Bence-Jones Research Articles

A case presenting with rapid renal damage caused by immunoglobulin D lambda-type multiple myeloma accompanied by granular lymphocyte proliferative disorder

A 69-year-old man was referred to our hospital for severe anemia. The atypical lymphocyte count, including granular lymphocytes, was 2,750/μL. Lymphocyte surface marker analysis showed CD3+, CD5+, CD16+, and CD56+ cells. Mixed T cell- and natural killer cell-type granular lymphocyte proliferative disorder (GLPD) was diagnosed. Because his serum creatinine levels deteriorated rapidly over the next 3months, from 0.96 to 3.27mg/dL, he was admitted to our hospital. The serum levels of immunoglobulins (Ig) other than IgD had decreased, and monoclonal protein was detected in the gamma-globulin region. Immunoelectrophoresis revealed IgD and lambda (λ) proteins in the serum and λ-type Bence-Jones protein in the urine. Renal biopsy examination revealed widespread tubular atrophy and interstitial fibrosis, and cast formation with λ protein deposits in tubular lumens, indicating cast nephropathy. These results indicated that the rapid renal damage was caused by IgD λ-type multiple myeloma accompanied by GLPD. The clinical course of GLPD is not usually aggressive and the findings of physical examinations are not significant. GLPD is usually associated with cytopenia (neutropenia or anemia), viral infections, collagen diseases, neoplasms such as malignant lymphoma, or chronic infections. To date, there are only 2 case reports of GLPD accompanied by multiple myeloma but without renal function or renal histological findings. When the clinical course of GLPD is aggressive and is accompanied with rapid renal damage, multiple myeloma should be considered as a complication.

A Case of Light Chain Deposition Disease (LCDD) in a Young Patient

Light chain disease is a variant of multiple myeloma in which the malignant population of marrow cells produces free monoclonal light chains but no heavy chain or complete immunoglobulin. The monoclonal light chains are small enough to be freely filtered by the kidneys and become Bence-Jones protein. Light chain disease comprises about 18% of multiple myeloma patients. Here we present a case report of a 38-year-old man who initially presented with complaints of pain in back and low grade fever off and on. He was found to have collapse of D9 and D12 vertebrae along with ascites and right pleural effusion and massive proteinuria. Multiple myeloma was considered as a differential diagnosis based on the investigations but eventually the patient was lost to follow up. This case is reported here as the light chain variant of multiple myeloma leading to deposition disease is less commonly reported and presents considerable difficulties in diagnosis.

Mott cells in CD20‐positive myeloma

A 63-year-old woman presented with a 2-month history of left thigh pain, no ‘B’ symptoms, no significant past medical illness and normal clinical examination. Her full blood count was normal. The erythrocyte sedimentation rate was elevated at 115 mm/h, total globulins were elevated but the rest of the serum biochemistry was normal. Serum immunoglobulin electrophoresis with immunofixation showed an IgGλ paraprotein at a concentration of 22 g/l and elevated IgM at 10·4 g/l. Urinary Bence–Jones protein was absent and the serum free light chain ratio was normal. A skeletal survey was normal. A bone marrow aspirate showed a lymphoplasmacytic infiltrate of 30% and cells with large intracytoplasmic inclusions (top right) often in doublets or triplets with the nuclei pushed to the rim of the cell. A bone marrow trephine biopsy showed extensive infiltration by lymphoplasmacytic cells and huge plasma cells (top left). Plasma cells with large Russell body inclusions occupied both paratrabecular and intertrabecular areas and stained positively for CD20, nuclear Cyclin D1 and lambda light chain (bottom right). Flow cytometry initially failed to identify light chain restricted plasma cells. It was recognised that the large sized plasma cells were outside the conventional lymphoid/plasma cell gate. Repeat ungated flow cytometric analysis demonstrated CD45+ cytoplasmic kappa+ = 11%; CD45+ cytoplasmic lambda+ = 17%; CD19+ cytoplasmic kappa+ = 12%; CD19+ cytoplasmic lambda+ = 14% and a reversed kappa: lambda ratio of 11:17. Fluorescence in situ hybridisation on separated plasma cells (CD138+ve) was carried out using the IGH/CCND1 dual fusion dual colour probe (Vysis, Berkshire, UK). Of 100 cells analysed, 78 showed a pattern of one fusion signal, which indicated the presence of the t(11;14) translocation (bottom left). The combined clinicopathologic features confirmed the diagnosis of myeloma. The patient remains asymptomatic and no therapeutic options have yet been offered. This case demonstrates an infrequent but impressive morphological appearance of plasma cells with huge intracytoplasmic immunoglobulin inclusions (Mott cells). The presence of t(11;14) is most commonly associated with mantle cell lymphoma but is found in up to 20% of patients with myeloma, using interphase cytogenetics. Lymphoplasmacytoid appearances, high CD20 expression and t(11;14) has been described as a sub-entity in myeloma. This case demonstrates the importance of always reviewing the flow cytometry data in conjunction with morphology.

Plasma cell tumors with neurologic symptoms: Cytological findings

Plasma cell neoplasms (plasma cell dyscrasias) are a group of entities characterized by the neoplastic proliferation of a single clone of plasma cells, typically producing a monoclonal immunoglobulin. These tumors can manifest as multiple myeloma, monoclonal gammopathy of undetermined significance, plasma cell myeloma, or plasmacytoma. We report two plasma cell tumors, one of them presented with headache and diplopia, and the second one complained from low back pain. The aspirate exhibited numerous plasma cells in various stage of maturation and was initially diagnosed as extra-skeletal solitary plasmacytoma on fine-needle aspiration cytology (FNAC). Immunohistochemistry demonstrated monoclonal expression of light immunoglobulin chains together with demonstration of CD 38 positivity. Systematic approach such as bone marrow examination, serum protein electrophoresis, skeletal imaging, and urine examination for Bence-Jones proteins were performed for patients. With these investigations, one case was labeled as multiple myeloma with secondary solitary plasmacytoma in pituitary gland and soft tissue and another one as primary extra-skeletal solitary plasmacytoma. Although fine-needle aspiration is a reliable and rapid technique for initial diagnosis, further work-up and clinical follow-up of these patients is necessary to rule out multiple myeloma. Because of cytomorphological similarity between plasma cells and endocrine cells, EMP of sellar region may be confused with pituitary adenoma especially at the time of intraoperative consultation.

Liver Amyloidosis Complicated with Liver Failure: A Case Report and Review of the Literature

Introduction: Liver involvement by amyloidosis is not uncommon. The clinical presentation is usually subclinical or with mild elevation of liver enzymes. Liver failure and rupture has rarely been reported. We report a case that presented with new onset ascites and rapidly progressed into liver failure and rupture with fatal outcome. Methods: A 53 years old male patient presented with progressive anasarca over 2 months. His evaluation revealed ascites with high serum-ascites albumin gradient. Liver imaging suggested mild hepatomegaly with nodular liver and splenomegaly with patent hepatic and portal veins. Cardiac workup was unremarkable. Non nephrotic range proteinuria was noted with hypoalbuminemia and mild hyperbilirubinemia. Esophageal varices were seen on gastroscopy. After thorough blood tests, the patient was labelled as cryptogenic cirrhosis and started on diuretics. Result: One week later he developed transient renal failure and confusional state. His serum bilirubin started to increase rapidly .Under evaluation for liver transplant, the patient underwent liver biopsy which showed massive deposits of amyloid with atrophy of hepatocytes. Rectal biopsy was unremarkable. Bone marrow biopsy showed hypercellular marrow with 5-10% abnormal looking plasma cells some appeared in abnormal clusters with thickened blood vessels which were positive for congo red stain. Kappa and lambda immunochemical stains were inconclusive and cytogenetic studies were not performed. Serum protein electrophoresis was normal. Urinary Bence-Jones proteins were negative. Skeletal survey could not be done due to the patient’s critical condition. Five days later the patient developed hypotension with leukocytosis and was transferred to the Intensive Care Unit with the impression of septic shock. Ascetic tap showed frank blood and computed tomography confirmed rupture of the liver. His liver enzymes and bilirubin continued to deteriorate and he developed refractory coagulopathy. A trial of hepatic artery embolization was unsuccessful and the patient succumbed shortly after. Conclusion: Liver amyloidosis can be fatal. It should be considered in any patient who present with features of ascites and hepatomegaly.

Fahr-Type Calcification and Neuropsychiatric Symptoms With M-Proteinemia

Back to table of contents Previous article Next article LettersFull AccessFahr-Type Calcification and Neuropsychiatric Symptoms With M-ProteinemiaAna Hategan, M.D., Usha Parthasarathi, M.B.B.S., Bruno Losier, Ph.D., and James A. Bourgeois, O.D., M.D.Ana HateganSearch for more papers by this author, M.D., Usha ParthasarathiSearch for more papers by this author, M.B.B.S., Bruno LosierSearch for more papers by this author, Ph.D., and James A. BourgeoisSearch for more papers by this author, O.D., M.D.Published Online:1 Oct 2011https://doi.org/10.1176/jnp.23.4.jnpe9AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Bilateral idiopathic calcification of the basal ganglia (ICBG), commonly identified as Fahr's disease, has been documented since the 19th century. This diagnosis has been applied variably to indicate either ICBG or cases of secondary Fahr-type mineralization, and it is referred to generally as basal ganglia calcification (BGC). A small number of studies have indicated a relationship between brain calcification and multiple myeloma (MM), but not monoclonal gammopathy of undetermined significance (MGUS). The following is a case description of this plausible association and its neuropsychiatric manifestations.Case ReportA 77-year-old man was admitted with an index episode of schizophrenia-like psychosis, including paranoid delusions and auditory hallucinations. He had been diagnosed with M-proteinemia at age 60. Physical examination revealed diminished arm swing, abnormal gait, micrographia, and dysarthria. These neurological symptoms had reportedly worsened over the years. Medical and psychiatric family history were noncontributory.Recent laboratory investigations revealed new anemia and presence of Bence-Jones proteins of 0.25g/liter (reference range: negative), raising concern of progression to MM or similar myeloproliferative disorders. Immunoelectrophoresis showed evidence of IgG of 16.6g/liter (reference range: 6.35–14.65g/liter) with lambda light chain M-proteinemia. Blood chemistry, ECG, and electroencephalographic examination were normal. The patient declined a bone marrow biopsy. Brain CT scan indicated mild fronto-temporal atrophy and bilateral calcification of the basal ganglia. The Montreal Cognitive Assessment (MoCA)1 score was 20 out of 30, with notable deficits in attention, recall, and executive function. Neuropsychological assessment battery was consistent with fronto-subcortical dysfunction.DiscussionThe presence of a rigid hypokinetic syndrome, psychotic symptoms, and cognitive impairment was particularly interesting in context of BGC. He had no significant symptoms or history requiring work-up for ruling out unlikely causes for BGC (e.g., hypoparathyroidism, systemic lupus erythematosus, or Wilson's disease), although his monoclonal lambda-chain gammopathy may have contributed to his brain calcification. As described by Isoe et al.,2 M-proteinemia was believed to have played some part in the development of intracranial calcification leading to dementia in a 66-year-old man. Much support exists to suggest that patients with BGC often present with neurological and psychotic features. Our patient exhibited many of these symptoms and was monitored by the hematology service for his progressive MGUS.There is evidence to support that almost all cases of MM are preceded by MGUS.3 What causes MGUS to transform into MM is unknown. Neuropsychiatric manifestations of MM have been described, including secondary mania, which can be one of the first presenting symptoms.4 By contrast, a search of the literature produced no reports of neuropsychiatric manifestations associated with MGUS. Therefore, this case illustrates the possible onset of psychotic and cognitive symptoms in MGUS preceding any frank evidence of progression to a hematological malignancy.Tentolouris et al.5 reported three cases of calcification of the aorta and aortic valve associated with a monoclonal lambda-chain gammopathy. They further indicated that immunologic abnormalities were associated with calcifications. Thus, an immunologic origin of our patient's brain calcification is plausible. Longitudinal assessment is needed of the evolution and progression of neuropsychiatric manifestations over the course of MGUS and perhaps immunologically-induced Fahr-type calcification.St. Joseph's Health CareHamilton Dept. of Psychiatry and Behavioral NeurosciencesMichael G. DeGroote School of Medicine Faculty of Health SciencesMcMasterUniversity Hamilton, Ontario CanadaDr. Ana Hategan; e-mail:[email protected]on.ca1. Nasreddine ZS , Phillips NA , Bedirian V , et al.: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53:695–699Crossref, Medline, Google Scholar2. Isoe K , Urakami K , Shoji M , et al.: Intracranial calcification with IgG lambda M-proteinaemia: a case report. J Neurol Neurosurg Psychiatry 1998; 64:561–563Crossref, Medline, Google Scholar3. Landgren O , Kyle RA , Pfeiffer RM , et al.: Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113:5412–547Crossref, Medline, Google Scholar4. Kushon DJ , Verma S , Elfatah M , et al.: Multiple myeloma presenting as secondary mania. Primary Psychiatry 2009; 16:22–24Google Scholar5. Tentolouris C , Kontozoglou T , Toutouzas P : Familial calcification of aorta and calcific aortic valve disease associated with immunologic abnormalities. Am Heart J 1993; 126:904–909Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 23Issue 4 Fall 2011Pages E9-E10 Metrics PDF download History Published online 1 October 2011 Published in print 1 October 2011

Aseptic meningitis in a patient receiving treatment with anti-tumour necrosis factor alpha

We read with interest the review by Antonio Tristano [1] regarding neurological adverse events associated with antitumour necrosis factor alpha (anti-TNF-a) treatment. We believe that aseptic meningitis is also a potential complication of anti-TNF-a treatment and we report the following case. A 53-year-old plumber presented with 3 weeks of night sweats, fevers and generalised headache. There was no weight loss, recent foreign travel, occupational exposure to sewage or chemicals. He had a single female sexual partner and a recent negative human immunodeficiency virus (HIV) test. He had a pet dog and no further contact with animals or insect bites. His past history included IgA nephropathy (currently quiescent), hypothyroidism and an undifferentiated seronegative inflammatory arthritis. This had involved generalised joint pains but had particularly involved his right ankle and a biopsy had shown synovitis. He was HLA B27 negative. He had been treated with sulphasalazine, which was not tolerated. Despite methotrexate and oral steroids he had continuing right subtalar joint inflammation and adalimumab was added. At presentation his disease was inactive. His medications were levothyroxine, Humira (adalimumab) 40 mg/week since 2008 and oral methotrexate 20 mg/week since 2007 and his arthritis symptoms were well controlled. He was not taking non-steroidal antiinflammatory medication, and took paracetamol (acetaminophen) only for his headache. On admission, examination revealed a pyrexia, \5 splinter haemorrhages, normal heart sounds, chest, abdomen, neurological examination and no meningism, lymphadenopathy or oro-genital ulceration. Investigations showed white cell count 12.7 9 10/L (reference range 3.8–10.6 9 10/L), neutrophil count 9.16 9 10/L (reference range 1.8–6.5 9 10/L), monocyte count 1.12 9 10/L (reference range 0.2–0.8 9 10/L) with C-reactive protein, lactate dehydrogenase and blood film normal. IgA was mildly elevated at 4.11 g/L (reference range 0.8–4.0 g/L). Liver, renal, and thyroid function, plasma viscosity, creatinine kinase, chest X-ray and unenhanced MRI brain/ enhanced MRI spine were normal. Three sets of blood cultures were negative. Urinalysis including Bence-Jones protein and a myeloma screen were negative. Two urine specimens and a sputum specimen were also negative for auramine-phenol stain and tuberculosis (TB) culture after 6 weeks. Complement, extractible nuclear antigens, lupus anticoagulant, anticardiolipin antibody, double stranded DNA and antinuclear antibody were negative. Classical anti neutrophil cytoplasmic antibody (cANCA) was positive (titre 1:320), MPO and PR-3 negative. Cerebrospinal fluid (CSF) was measured serially (see Table 1). Oligoclonal bands were negative. A cytospin with immunophenotyping showed evidence of lymphocyte infiltration, the lymphocyte population consisting of both B and T cells. Cytology revealed reactive lymphocytes. Auramine-phenol stain for TB and TB culture was negative. Cryptococcal antigen and fungal cultures were negative after extended incubation. Herpes simplex virus DNA, enterovirus RNA and CMV (via PCR) were not detected. A CT scan of the thorax/abdomen/pelvis and trans-thoracic echocardiography were normal. HIV and hepatitis A. J. Hamilton (&) N. J. Gutowski Department of Neurology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK e-mail: alexander.hamilton@nhs.net

A Phase II Trial of TBL 12 Sea Cucumber Extract In Patients Withuntreated Asymptomatic Myeloma

AbstractAbstract 5042Patients with smoldering multiple myeloma (MM) may remain asymptomatic (ASx) for variable amounts of time and are therefore typically monitored without treatment. Chemoprevention trials using thalidomide found prohibitive toxicity and longer follow up is needed for early systemic treatment with lenalidomide/dexamethasone of high risk ASxMM. Based on encouraging preclinical data with bioactive food supplements in MM curcumin (Blood 2003), resveratrol (Blood 2006), and a component of green tea extract (Blood 2006) many patients are already using these agents without definitive proof of efficacy or safety. Preclinically, sphingolipids/glycosides contained in sea cucumbers have also demonstrated antitumor properties including antiangiogenesis direct tumor cytotoxicity, and also of particular relevance to MM, the inhibition of osteoclastogenesis. TBL12, an extract of sea cucumber, has been commercially available since 1981 and used by human subjects as a food supplement without any reported toxicities. We therefore designed a pilot phase II study to determine the safety and efficacy of TBL12 in patients with ASxMM. MethodsPatients were required to have ASxMM with measurable disease, defined as serum m spike ≥ 1 g/dL and/or urine m spike ≥ 200 mg/24 hours. If non-secretory, patients were required to have abnormal free light chains (FLC). A total of 20 patients with ASxMM were given TBL12, formulated as a liquid gel (manufactured by Unicorn Pacific Corporation, IND 103,543) to be kept frozen until the time of consumption. Patients ingested 2 units of 20 ml twice per day, for a total of 80 units per day. Disease parameters were monitored monthly and treatment was continued until progression of disease (PD). Results23 patients were screened, with 3 failures, and the remaining 20 patients proceeded with study treatment. The median age of the patient was 58 years (range 22–75), with 11 males and 9 females. The phenotypes were 14 IgG, 5 Ig A, and one kappa light chain. Generally, this was a high risk ASxMM population, with 14 patients having a serum m spike ≥ 3 g/dl and bone marrow plasma cells (PC) ≥ 10%. The median bone marrow PC involvement for all patients was 38% (range 10 to 90). (With the additional high risk criteria of a FLC ratio <0.125 or >8, 13 patients were high risk.) Of the remaining 6 patients, all had immunoparesis and 4 had markedly elevated FLC ratios (range 307-incalculable) and the remaining 2 patients had 9.2 g of bence jones proteinuria (BJP) and an IgA phenotype.Compliance was excellent and the treatment was well tolerated with only grade 1 nausea. There was one SAE, a pneumococcal pneumonia requiring admission, which was felt to be unrelated to study treatment. A total of 11 patients remain on treatment, having completed a median of 11 monthly cycles of TBL12 (range 6–17 cycles). The best response to date has been stable disease. Notably, one high risk patient demonstrated a flattening in the rate of rise of the m spike concordant with the initiation of study treatment (see Figure 1).6 patients came off study for PD after a median of 6.5 cycles (range 2–10). The reasons for PD include: 1 hypercalcemia, 1 acute renal insufficiency (after 2 cycles with 9.2g BJP at screening), 1 for anemia (after 3 cycles with 90% marrow PC at screening), and 1 for a new bony lesion on MRI. 2 patients withdrew consent after cycle 6 and 8, and 1 was removed after cycle 13 due to investigator discretion after the pneumonia SAE.-1 year I + 1 yearTBL 12 initiated ConclusionsIn this pilot study of high risk ASxMM patients, TBL12 was well tolerated and 11 patients (65%)remain on treatment. The expected rate of progression for this population from diagnosis is 52% at 2 years, however, the median time to progression has not been yet reached in this study. Additional follow up is required and data will be updated at the annual meeting. The decrease in the rate of rise in the m-spike in a high risk patient concomitant with the initiation of study treatment is suggestive of a biologic effect of TBL12 in MM and warrants further study of TBL 12 in a larger cohort of patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Immunological evidence of monoclonal gammopathy in North India: a hospital based study

Immunological evidence of monoclonal gammopathy in North India: a hospital based study Kalpana Singh1, Bhawna Singh2, Sarika Arora2, Alpana Saxena11Department of Biochemistry, Maulana Azad Medical College and LN Hospital, New Delhi, India; 2Department of Biochemistry, GB Pant Hospital, New Delhi, IndiaBackground: Monoclonal gammopathy of unknown significance (MGUS) is a condition in which a paraprotein is found in the blood during standard laboratory tests. It is age-related and characterized by accumulation of bone marrow plasma cells derived from a single abnormal clone. The aim of this study was to investigate the pattern of MGUS in North Indian urban population.Methods: Serum and urine samples were collected from 320 suspected cases of gammopathy, were analyzed by sensitive immunological technique based protein electrophoresis followed by immunofixation for detection and type of monoclonal/polyclonal gammopathies. Twenty-five healthy subjects were included as controls.Results: Gammopathies were observed in 38 (11.88%) patients. Out of these 7.5% were &not;monoclonal and 4.3% were polyclonal. Overall age of presentation of these monoclonal &not;gammopathies in both sexes was between 21 and 76 years. Gender-related ratio (men:women) for these gammopathies was 1:1.18. Predominant heavy chain isotype was IgG (62.5%) followed by IgA (37.5%). Among light chains, kappa (&kappa;) and lambda (&lambda;) chains appeared in 91.6% and 8.4% gammopathies respectively. Paraprotein fractions obtained were IgG&kappa; (58.3%), IgG&lambda; (4.16%), IgA&kappa; (33.3%), and IgA&lambda; (4.16%) with 25% samples being positive for Bence Jones proteinuria.Conclusions: Clinical laboratories play an important role in confirming the immunological diagnosis of gammopathies. Determination of nature of paraproteinemia and its associated diseases calls for more extensive studies in India.Keywords: monoclonal gammopathy, immunoelectrophoresis, multiple myeloma, bence jones protein, immunoglobulins

AL amyloidosis with IgD-lambda monoclonal gammopathy and lambda-type Bence-Jones protein: successful treatment by autologous stem cell transplantation

A 45-year-old Japanese woman had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS) featuring urinary Bence-Jones protein of the lambda type (BJP-lambda) for 11years. She then developed eyelid purpura, dyspnea, and flank pain. Abdominal CT scans revealed renal infarction. Biopsy of the kidney, heart, jejunum, and skin demonstrated amyloid deposits in the vessel walls, but not in the glomeruli. She was diagnosed as having AL amyloidosis with IgD-lambda monoclonal gammopathy and BJP-lambda. Autologous stem cell transplantation (SCT) was done after chemotherapy with vincristine, daunorubicin, dexamethasone (VAD), and high-dose melphalan (HDM). This reduced the IgD level from 156 to 0.1mg/dL, along with the disappearance of BJP, despite cerebral infarction during chemotherapy. We recommend SCT for patients with IgD-associated AL amyloidosis.

Amyloid myopathy: a therapeutic trial for the rare and underdiagnosed myopathy with bortezomib

A 69-year-old woman was referred to our clinic because of a 6-month history of progressive muscle weakness. Five years previously, when she was diagnosed as having nephrotic syndrome, the renal biopsy showed deposition of AL-amyloid. Subsequent investigations revealed multiple myeloma with k-type Bence-Jones protein at stage 3 according to the international staging system. A course of vincristine, doxorubicin and dexamethasone (VAD) and an additional course of cyclophosphamide were administered, followed by another course of melphalan (L-PAM) at age 67. The proteinuria slightly improved but persisted for 5 years, when proximal weakness developed. Neurological examination revealed proximally dominant weakness with MRC scale 4 in the deltoid and 3 in the iliopsoas muscles and she was unable to stand up from a full squat. Serum creatine kinase (CK) elevated to 3,399 U/L. Electromyography showed a myogenic pattern with small motor unit potentials, fibrillation potentials and early recruitment pattern. Muscle biopsy revealed a variation of fiber size, little infiltration of inflammatory cells, and homogeneous accumulations beneath the muscle membrane (Fig. 1a). Congo red-positive materials were noted both in vessel walls and in muscle fibers (Fig. 1b, c, d) with fluorescence for rhodamine, consistent with amyloid deposition, the hallmark of amyloid myopathy. We were not able to identify whether the deposits were located beneath the basal lamina or the plasmalemma due to lack of electron microscopic preparation. Five years ago, the serum CK value was 110 U/L (Fig. 2). Two years later, when her nephrotic syndrome deteriorated, the CK elevated to 2,336 IU/L without overt weakness. Interestingly, after she received L-PAM, the CK decreased to 120 U/L just 1 month after the treatment. When girdle weakness developed 6 months ago, the CK again soared to 3,378 U/L. The fluctuation of CK and the amyloid deposition in the muscle led us to the diagnosis of amyloid myopathy due to multiple myeloma. We then administered two consecutive courses of bortezomib (1.3 mg/m on days 1, 4, 8, and 11 for the first course and 1.0 mg/m on days 1, 4, 8, and 11 for the second course). The treatment reduced the proportion of myeloma cells from 16.8 to 1.2%. The CK started to fall a few weeks after the first course and eventually fell to 187 U/L 1 month after the second course, when she was able to rise from a sitting position more easily. However, multiple myeloma deteriorated in the following months and the CK again elevated to 694 U/L. She was not able to receive additional treatment because of her poor general status. Amyloid myopathy, a progressive myopathy in a proximally dominant fashion, is caused by a variety of primary amyloidoses, such as familial amyloidosis, AL-amyloidosis and multiple myeloma [1–3]. Postulated mechanisms include impaired muscle metabolism or failed electrical conduction by amyloid deposition beneath the muscle membrane [4, 5]. Therapeutic trials have included plasmapheresis, administration of corticosteroid, and high-dose K. Shiga (&) R. Mizutani R. Isayama T. Tokuda M. Nakagawa Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan e-mail: kenshiga@koto.kpu-m.ac.jp

Thyroid hormone: a “prime suspect” in human immuno deficiency virus (hiv/aids) patients?

Acquired Immunodeficiency Syndrome (AIDS) is the final and most serious stage of the disease caused by human immunodeficiency virus. The Immune system is the target of AIDS. We investigate presently any possible involvement of thyroid hormone, the deficiency of which gives rise to oedema and susceptibility to nonspecific infections; with a view to finding the primary factor seeding the disease. It has been reported that circumcision reduced the incidence of HIV/AIDS infection. Beyond circumcision however there might be some constitutional factor that comprises HIV infection to clinical AIDS. It is against this background that our research team turned to possible dyshormonopoisis and to thyroid hormone as a prime suspect among other possible factors that cause clinical AIDS. Moreover the hormone has been reported to be crucial for optimum immune function. A population of 200 seropositive AIDS patients were investigated against a control of 50 subjects made up of 25 healthy circumcised males and 25 healthy females; all of who were seronegative for the disease. The parameters investigated include thyrotropin (TSH), Thyroxine (T4), Total protein (TP), Albumin (Alb), Globulin (Glob), Immune complex (IC3) and Bence Jones proteins (BJP) levels in serum or urine. All seropositive clinically HIV/AIDS patients were hypothyroid. Seronegatives had significantly higher T4, TP, and Alb levels at P < 0.001 and P < 0.05 for Glob than seropositives. Seropositive females exhibited significant (P < 0.001) higher levels of IC3 than seronegative males. The globulin levels of all HIV patients were significantly (P < 0.05) higher than control. BJP was also isolated in the urine of patients. The findings suggest that thyroid hormone deficiency is a primary culprit for the other inert or dormant factors to be activated.

Extramedullary plasmacytoma of the dura mimicking meningioma

In December 2005, a 59-year-old man presented at ourNeurosurgery Department with a 2-month history ofamnesia and gait disturbance. A solid mass lesion wasdetected in the right temporal region on magnetic reso-nance imaging (MRI), presumed to be a meningioma(Fig. 1). He underwent surgery via a right temporal frontalcraniotomy and partial resection of the mass. Biopsy of themass demonstrated a densely cellular tumor composed ofplasma cells, positive for IgG and kappa light chain(Fig. 2), and negative for lambda chain, CD56 and cyclinD1. These findings were consistent with intracranialplasmacytoma.No additional sites of plasmacytoma were identified oneither computed tomography or bone scintigraphy, and bonemarrow plasmacytosis was absent (1.8% plasma cells,morphologically normal), and bone marrow cells showed anormal karyotype. Serum immunoglobulin levels werealmost normal (IgG 1,374 mg/dL, IgA 443 mg/dL, IgM54 mg/dL, IgE 81 IU/mL, IgD 7.6 mg/dL), and postopera-tive serum protein immunoelectrophoresis showed a smallM-component only (IgG-j). Urine Bence-Jones protein wasnot detected. Other organopathies, such as nephropathy,hypercalcemia and bone region, were absent. Thus, a diag-nosis of extramedullary plasmacytoma was made accordingto the classification of the International Myeloma WorkingGroup (IMWG) [1]. He underwent external beam radio-therapy to the brain at a dosage of 50 Gy, which resulted inthe disappearance of the remaining tumor region.In January 2007, he developed hoarseness and thoracicpain. Since CT scans demonstrated new masses at other sites(rib and vertebral bones), he was diagnosed with diseaseprogression. Laboratory findings showed an increased totalserum protein of 8.6 g/dL, IgG 3,629 mg/dL, and serumprotein immunoelectrophoresis revealed an evidentM-component of IgG-j. Bone marrow examination showedno evidence of plasmacytosis (2.4% plasma cells, withoutatypia) and chromosomal analysis revealed a normalkaryotype. Thereafter, he received several courses of che-motherapy with vincristine, doxorubicin and dexametha-sone. Despite treatment, regrowth of the mass was observed.He refused further therapy and was discharged from ourhospital.Patients with a solitary dural plasmacytoma have beenreported with a female predominance of 84% and a meanage of 50.2 years. Clinically, combination therapy includ-ing surgical resection followed by at least 50 Gy radio-therapy is recommended, and long-term survival has beenobserved. On the other hand, patients with myelomatousmeningeal involvement have shown an extremely poorprognosis despite intensified treatment, including intrathe-cal and/or systemic chemotherapy and cranial radiotherapy[2]. Our patient showed a recurrence almost 1 year after theinitial diagnosis. We consider that postoperative radio-therapy was delayed by about 2 months because of inten-sive care, which might have caused the early recurrence.

Plasma cell tumours: cytomorphological features in a series of 12 cases diagnosed on fine needle aspiration cytology

Plasma cell tumours represent autonomous proliferation of plasma cells and can manifest as multiple myeloma, monoclonal gammopathy of undetermined significance, variants of plasma cell myeloma or plasmacytoma. We report 12 cases of plasma cell tumours, which were initially diagnosed as plasmacytoma on fine needle aspiration cytology (FNAC). The patients were further subjected to bone marrow examination, serum electrophoresis, urine examination for Bence-Jones proteins, and x-ray examination of the skeleton. The cytological smears from all cases were cellular and showed numerous plasma cells in varying degrees of maturity. Subsequent to investigations, five cases were labelled as multiple myeloma with secondary extramedullary plasmacytoma, three as solitary bone plasmacytoma and two as primary extramedullary plasmacytoma. In the remaining two cases, bone marrow and urine examination findings were not available, so a conclusive diagnosis of multiple myeloma or solitary plasmacytoma could not be made. The study highlights the role of FNAC in the diagnosis of plasma cell tumours. Subsequent work-up and follow-up of these patients is important to rule out the presence of multiple myeloma.

Multiple myeloma presenting as an intracranial plasmacytoma: a case report

Multiple myeloma presenting as an intracranial tumor (plasmacytoma) is very rare. An 81-year-old woman was admitted to our hospital because of gait disturbance. A blood laboratory test revealed a mildly increased lactate dehydrogenase (236 IU/L) and glucose (121 mg/dl). Blood protein fractions were normal. Brain computed tomography and magnetic resonance imaging revealed an intracranial mass (5 × 4 × 3 cm) in the brain base next to the clavus, and it was clinically diagnosed as chordoma. An excision of the brain tumor was performed. Imaging modalities including ultrasound, x-ray, computed tomography, magnetic resonance imaging and positron emission tomography did not reveal any tumors other than the brain tumor. The tumor was soft, fragile, and bloody. Microscopically, a monotonous proliferation of atypical plasma cells with hyperchromatic nuclei was recognized. Histochemically, the tumor cells were pyroninophilic and the congo-red stain revealed amyloidosis. Immunohistochemically, the tumor cells were positive for κ-chain and negative for cytokeratin, epithelial membrane antigen, vimentin, CD45, CD20, CD45RO, λ-chain, IgM, IgA, IgG, synaptophysin, chromogranin, S100 protein, desmin, α-smooth muscle antigen, myoglobin, p53 protein, and glial fibrillary acidic protein. The Ki-67 labeling was 11%. Intracranial plasmacytoma was pathologically diagnosed. The patient was treated by adjuvant chemoradiation, and entered into the complete remission stage. However, multiple metastases emerged in the vertebral bones and ribs six months after the remission. A diagnosis of multiple myeloma was made. The urine revealed Bence-Jones protein of monoclonal IgG κ-chain type, but blood M protein was not recognized. The patient's condition gradually deteriorated. The patient died of respiratory failure due to bronchopneumonia 18 months after the admission. The present case indicates that multiple myeloma may manifest as an intracranial brain tumor (plasmacytoma).

Fanconi Syndrome and CKD in a Patient With Paroxysmal Nocturnal Hemoglobinuria and Hemosiderosis

Fanconi syndrome and chronic kidney disease associated with paroxysmal nocturnal hemoglobinuria is rarely reported. We describe a 51-year-old woman with glomerular filtration rate decrease and hypokalemia, glucosuria, and proteinuria during a 4-year period. Paroxysmal nocturnal hemoglobinuria was diagnosed 17 years earlier, and she has received multiple blood transfusions because of hemolytic episodes during the last 5 years. Deteriorating kidney function and persistent Fanconi syndrome were accompanied by a progressive increase in serum ferritin levels. Laboratory studies showed proximal renal tubular acidosis, hypophosphotemic hyperphosphaturia, normoglycemic glucosuria, and aminoaciduria. Serologic testing, tumor markers, Bence-Jones protein, and heavy-metal screening results were negative. Abdominal magnetic resonance imaging showed characteristic features of iron deposition in the bilateral renal cortices. Kidney biopsy showed chronic interstitial nephritis with prominent hemosiderin deposition in the proximal tubules. With potassium citrate, calcitriol, and deferoxamine therapy, Fanconi syndrome persisted, but kidney function was stable. Renal hemosiderosis secondary to both chronic repetitive hemolytic episodes and transfusion-related iron overload in patients with paroxysmal nocturnal hemoglobinuria can lead to Fanconi syndrome and chronic kidney disease.

Successful treatment of primary AL amyloidosis by VAD therapy, high-dose melphalan, and autologous peripheral stem cell transplantation

We report a 58-year-old Japanese man with primary systemic AL amyloidosis who achieved disappearance of proteinuria including Bence-Jones protein (lambda-type) after two courses of VAD therapy (vincristine, doxorubicin, and dexamethasone) and subsequent high-dose melphalan, followed by autologous peripheral blood stem cell transplantation. Because this patient did not have any apparent amyloidosis-related heart or liver damage and met all of the eligibility criteria for this therapy, this treatment was performed. Both proteinuria and M-protein disappeared completely, and he is doing well clinically at 19 months after treatment. However, amyloid deposits were still found in the kidneys, including the glomeruli and tubulointerstitium, when renal biopsy was done at 8 months after treatment. In the future, we may reach a time when clinical remission corresponds to histological remission.

UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M‐proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)

Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Helier Hospital, Carshalton, Surrey, UK, Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Medicine, Malmo University Hospital, Malmo, Sweden, Division of Immunity and Infection, University of Birmingham, Birmingham, Department of Clinical Biochemistry, Frenchay Hospital, Bristol, Department Haematology, University College, London, Glasgow Western Infirmary, Glasgow, UK, Department of Haematology, NTNU/St Olavs Hospital, Trondheim, Department of Haematology, Ulleval University Hospital, Oslo, Norway, Department of Haematology Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, and Myeloma UK.

Abnormal laboratory results: Screening for multiple myeloma

Patients with suspected multiple myeloma should be investigated with screening tests. They may have a paraprotein in the serum, Bence-Jones protein in the urine, or both.

Painful Lower Extremities Related to Diaphyseal Dysplasia: Genetic Diagnosis and Treatment

To the Editor: Camurati-Engelmann disease (CED) is an autosomal-dominant condition, initially described by Cockayne in 19201. Camurati was the first to suggest the hereditary component in 1922, when he reported a rare symmetrical osteitis of lower limbs in a father and son and several others in a total of 4 generations2. Later, Engelmann reported a case with muscular wasting and important bone involvement3. The disease begins in an age span between 3 months and 50 years old, with higher prevalence in males. It is characterized by progressive cortical expansion, sclerosis, and symmetrical hyperostosis affecting the diaphyses of the long bones4,5. We describe a case of CED in a female patient with lower limb pain with progressive worsening and difficult diagnosis. A 37-year-old woman from Manaus, Brazil, was referred for investigation of a 5-year history of fatigue, headache, and pain in both legs, worsening over the preceding year, that had not responded to a variety of analgesics. The initial investigation included the following: normal blood count, erythrocyte sedimentation rate 15 mm/h (ESR; normal 0 to 20); rheumatoid factor 47 II/ml (normal 10 IU/ml), C-reactive protein 10.3 mg/dl (normal < 8 mg/dl), a negative antinuclear factor, alkaline phosphatase 111 U/l (normal 38–126 U/l); serum calcium was 8.7 mg/dl (normal 8.4–10.6), ionized calcium 1.42 (normal 1.2–1.6), urinary calcium 421 mg/24 h (normal 200), inorganic phosphorus 2.8 mg/dl (normal 2.5–4.5), parathyroid hormone 62 pg/ml (normal 7–53); and negative Bence-Jones proteins and normal urinary sediment. Radiographs of both lower limbs showed cortical thickening at the diaphyses, the medium third of the tibias, and … Address reprint requests to Dr. S.L.E. Ribeiro, Avenida Apurina 04, Bairro Praca 14, Manaus, Amazonas State, Brazil 69020-170. E-mail: sandraeuzebio{at}vivax.com.br