortezomib Maintenance Therapy to Treat Patients with Relapsed and Refractory Multiple Myeloma - Analysis of Background Factors That Affect the Continuity of Therapy-

Abstract 1866 Objective:This was a pilot study for a planned prospective trial of Bortezomib-Maintenance therapy to treat relapsed or refractory multiple myeloma (MM) patients. The purpose was to explore whether this maintenance therapy can lead to long-term progression free survival with good quality of life. We also analyzed and verified background factors that affected the continuity of maintenance therapy with Bortezomib using the data obtained. Materials and Methods:Relapsed or refractory MM patients (N=38) who experienced at least one prior treatment and reached more than very good partial response (VGPR)/partial response (PR) after Bortezomib and Dexamethasone (BD) induction therapy between September 2008 and January 2012 were enrolled. All patients provided written, informed consent. The patients received Bortezomib once a month until progression disease (PD) as maintenance therapy (Clinical data cutoff date was May 2012). Results:The average age of the patients was 64.8 years old (range, 29–86 years, 10 males, 28 females). The MM disease type classification was IgG-type in 23, IgA-type in 8, IgD-type in 1, and Bence Jones Protein(BJP) in 6. Therapy evaluation at the start of maintenance therapy was VGPR in 22 cases (58%) and PR in 16 cases (42%). The average period of continuous disease control was 20 months. Other than 2 cases of mild zoster and 4 cases of mild diarrhea, there were no G3/4 adverse events, including any peripheral neuropathy, which necessitated discontinuation of treatment during the maintenance therapy period. Statistical analysis according to patient age3 a 65 y/o and <65 y/o, ISS (I, II, III), the number of prior treatments (more than 1 or 2), period of induction therapy with Bortezomib, gender, presence or absence of complex karyotypic abnormalities, and time to progression (TTP) separated by a median of 24 months in disease duration was performed to determine whether any factor affected the continuity of maintenance therapy. A significant difference in the presence or absence of complex karyotypic abnormalities was observed. Slightly significant differences in ISS, the number of prior treatments, and the period of induction therapy with Bortezomib were also observed. The other factors did not affect the continuity of treatment. Discussion:The current results showed the median duration of maintenance therapy with Bortezomib was 20 months and the period of disease control including induction therapy was 26 months. We found that high TTP could be obtained by monthly maintenance therapy with Bortezomib, even when compared with the 6.2 months of TTP in the APEX global phase III trial that involved patients with relapsed and refractory MM treated with Bortezomib. The occurrence of peripheral neuropathy is thought to be associated with the dosing interval of Bortezomib, and the fact that monthly administration of Bortezomib decreases the risk of adverse events, including peripheral neuropathy, supports this. The present study confirmed the efficacy and safety of monthly administration of Bortezomib. Patients with complex karyotypic abnormalities may not be appropriate candidates for controlling the disease with monthly maintenance therapy. Thus, further studies on the dosing interval of Bortezomib during maintenance therapy are needed. Conclusion:The results of the present study demonstrated the continuity and tolerability of monthly maintenance therapy with Bortezomib. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Lupus anticoagulant hypoprothrombinemia syndrome in Bence-Jones protein κ-type multiple myeloma patient with phosphatidylserine-dependent antiprothrombin antibody

Dear Editor, Approximately 2 % of multiple myeloma (MM) patients present with hemorrhage at diagnosis. However, hemorrhage due to abnormalities in the coagulation system is a rare complication [1, 2]. Although lupus anticoagulant (LA), which is infrequently reported to be in association with MM, is commonly a risk factor for arterial or venous thrombosis, bleeding tendencies in patients with LA are strongly related to a low prothrombin activity [3–6]. Acquired hypoprothrombinemia with LA, also called LA hypoprothrombinemia syndrome (LAHPS), is a rare disease which appears mostly in young females with systemic lupus erythematosus or in healthy children after viral infection and is usually associated with the presence of antiprothrombin antibodies [7]. We herein report the case of an 86-year-old male with Bence-Jones protein (BJP) κ-type MM who presented with hypoprothrombinemia and LA associated with antibodies directed to the phosphatidylserine–prothrombin complex (or phosphatidylserine-dependent antiprothrombin antibodies, aPS/PT). The patient was admitted with anemia and had no past history of bleeding disorders or thrombotic events. A urinalysis showed massive proteinuria (5.3 g/day), which was determined to be κ-type BJP using immunoelectrophoresis. Bone marrow aspiration showed proliferation of abnormal plasma cells. Computerized tomography showed hematomas in the bilateral gluteus maximus muscle and the supraclavicular area. Initial coagulation tests showed prolonged prothrombin time and activated partial thromboplastin time (aPTT) (Table 1). Reduced clotting activity of factors II (FII), VIII (FVIII), and IX (FIX) was noted in a pattern typical of that observed in previously reported cases of LAHPS [8, 9]. FVIII and FIX inhibitors were not detected. The prolonged aPTT with LA-sensitive aPTT reagent (PTT-LA Roche Diagnostics, Tokyo, Japan), which could not be corrected by mixing with normal plasma, suggested the presence of LA. The results were confirmed using the Staclot LA® assay, and the dilute Russell viper venom time test was used to confirm the presence of LA with the phospholipid-neutralizing LA test (Gradipore, Frenchs Forest, Australia). IgG/M anticardiolipin antibodies and IgG aPS/PT were negative, while strong positive IgM aPS/PT was detected, which was measured with ELISA using the phosphatidylserine–prothrombin complex as antigen immobilized on ELISA plates in the presence of CaCl2 [10]. Based on these findings, the patient was diagnosed as MM with LAHPS associated with aPS/PT and treated with melphalan and prednisolone (MP) therapy. The FII levels were observed to normalize after one cycle of MP therapy and the patient has remained in remission without any hemorrhage for 10 months. Table 1 Laboratory findings In our case, aPTT continued to be prolonged with reduced levels of FVIII and FIX in spite of normalizing the FII level after therapy. LA and IgM aPS/PT remained positive, although these values were improved, suggesting that the presence of LA might have an influence on coagulation tests after treatment. There are very rare reports showing the presence of aPS/PT in patients with LAHPS [9]. These reports describe the patients as having bleeding tendencies with mildly reduced FII levels, similar to that observed in our patient. However, in previously reported child cases of LAHPS, severe hemorrhage usually occurs when the FII levels are very low (under 10∼15 %). It is possible that other coagulation factors associated with aPS/PT in LAHPS might be present. A diagnosis of LAHPS should always be considered in MM patients with bleeding tendencies associated with LA, and aPS/PT detection should be performed in conjunction with LA tests.

Systemic and rapidly progressive light-chain deposition disease initially presenting as tubulointerstitial nephritis.

A 42-year-old woman was admitted to a hospital after first-time detection of proteinuria and hematuria during a routine medical check-up. Because her serum creatinine level had rapidly increased from 0.9 to 3.2mg/dl since measurement 3months earlier, she was referred to our hospital. Renal biopsy revealed extensive tubular atrophy and interstitial fibrosis with mild leukocyte infiltration. Glomeruli showed minimal changes, and no immunoglobulin or complement deposition was observed by immunofluorescence. Oral prednisolone was commenced under the diagnosis of chronic tubulointerstitial nephritis, and she discharged once. However, its effects were transient; her renal function deteriorated rapidly and hemodialysis was initiated 5months after her initial check-up. On readmission, urinary Bence-Jones protein κ-type was detected, and examination of bone marrow led to a diagnosis of Bence-Jones κ-type multiple myeloma. Light-chain staining using a renal biopsy specimen obtained 2months earlier showed κ-light-chain deposition on tubular basement membranes but not glomeruli. Despite undergoing chemotherapy with vincristine, doxirubicin, and dexamethasone, the patient died suddenly from a cardiac arrhythmia. Autopsy showed κ-light-chain deposition in the heart, thyroid, liver, lungs, spleen, and ovaries. Congo red staining yielded negative results. Typical light-chain deposition disease (LCDD) characterized by nodular glomerulosclerosis was observed in the kidneys. This case demonstrates that tubulointerstitial nephritis can be an early pathological variant of LCDD, which may be followed by accelerated and massive light-chain deposition in glomeruli.

Prevalence and type of monoclonal gammopathy of undetermined significance in an apparently healthy Nigerian population: a cross sectional study

BackgroundThe prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder has not been determined in our geographic area Nigeria.MethodsA cross sectional survey was carried on apparently healthy Nigerians selected by multistage sampling technique from the cosmopolitan city of Lagos, Nigeria. Subjects enrolled into the study had 2-step screening for the presence, type and concentration of monoclonal band. Agarose-gel electrophoresis was performed on all serum samples, and any serum sample with a discrete band of monoclonal protein or thought to have a localized band was subjected to Immunofixation. Subjects were also evaluated for Bence jones proteinuria, haematological and biochemical parameters.ResultsFour hundred and ten subjects with a mean age of 45.68 ± 10.3 years, a median of 45.00 years and a range of 20 to 80 years were enrolled into the study. MGUS was identified in only one (0.24 percent) of the 410 study subject. This subject was demonstrated to have a double monoclonal gammopathy; IgGλ at 16.9 g/L and IgAκ at 8.5 g/L. None of them including the sole subject with MGUS had a monoclonal urinary light chain.ConclusionAmong residents of Lagos, Nigeria, MGUS was found in only 0.24% percent of apparently normal persons with a median age of 45 years. This suggests that MGUS which represents the earliest stage of monoclonal plasma/lymphoid cell proliferation is not a common finding in the relatively young population of Nigeria. Future epidemiologic studies dealing with plasma cell disorders in older people are required to carefully examine the relationship between environmental factors and prevalence of MGUS and its ultimate progression to MM.

Sporadic transthyretin amyloidosis with a novel TTR gene mutation misdiagnosed as primary amyloidosis

Light-chain amyloidosis [1] is a rare disease caused by a clonal plasma cell dyscrasia associated with multiorgan deposition of amyloidogenic immunoglobulin light chains. Autosomal dominant transthyretin amyloidosis (ATTR) is an even rarer disorder caused by amyloidogenic mutant alleles of TTR manifesting with progressive and fatal involvement of the peripheral nerves, ganglia, heart, kidney, and eyes. The specific therapy is orthotopic liver transplantation [2]. ATTR may be overlooked because of phenotypical variability [3], and also misdiagnosed as AL because of possible coexistence of monoclonal gammopathy and limited sensitivity/specificity of light chain immunostaining of biopsy specimens [4, 5]. We describe a patient with restrictive cardiomiopathy misdiagnosed as light chain AL amyloidosis, who was affected with ATTR associated with a novel p.Glu62Lys. The final diagnosis with immunogold electron microscopy was possible only in autoptic tissue. A 75-year-old man with type II diabetes, coronary artery disease, and no history of neurological or cardiological disorders presented with signs and symptoms of right-sided heart failure. Electrocardiogram revealed sinus rhythm, first degree A-V block, left anterior fascicular block, and Q waves at the inferior leads. At bidimensional echocardiogram, left ventricular wall thickening, mild systolic dysfunction, and restrictive diastolic pattern were found. Cardiac MRI findings were suggestive of amyloid deposition. Abdominal fat fine-needle aspiration was negative. Endomyocardial biopsy was positive at Congo Red stain and anti-k chain immunohistochemistry. Bone marrow biopsy was normal. A mild IgG/k monoclonal gammopathy was present (2.5 g/l); no Bence-Jones protein was detected, but a slightly abnormal j/k serum free light chain (sFLC) ratio was present. Cardiac troponin I (cTnI) was increased (0.21 lg/l, normal values 0–0.15) as well as NTproBNP (2,842 ng/l, nv 0-900); ALP was also elevated, suggesting a hepatic involvement. The patient was started on melphalan and dexamethasone, and the liver cholestasis enzymes normalized, but cTnI, NT-proBNP, and the j/k FLC chain ratio did not change. A shift to bortezomib-dexamethasone was not effective, and a possible hereditary amyloidosis was considered. Mutational analysis of the TTR gene demonstrated a heterozygous c.183G[A transition in exon 3 that substituted a glutammic acid with a lysine at residue 62 (p.Glu62Lys) of the mature protein; to the best of our knowledge, the nucleotide change was unreported. After re-evaluating the endocardial biopsy, immunohistochemistry demonstrated only a weak TTR positivity. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6529-z) contains supplementary material, which is available to authorized users.

T-Cell Prolymphocytic Leukemia Accompanied by Plural M-Proteins with Myelodysplastic Syndroxme in a Nonagenarian

T-cell Pro-Lymphocytic Leukemia (T-PLL) is a rare disease caused by malignancy of mature post-thymic T-cell. Myelodysplastic Syndrome (MDS) is caused by abnormal differentiation of myeloid lineage cells resulting in myeloid leukemia. Both of these hematological disorders are frequently diagnosed in elderly persons. Myeloid lineage is believed to be situated at the position far from lymphoid one as it is regarded on a tree diagram about the blood cell maturation. We reported herein a rare case of T-PLL accompanied by plural M-proteins with MDS a nonagenarian. The 96 years old patient was admitted to our hospital because of lymphocytosis and abnormal lymphocytes. From the bone marrow aspirate, biopsy and hematological findings, abnormalities were observed in cells of three different lineages, namely, (i) neutrophils with hypersegmented-nuclei (ii) erythroblasts with nuclear division, large platelets and megakaryoblastic cells, and (iii) reticulum cells with phagocytosed iron in their cytoplasm. Lymphocytes showed CD3 (+), CD4 (±), CD5 (+), CD8 (+), CD10 (+), CD56 (-) and CD57 (-). Mast cells and large lymphocytic cells with nuclear pockets were also seen. Anti-HTLV-1 antibody was negative. Soluble IL-2 receptor was significantly elevated to 7910 U/ml. Both IgGλ and IgGκM-protein were detected. No Bence-Jones protein was detected in the urine. Chromosomal abnormality of 45 (X, 0) or loss of Y chromosome was also demonstrated. Due to his high age, it was difficult to classify his condition according to the conventional classification. Thus, what we had experienced is truly a rare case that coincidentally showed T-PLL and MDS with plural M-proteins.

Clinical, electrophysiological and immunological study of peripheral nerves in Egyptian patients with monoclonal gammopathies

Monoclonal antibodies are found in approximately 10% of patients with peripheral neuropathy (PN) of unknown etiology. Several autoantibodies, including anti-MAG (myelin-associated glycoprotein) antibodies, have been reported to induce neuropathy. It has been suggested that over 50% of patients with PN and IgM monoclonal gammopathy (MG) have anti-MAG IgM antibodies in their sera. This work aimed at studying the frequency and characteristics of PN in a group of Egyptian patients with MGs and to estimate the serum level of anti-MAG antibodies and its relationship to peripheral nerve dysfunction. Forty patients with MGs were enrolled in the study. Their mean age was 56.65±8.55years. There were 17 males and 23 females. Patients were subjected to complete general and neurological examination, laboratory investigations including serum LDH, β2 microglobulin, serum protein electrophoresis, urinary Bence-Jones protein, bone marrow aspiration and/or trephine biopsy, quantitative estimation of serum IgM and IgG by nephelometry, detection of anti-MAG antibodies by indirect immunofluorescence, radiological assessment and nerve conduction study of both upper and lower limbs. Clinical and electrophysiological evidences of PN were found in 32 (80%) out of the 40 patients with MG. Twenty-five patients (62.5%) had distal symmetrical polyneuropathy and seven (17.5%) had mononeuritis or mononeuritis multiplex. The majority of patients (65%) had sensory or predominantly sensorimotor polyneuropathy. The neuropathy was mainly demyelinating in 22 patients (55%) and axonal in the other 10 (25%) patients. Anti-MAG antibodies were positive in nine patients (22.5%) and six of them (66.6%) had PN. The latter was predominantly demyelinating motor neuropathy in 4 and axonal in the remaining 2. However, the relationship between the presence of anti-MAG antibodies and the development and type of PN was not statistically significant. Anti-MAG showed significant association with IgM level (P=0.003**) and the MG subtypes: Waldenström's macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) (P=0.004**). The present study showed high frequency (>60%) of distal symmetrical polyneuropathy in Egyptian patients with MG. The neuropathy was predominantly sensory and demyelinating. Anti-MAG antibodies were detected only in 22.5% of the patients, especially those with WM and MGUS and were associated with more motor and demyelinating neuropathy. We recommend that patients with chronic polyneuropathies should be evaluated for underlying plasma cell dyscrasia.

Evaluating Trends in Diagnostic and Prognostic Testing for Multiple Myeloma

Abstract 2067 Introduction:A battery of diagnostic and prognostic testing is recommended by both the NCCN and the International Myeloma Working Group (IMWG) at the time of diagnosis of myeloma. It has been our observation that many patients referred for Autologous Stem Cell Transplant (ASCT) to our center have not had a complete myeloma workup. In this report, we attempt to quantify the adherence to recommended guidelines for the workup of myeloma. Methods:We reviewed the records of all patients with a diagnosis of myeloma referred to our center for ASCT between 2006 and 2011. We looked for the following tests at the time of diagnosis: bone marrow biopsy, SPEP, 24hr urine for Bence-Jones proteinuria, serum β2 microglobulin, skeletal survey, serum free light chains, serum albumin and myeloma FISH panel. We used descriptive statistics to evaluate our results. Results:There were a total of 64 patients who underwent an ASCT in our center between 2006 and 2011. Of these 64 patients, 9 patients were excluded from this review due to incomplete records. At the time of initial diagnosis, the most commonly obtained tests included an albumin level (55/55, 100%), SPEP (54/55, 98%), bone marrow biopsy (52/55, 95%), skeletal survey (52/55, 95%), standard cytogenetics (47/55, 85%), and β2-microglobulin (46/55, 84%). The most commonly omitted studies included the myeloma FISH panel (26/55, 47%), 24-hour urine for Bence-Jones protein (30/55, 55%), and serum free light chains (37/55, 67%). Compliance with the use of serum free light chain assay improved over time, while the frequency of obtaining a myeloma FISH panel remains relatively low and the frequency of obtaining a 24-hour urine for Bence-Jones protein decreased (Tables 1 and 2).Table 1:Tests ordered at the time of diagnosisBone marrow biopsy52/55 (95%)Cytogenetics47/55 (85%)SPEP54/55 (98%)24 hour urine for BJP30/55 (55%)Free light chains37/55 (67%)Skeletal survey52/55 (95%)Beta2-MG46/55 (84%)Myeloma FISH panel26/55 (47%)Table 2:Trends in Serum Free Light Chains, Bence-Jones Protein Testing and MyelomaFish Panel between 2006 and 2009 Conclusions:The most commonly omitted studies were the serum free light chains, 24hr urine and myeloma FISH panel. When assessed over time, compliance increased with the ordering of the SFLC assay, stable for the myeloma FISH panel but decreased for the 24hr urine for Bence-Jones protein. This trend reflects the perception that the serum free light chain assay is replacing the 24hr urine for Bence-Jones proteinuria. Referring community physicians need further education on the ordering of initial diagnostic and prognostic tests for multiple myeloma. Disclosures:No relevant conflicts of interest to declare.

Giant cavernoma of the skull and skeletal-extraskeletal angiomatosis associated with paraproteinemia

Abstract Skeletal-extraskeletal angiomatosis is defined as a benign vascular proliferation affecting the medullar cavity of the bone and at least one other type of tissue, including skin, subcutaneous tissue, viscera, muscle, or synovium, and which does not spread to avascular tissue such as cartilage. Primary hemangiomas/cavernous hemangiomas (cavernomas) are exceedingly rare in the skull, accounting for 0.2% of all osseous neoplasms and are usually located in frontal and parietal bones. The authors present the case of a 66-year-old man who was admitted with right-side hemiparesis. MRI revealed a destructive bone lesion of the left frontal bone. Digital subtraction angiography of the brain did not reveal pathological vascularization, but a minor submucous hemangioma was seen in the nasal airway. Urine test for Bence-Jones proteins was positive for IgG λ light chain. Bone marrow aspiration and CSF analysis revealed no evidence of systemic myelomatosis suggesting a monoclonal gammopathy of undetermined significance. A highly vascular tumor was surgically removed. The histopathology verified cavernous hemangioma of the skull and the nasal submucous hemangioma. We discuss the diagnostic procedure, possible pathophysiological mechanisms and treatment implementation. It is possible that immunoglobulins from monoclonal gammopathies have an etiologic role in the development of the bone and skin changes in older patients, as an acquired condition, by producing a vascular injury that could lead to the multiple hemangiomas in skeletal-extraskeletal angiomatosis. To prevent misdiagnosis with lesions of other origins, multiple lesions of the head must be resected and histopathologically verified. In conclusion, to the best of our knowledge, this is the first case of giant cavernous hemangioma of the skull associated with paraproteinemia and skeletalextraskeletal angiomatosis limited to the head.

Twenty-Four–Hour Bence-Jones Protein Determinations: Can We Ensure Accuracy?

Light chain disease represents 15% to 20% of cases of multiple myeloma. Current guidelines recommend monitoring these patients with 24-hour urine collections. To determine the reliability of 24-hour urine collections in assessing the amount of Bence-Jones protein (BJP). We included all patients from our institution from 2003 through 2008 with BJP who had more than four 24-hour urine collections. We compared BJP excretion calculated from the submitted 24-hour collection with BJP excretion calculated by normalizing the collection to that patient's mean 24-hour creatinine excretion. We also looked at differences in serial values with these 2 methods. In addition, we evaluated the feasibility of using random urine samples to determine BJP excretion. A total of 14 patients with 135 24-hour urine collections met our inclusion criteria. The 24-hour urine creatinine excretion for each patient, which should be reasonably constant, varied considerably (coefficient of variation range 12%-30%). Differences in the 2 methods of calculating BJP excretion ranged from -1588 to 2315 mg/d. Among a total of 121 serial 24-hour measurements, the differences were clinically significant in 37 (30%). Among a total of 23 random urine samples from 11 of these patients submitted within 10 days of a 24-hour collection, the estimated BJP excretion appeared to be accurate in at least 18 (78%). Twenty-four-hour urine collections for BJP are, in practice, often misleading. At a minimum, one should verify that the 24-hour creatinine excretion is accurate. In addition, it may be possible to use the protein/creatinine ratio from random urine samples to determine 24-hour BJP excretion.

Proteinuria: Measurement and Interpretation

Proteinuria is a general term that describes the presence of any type of protein in the urine (e.g., albumin, globulins, mucoproteins, and Bence-Jones proteins); however, albumin is the predominate protein in urine in healthy dogs and cats as well as dogs and cats with renal disease. Proteinuria can arise from several different physiologic and pathologic causes, but persistent proteinuria associated with normal urine sediment is consistent with kidney disease. The urine dipstick colorimetric test is the usual first-line screening test for the detection of proteinuria, but false-positive reactions are common. When proteinuria of renal origin is suspected, the next diagnostic steps are quantitation and longitudinal monitoring via the urine protein/creatinine ratio. The recent availability of a species-specific albumin enzyme-linked immunosorbent assay technology that enables detection of low concentrations of canine and feline albuminuria has both increased diagnostic capability and stimulated discussion about what level of proteinuria/albuminuria is normal. Beyond being an important diagnostic marker, proteinuria is associated with kidney disease progression in both dogs and cats: the greater the magnitude of the proteinuria, the greater the risk of renal disease progression and mortality. Treatments that have attenuated proteinuria in dogs and cats have also been associated with slowed kidney disease progression and/or improved survival. For these reasons, screening for renal proteinuria and longitudinal assessment of renal proteinuria has recently received renewed interest.

103 Senile systemic amyloidosis: a common cause of heart failure in the elderly?

Senile systemic amyloidosis (SSA) is a rare cause of heart failure due to the deposition of wildtype transthyretin. The clinical features and outcome are ill defined; our aim was to evaluate the natural history of the disease in the UK in a group of thoroughly characterised patients. The series included all cases of biopsy proven transthyretin (TTR) amyloidosis with wildtype TTR gene sequencing who were prospectively followed up between January 2001 and May 2010. Clinical, biochemical, ECG and echocardiographic evaluation were performed at presentation to our centre. Patient survival was estimated using Kaplan–Meier analysis. 55 patients with histologically proven SSA; 36 (65.5%) from cardiac, 14 (25.4%) from GI tract, 3 (5.5%) from bladder, 1 (1.8%) from fat and 1 (1.8%) from carpal tunnel tissue were identified. 49 (89%) were male. The median age at diagnosis and death were 74 (range 66–89) and 79 (range 69–84) years respectively. Survival from symptom onset and diagnosis was 7.04 (range 0.54–8.41) and 4.58 (range 0.07–5.41) years respectively. In recent years more patients have been diagnosed with 2 (3.6%), 14 (25.5%) and 39 (70.9%) patients between 2001–2003, 2004–2006 and 2007–2009 respectively. The most common presentation was with breathlessness in 28 patients (51%). Twenty-four patients (43.6%) had prior carpal tunnel operations. Twelve (21.8%) patients had a history of ischaemic heart disease. Fifteen had had a coronary angiogram; 8 were reportedly normal and 7 required intervention. Arrhythmias were common, 20 patients (36.3%) had a history of atrial fibrillation and 6 (10.9) had pacemakers in situ. ECG findings were; 24 (43.6%) in AF, 6 (10.9%) first degree block, 10 (18.2%) left bundle and 6 (10.9%) right bundle branch block, 27 (49%) T wave changes, 11 (20%) &lt;5 mm complexes in all inferior leads. Echocardiographic findings revealed the median IVSd was 1.7 (range 1.1–2.5) cm, median E/A ratio was 2.7 (range 0.79–5.4), E/E′ 15.81 (range 7.5–41.1) and ejection fraction was 45.5 (range 13–83)%. Blood results showed; the median baseline NT-proBNP was 356.1 (range 5–2611) and troponin T 0.03 (range 0.01–0.28). Twenty-five patients had a troponin T &gt;0.03 (45%). Ten patients (18%) had a detectable paraprotein and 2 (3.6%) had bence jones proteins. SSA is present in &gt;25% of the very elderly at post mortem but was rarely diagnosed during life. It is becoming more frequently recognised perhaps due to widespread use of cardiac MRI. Most patients are male but women can be affected. A history of carpal tunnel syndrome is common. The diagnosis is often made after the onset of breathlessness. Systolic and diastolic dysfunction can be seen on echocardiogram. A positive troponin is a common finding with a subsequent normal coronary angiogram. Incidental paraproteins are prevalent in up to 8% of this population and it is important to obtain a tissue diagnosis to rule out AL amyloidosis. With supportive management medium term outcomes are good.

Bence-Jones Protein–Type Myeloma With Amyloid Myopathy Presenting as Amyloidomas and Extensive Amyloid Deposits in the Muscularis Propria

This study reports a 59-year-old man who suffered from multiple skeletal muscle amyloidomas and showed a rapidly fatal course. He noticed left inguinal pain and gait disturbance due to muscle weakness of the left leg. Protein in urine (3.3 g/d) and Bence-Jones protein of the κ type (2.3 g/d) were detected. Bone marrow aspiration showed 11.6% monoclonal plasma cells in nucleated cells. A core needle-biopsied and resected left inguinal tumor showed the deposition of eosinophilic amorphous materials positive for Congo red stain and the κ-light chain. He was diagnosed with plasma cell myeloma with AL (amyloid light chain) amyloidosis. Multiple soft-part tumors developed, grew rapidly, and he died 3 months after admission. At autopsy, 3 large amyloidomas were observed in the skeletal muscles, and prominent amyloid deposits were also seen in the diaphragm, intercostal muscle, iliopsoas muscle, and cervical skeletal muscles examined. Massive amyloid materials deposited diffusely in the propria muscularis of the gastrointestinal tract: the tongue to the rectum.

Nodular parenchymal amyloid, an unusual cause of multiple pulmonary nodules with favourable long term prognosis

A previously healthy 80-year-old woman was diagnosed with an incidental right-upper-lobe (RUL) opacity on a plain chest radiograph (CXR) in 1992. She had never smoked. Surveillance radiographs over 9 months remained unchanged and she was discharged. A repeat CXR in 1996 following a productive cough, but no haemoptysis or weight loss, suggested a slight increase of the RUL lesion. Her father and mother died of lung cancer and leukaemia, respectively. Physical examination was unremarkable. Screening blood tests were normal except for an elevated IgM of 7.7 g/dl (normal range 0.3–1.4). Serum electrophoresis showed no paraprotein band and urinary Bence-Jones protein was undetected. Thoracic and abdominal computerized tomographic (CT) scans were reported as showing multiple spherical/lobular masses throughout the right lung (largest 1.7 cm in diameter), a liver cyst and para-pelvic renal cyst. A percutaneous CT-guided …

Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial

Vascular endothelial growth factor (VEGF) is upregulated in multiple myeloma (MM), and circulating VEGF levels may correlate with response to therapy (Hideshima, et al 2005, Pittini, et al 2002). Thalidomide has been part of the standard treatment for MM and is thought to inhibit VEGF-associated angiogenesis (Du, et al 2004). Bevacizumab, a monoclonal antibody directed against VEGF-A, inhibits VEGF (Jenab-Wolcott and Giantonio 2009). Accordingly, we set out to test the efficacy and safety of bevacizumab alone and in combination with thalidomide in MM patients.