Daily Archives: December 19, 2018

Say: wanna have your picture taken? What do you say?


What do you think? https://pin.it/r6bb3ievblf7qk

Watch “Muslim CONFRONTS Jordan Peterson, Watch How He Responds” on YouTube


Vladimir Tismaneanu: Nazificarea Romaniei: In cartea sa “Germania hitlerista” (1933), ganditorul politic, filosoful juridic si formidabilul eseist Petre Pandrea amintea distinctia nazista dintre capitalul industrial (arian, creativ, schaffendes) si cel bancar (poluat de spiritul evreiesc, egoist, lacom, cosmopolit, jefuitor, raffendes).


Nazificarea Romaniei: In cartea sa “Germania hitlerista” (1933), ganditorul politic, filosoful juridic si formidabilul eseist Petre Pandrea amintea distinctia nazista dintre capitalul industrial (arian, creativ, schaffendes) si cel bancar (poluat de spiritul evreiesc, egoist, lacom, cosmopolit, jefuitor, raffendes). Iata ca un partid care se numeste, antifrastic, social-democrat recurge la acest mit politic cu consecinte catastrofale…

Claudiu Nasui – Deputat USR Coaliția PSD-ALDE va distruge economia României


Claudiu Nasui – Deputat USR

Coaliția PSD-ALDE va distruge economia României

Pregătiți-vă pentru o mare prăbușire a bursei azi. Aceiași politicieni care nu se mai opresc din a ne tot taxa (supra-accize pe carburanți și creșterea impozitării muncii) și care recent și-au mărit pensiile speciale și indemnizațiile, vin acum cu noi taxe și impozite pe care va trebui să le suportăm tot noi. Exact cum v-am spus acum o săptămână, ei explodează cheltuielile statului după care vin tot la noi să ne ceară să strângem cureaua.

1 – Așa zisa taxă pe „lăcomie” nu este o taxă pe lăcomia guvernului. Taxa o vom plătit tot noi. Se numește asupra „lăcomiei” în mod ipocrit ca să fie înghițită mai ușor de populație. De fapt va fi o taxă pe care o vom vedea în comisioanele bancare și în dobânzile bancare. Vom primi mai puțini bani pentru sumele pe care le economisim și vom plăti mai scump creditele, deci tot românii vor pierde.

2 – Fondurile din pilonul 2 se vor desființa și, astfel, statul va încasa tot CAS-ul pe care îl plătesc românii. Guvernul desființează de facto fondurile din pilonul 2 pentru că le face profitabilitatea imposibilă și, în același timp, le cere să vină cu 800 de milioane de euro în plus ca să mai existe în România. O sumă colosală pe care fondurile nu o vor da. În plus, ~80% din români au contribuit deja de 5 ani și își vor putea retrage sumele din pilonul 2, ceea ce va duce la retrageri masive și o prăbușire bursieră de toată frumusețea. De ce? Pentru că pentru a da acei bani, fondurile vor trebui să vândă ce au, iar asta va prăbuși indicii bursieri.

3 – Guvernul introduce o nouă taxă pe internet. Practic guvernul vrea să îngreuneze un serviciu care mergea bine în România. Atât de bine încât eram chiar dați de exemplu internațional. Acum vedem că se introduce o nouă taxă, peste toate cele care existau deja, de 3% pe cifra de afaceri! Acest lucru contravine chiar normelor europene, dar voi reveni asupra acestui aspect.

4 – Plafonarea prețului gazelor înseamnă oprirea imediată a tuturor investițiilor în extracția de gaze. Iar de asta cine va beneficia? Cei de la care importăm gaze. Să nu ne bucurăm că vom avea gaze ieftine. Vom avea gaze ieftine pe hârtie. În practică nu vom avea nimic ieftin.

5 – Toate creșterile de taxe și impozite vor intra în vigoare în mai puțin de două săptămâni de acum. De la 1 ianuarie. Vă dați seama ce înseamnă asta pentru o companie serioasă care și-a făcut deja bugete și planuri pentru anul următor? Vă dați seama în ce hal gonim investitorii cu aceste semnale? Cei care au investit în România acum plâng. Iar cei care au ales Ungaria, Bulgaria sau alte țări din jurul nostru răsuflă ușurați că nu trebuie să-și bată capul cu haosul acesta fiscal. În halul acesta ne-a adus PSD-ALDE.

🇧🇪🕊Laura Codruța Kövesi “Asistăm la un festival disperat al inculpaților care vizează îngenuncherea statului român, umilirea societății , justiția fiind sub asalt de peste un an de zile”….


🇧🇪🕊Laura Codruța Kövesi
“Asistăm la un festival disperat al inculpaților care vizează îngenuncherea statului român, umilirea societății , justiția fiind sub asalt de peste un an de zile”….

Watch “Becoming Human – Episode 1 – First Steps (Homo Sapiens)” on YouTube


Management of paraproteinaemia


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600027/

Management of paraproteinaemia

Lucy Cook and Donald H C Macdonald
Additional article information

Abstract

A paraprotein is a monoclonal immunoglobulin or light chain present in the blood or urine; it is produced by a clonal population of mature B cells, most commonly plasma cells. In individuals aged >50 years the incidence of a paraprotein is 3.2%. Plasma cell disorders can be considered as a spectrum of conditions ranging from monoclonal gammopathy of undetermined significance (MGUS), through asymptomatic, to symptomatic myeloma. MGUS is defined by a low level of paraprotein <30 g/l, bone marrow plasma cells <10% and the absence of myeloma related organ or tissue damage (predominantly renal, skeletal or bone marrow impairment.) MGUS requires no therapy and the overall risk of progression to myeloma is 1% per year. Myeloma remains incurable with a median survival of 3–4 years; autologous stem cell transplant can prolong survival, if appropriate. Thalidomide in combination with dexamethasone has an emerging role in the treatment of myeloma.A paraprotein is a monoclonal immunoglobulin or immunoglobulin light chain (Bence Jones protein) present in the blood or urine and arising from clonal proliferation of mature B‐cells, most commonly plasma cells or B‐lymphocytes. Alternative terms include monoclonal protein or M‐band. Paraproteins are characterised by homogenous electrophoretic migration and the expression of a single light chain type, either κ or λ. There are several situations in which a paraprotein may be identified and these scenarios have differing clinical significance. At one extreme there may be an overtly malignant clonal proliferation of plasma cells resulting in multiple myeloma, or solitary plasmacytoma (skeletal or extramedullary.) At the other extreme there may be a low level paraprotein ultimately classified as monoclonal gammopathy of undetermined significance (MGUS) which may be of little clinical relevance. The aim of this article is to aid the physician in developing a strategy which can identify the likely clinical condition underlying a paraprotein, deal with the important clinical scenario of distinguishing between MGUS and multiple myeloma, and provide a brief overview of important clinical aspects of multiple myeloma.WHAT IS THE INCIDENCE OF PARAPROTEINAEMIA?Recently published population based studies from Minnesota have clarified the incidence of paraproteinaemia in the general population. In individuals aged >50 years the overall incidence of a paraprotein is 3.2%; this varies with age (age 50–59, 1.7%; age >70, 5.3%) and sex (men: women, 4.0%: 2.7%.)1There is also an ethnic variation with previous reports noting the age adjusted prevalence of MGUS being threefold higher in African Americans than the white population.2 Paraproteins are therefore a common laboratory finding in an elderly population.

DISORDERS ASSOCIATED WITH A PARAPROTEIN

A wide range of mature B cell disorders may be associated with a circulating paraprotein (table 11).). In a review of more than 1000 cases of M‐protein seen at the Mayo Clinic the underlying diagnosis was MGUS (51%), multiple myeloma (18%), AL amyloidosis (11%), lymphoproliferative disorder (4%), and other disorders such as smouldering myeloma or solitary plasmacytoma (16%).3 The lymphoproliferative disorders chronic lymphocytic leukaemia (CLL) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia (LPL/WM) generally have associated clinical and laboratory features which greatly facilitate diagnosis. CLL can infrequently be associated with a paraprotein. In practice CLL is usually diagnosed as a result of investigating a persisting monoclonal peripheral blood lymphocytosis and generalised lymphadenopathy. Immunophenotyping of the circulating B lymphocytes in CLL reveals a characteristic pattern of surface antigen expression. This profile has been used to formulate a CLL diagnostic score based on the expression of CD23, CD5, FMC7, CD79b/CD22, and SIg. Immunophenotyping by flow cytometry of a persisting lymphocytosis is now routinely performed to establish the diagnosis of CLL.4 The other non‐Hodgkin’s lymphoma commonly associated with a paraprotein is LPL/WM, a rare disorder (15% of all lymphomas) which presents at a median age of 63. There is lymphomatous infiltration of nodes, bone marrow, or spleen and the majority of patients have a circulating IgM paraprotein >30 gm/l. Of particular note, IgM paraproteins may have autoantibody or cryoglobulin activity resulting in peripheral neuropathy (10% of patients) or cryoglobulinaemia. Additionally high levels of circulating IgM pentamers cause hyperviscosity (10–30% of patients) with reduced visual acuity and increased risk of cerebrovascular accidents.5Therefore the finding of a high concentration IgM paraprotein should raise the suspicion of LPL and may require urgent specialist investigation and treatment to prevent the complications of hyperviscosity. The diagnosis and management of CLL and LPL/WM is beyond the scope of this article and is dealt with fully in the British Society for Haematology Guidelines (www.bcshguidelines.com).

Table 1 Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma and symptomatic myeloma (based upon BCSH guidelines 2005)

By definition all paraproteins are the product of a B cell clone which may be large, small or possibly undetectable using available techniques. The disorders described above are examples of B cell disorders where the clinical features are defined either by the systemic effects of expansion of the malignant clone or which may be entirely asymptomatic and meet the diagnostic criteria of MGUS. Alternatively, in some B cell conditions, while the clone may be undetectable the clinical features are dominated by the biological effects of the paraprotein, so called “dangerous small B‐cell clones”.6There are two pathogenetic mechanisms for this type of disorder. Either the monoclonal protein may aggregate and deposit systemically, causing disorders such as light‐chain amyloidosis, crystal storing histiocytosis or cryoglobulinaemia type I. Alternatively the monoclonal protein may have antibody activity towards an autogenous antigen causing disorders such as polyneuropathy, monoclonal cold agglutinins and cryglobulinaemia type II.

Box 1 Disorders associated with a paraprotein

Malignant B‐cell disorders

Multiple myeloma (IgG, IgA, IgD, IgE, or κ, λ free light chains)Symptomatic myelomaAsymptomatic myelomaPlasma cell leukaemiaNon‐secretory myeloma

POEMSPolyneuropathy, organomegaly, endocrinopathy, M‐protein, skin changes

PlasmacytomaSolitary plasmacytoma of boneExtramedullary

Lymphoproliferative disordersChronic lymphocytic leukaemiaNon‐Hodgkin lymphomas including lymphoplasmacytic lymphoma(Waldenstrom macroglobulinaemia)

Heavy chain diseaseγ, α, μ

Amyloidosis (AL)

MGUS

Paraprotein detected with no evidence of other B cell disorder

Non‐malignant systemic disease

Autoimmune diseaseRheumatoid arthritisSclerodermaHashimoto thyroiditis

Cutaneous diseasePyoderma gangrenosumNecrobiotic xanthogranulomatosis

Liver diseaseHepatitis/cirrhosis

Infectious diseaseMycobacterium tuberculosisBacterial endocarditis

MGUS, monoclonal gammopathy of undetermined significance
In view of the significant side effect profile of thalidomide, analogues of this agent have been developed. Lenalidomide is a third generation immunomodulatory drug which retains anti‐TNFα, immunomodulatory and anti‐cancer activity. It does not cause sedation or constipation, and has a reduced incidence of neuropathy. The prothrombotic effect remains and there is a greater myelosuppressive effect than is seen with thalidomide. In clinical trials of relapsed refractory myeloma, a combination of lenalidomide and dexamethasone has a response rate of 38%. Randomised trials of lenalidomide and dexamethasone compared to placebo and dexamethasone have shown a time to progression of 11.3 months versus 4.7 months, with a survival advantage in the lenalidomide arm. It is likely that lenalidomide, with an improved side effect profile compared to thalidomide, will soon be licensed in Europe as a second line therapy for myeloma.35
Bortezomib is an inhibitor of ubiquitin‐mediated proteasome degradation. It is effective in relapsed myeloma and in a randomised study of 607 patients produced a better response rate (45%) and median 1 year survival (89%) than dexamethasone alone (26% and 72%, respectively).36,37

The final group of disorders are paraproteins found in association with a non‐malignant systemic disorder. In these circumstances neither the small B cell clone nor the monoclonal protein causes the predominant clinical features, but the case cannot be labelled as MGUS because of the presence of a co‐existing systemic disorder. These paraproteins are often small and may occasionally be transient. Examples include paraproteins associated with autoimmune, liver and skin diseases as listed in box 1.

WHEN SHOULD ONE TEST FOR THE PRESENCE OF A PARAPROTEIN?

Multiple myeloma is the most common clinically important disorder associated with a paraprotein, and may have a wide range of clinical presentations. It is therefore prudent that a patient should be screened for the presence of an M‐protein when presenting with any of the clinical findings listed in box 2.7
It is an important practice point to emphasise that if considering myeloma as a diagnosis then both the urine and blood must be screened for a paraprotein, because in 15% of myeloma cases a monoclonal immunoglobulin light chain may be the only M‐protein present. Such cases would be missed if serum protein electrophoresis were the only investigation performed. The measurement of serum‐free light chains introduced relatively recently into clinical practice allows the quantification of free κ and λ light chains secreted by plasma cells. An abnormal κ:λ ratio suggests an excess of one light chain type and, although the mechanism is poorly understood, is used as a surrogate marker for clonal expansion. The use of such a serum assay will abrogate the need to test both blood and urine for diagnosis.5

HOW SHOULD A PATIENT WITH PARAPROTEINAEMIA BE INVESTIGATED FURTHER?

As noted above, the underlying disorders associated with a paraprotein can broadly be divided into non‐Hodgkin lymphoma subtypes and plasma cell disorders. The lymphoproliferative disorders CLL and LPL/WM do not generally present diagnostic difficulties and are generally referred to a haemato‐oncologist. In clinical practice the most frequent scenario is the assessment of a paraprotein found in association with a plasma cell disorder. The significance of such a finding can range from a medical emergency to a coincidental finding of little clinical relevance. All patients with an M‐protein should be referred for specialist review. The goal of such review will be to establish the precise diagnosis this generally entails distinguishing between MGUS, asymptomatic, or symptomatic myeloma, with consideration of other linked diagnoses such as solitary plasmacytoma and/or AL amyloidosis. The degree of urgency for such referrals varies: clearly those with associated renal failure, hypercalcaemia, or cord compression are medical emergencies requiring immediate specialist treatment; those patients with suspected myeloma should be referred for urgent specialist advice; and those in whom a paraprotein is detected routinely should be referred for non‐urgent advice as they will require long term follow‐up. It is also prudent to remember that in an elderly population a paraprotein may well be a clinically insignificant MGUS with a co‐existent second pathology. Consequently, if anaemia is detected then haematinics should be checked, and if iron deficiency is present then gastroenterological investigation is required to exclude blood loss. Similarly, if hypercalcaemia is present then primary hyperparathyroidism should be excluded.

Box 2 Clinical indications for screening for M‐protein

Malaise and fatigue

Bone disease (persistent back pain, osteopenia or lytic lesions)

Impaired renal function

Normochromic normocytic anaemia ± pancytopenia

Hypercalcaemia

Recurrent bacterial infections

Hyperviscosity

Nephrotic syndrome, cardiac failure, malabsorption

Peripheral neuropathies, carpal tunnel syndrome

Incidental persistent elevated erythrocyte sedimentation rate

HOW IS MGUS DISTINGUISHED FROM MYELOMA?

In patients with a plasma cell disorder and a circulating paraprotein, current practice is to subdivide these patients into three groups: MGUS, asymptomatic myeloma (previously termed smouldering, indolent or equivocal myeloma), and symptomatic myeloma. The distinction is important as it determines prognosis, and the need for treatment. Three variables define these groups: (1) M‐protein level, (2) bone marrow plasma cell percentage, and (3) the presence or absence of myeloma related organ or tissue impairment (ROTI). The relevant investigations are therefore to estimate M‐protein levels: serum protein electrophoresis, immunofixation and paraprotein quantification plus 24 h urinary light chain quantification. Bone marrow aspirate and trephine biopsy are also required to determine the extent of bone marrow infiltration. It should, however, be emphasised that while plasma cell percentage is part of the diagnostic criteria for MGUS, to avoid inappropriate over investigation bone marrow biopsy is not required in all cases where a circulating paraprotein is detected. This is detailed below in the section managing MGUS. These basic investigations are supplemented with tests to establish the presence or absence of ROTI. The diagnostic criteria for MGUS and myeloma are set out in table 11.. The clinicopathological features of myeloma ROTI are set out in table 22.. The necessary investigations include full blood count, assessment of renal function, corrected calcium, and skeletal imaging, most commonly a skeletal survey. In certain circumstances, as detailed below, further imaging may be required. Two important practice points should be emphasised; in a patient with a circulating paraprotein, low levels of Bence Jones protein and an immune paresis of the polyclonal immunoglobulins are compatible with the diagnosis of MGUS. Although the term symptomatic myeloma is used, in any patient with laboratory criteria for myeloma the presence of myeloma‐related skeletal damage, though it may not be causing symptoms, is evidence of ROTI and would automatically classify the patient as having symptomatic myeloma.7

Table 2 Myeloma‐related organ or tissue impairment (ROTI). Based upon BCSH guidelines 2005

WHAT IS THE PROGNOSIS AND HOW DO WE MANAGE MGUS?

MGUS is defined as an M‐protein in the serum <30 g/l, clonal plasma cells in the bone marrow <10%, and absence of myeloma ROTI. Clearly it is inappropriate to perform a skeletal survey and bone marrow investigation in all patients in whom a low level paraprotein is detected. Clinical judgement is required and current UK practice in the investigation of MGUS is to reserve these investigations for younger patients and those in whom the paraprotein is >20 g/l. Characteristically, individuals with MGUS have no symptoms or signs related to the monoclonal population and MGUS does not require treatment; they do, however, require indefinite follow up, the details of which are set out below. Occasional patients have monoclonal antibodies that are directed against coagulation proteins resulting in Von Willebrand disease; against insulin, resulting in hypoglycaemia; and against peripheral nerve myelin resulting in peripheral neuropathy.8,9
Overall the risk of progression of MGUS to myeloma or related disorder is 1% per year. Although the prevalence of MGUS increases with advancing age, after adjustment for the level of the M‐protein, the annual risk of progression to myeloma or a related cancer is not affected by age or the duration of MGUS. Younger patients are more likely to have progression to cancer during their lifetime because they are at risk for longer. In contrast to age and duration, other factors, notably the level of M‐protein, do predict the risk of progression. The percentage risk of progression in 10 years roughly equates to the level of the M‐protein—for example, 20 g/l is associated with 20% risk at 10 years of malignancy. However, in reality, when competing causes of death are taken into account, the true life‐time probability of progression is substantially lower.
Given the uncertainty of disease progression with MGUS attempts have been made to identify those patients at highest risk. The parameters which are useful for predicting the likelihood of progression are: the size of the M‐protein,10 the type of the M‐protein with IgA and IgM paraproteins having a higher risk compared to IgG paraproteins,11 the percentage of bone marrow plasma cells,12 and an abnormal serum‐free light chain ratio. A large population based study suggested that the risk of progression to myeloma or related malignancy with an abnormal ratio at diagnosis was 17% at 10 years as compared to 5% at 10 years in those patients with a normal ratio.3,13,14
On the basis of these findings a risk stratification system set out in table 33 has recently been proposed for MGUS. High risk patients had a risk of progression of 58% at 20 years. The low risk group, which constitutes 40% of the cohort, carries a risk of only 5% at 20 years. In practice, when competing causes of death are taken into account in this predominately elderly population, the actual risk of progression is lower. On the basis of these findings current recommendations are that low risk patients are seen initially at 6 months and then once every 2 years if asymptomatic. At each follow‐up visit patients are assessed by means of history and examination, full blood count, serum calcium, renal function and paraprotein quantification. There are currently phase I and II clinical trials of chemoprophylaxis underway for those with high risk MGUS. It must be emphasised that outside the setting of a clinical trial, no specific therapy is required for MGUS.3

Table 3 Risk stratification model to predict progression of monoclonal gammopathy of undetermined significance (MGUS) to myeloma or related disorders

HOW DO WE INVESTIGATE AND MANAGE ASYMPTOMATIC AND SYMPTOMATIC MYELOMA?

The initial investigations are as described previously: M‐protein quantification, bone marrow biopsy, skeletal survey and investigations to identify the presence of myeloma ROTI. Additional imaging studies are often required. Magnetic resonance imaging (MRI) is an essential investigation for patients presenting with signs of spinal cord compression and is useful to assess the extent of soft tissue disease. Computed tomography (CT) scanning can be useful to clarify the significance of equivocal abnormalities on a plain radiograph, and is essential in planning radiotherapy. In addition the prognostic factors albumin and β2microglobulin are measured.
Asymptomatic myeloma accounts for approximately 15% of all cases of newly diagnosed myeloma. Most patients will progress eventually to symptomatic disease—the median time to progression from asymptomatic to symptomatic myeloma is 12–32 months. All patients with myeloma are felt to evolve from MGUS/asymptomatic myeloma, although in many these pre‐malignant stages are unrecognised clinically because of their asymptomatic nature. A known prior history of MGUS or asymptomatic myeloma has no impact on the prognosis of myeloma. No specific treatment is recommended for asymptomatic myeloma, but patients require follow‐up at least once every 4 months. Patients should be educated about symptoms such as new or progressive bone pain, and persistent or recurrent infection, which might suggest disease progression. In addition to the laboratory tests, patients should have an annual skeletal survey and if the patient has known urinary free light chains, these should be quantified periodically. Thus far, early intervention before the development of symptomatic myeloma has shown no benefit in two randomised control trials.7,15,16Large centres treating myeloma are conducting clinical trials to determine whether newer agents such as thalidomide in combination with bisphosphonates can delay disease progression in asymptomatic myeloma.

MANAGEMENT OF SYMPTOMATIC MYELOMA

The purpose of this article is not to provide a practical guide to myeloma therapy but rather an overview of strategy. The management of symptomatic myeloma is complex and requires a range of specialist expertise from haematology, clinical oncology, nephrology, orthopaedics and palliative care. Without treatment the median survival of myeloma is 7 months and with chemotherapy this is increased to 3–4 years. Autologous stem cell transplantation can prolong overall survival by approximately 18 months in selected patients.
There have been several attempts to construct prognostic models since the Durie/Salmon staging system was devised in 1975. Currently the most useful system (international prognostic index, IPI) is based on the albumin and β2 microglobulin levels (table 44).). This is irrespective of the type of treatment selected.7

Table 4 International prognostic index

The treatment of myeloma is divided into supportive care with the goal of preventing or ameliorating complications of myeloma; these are most commonly renal, skeletal, infective and treatment related to bone marrow failure. The second aspect is specific treatment directed against the malignant plasma cells.

SUPPORTIVE CARE

Pain control—Pain arising from the skeleton is the most common presenting complaint and will complicate 80% of patients during the course of their disease. The management requires both systemic treatment often with opioid analgesia and the use of local measures such as radiotherapy, orthopaedic, neurosurgical or interventional radiology—for example, vertebroplasty. Chemotherapy is also an important part of pain control as it is aimed at the underlying pathological process.

Hypercalcaemia—This occurs in up to 30% of patients typically in the presence of active disease—for example, at diagnosis or at relapse. Hypercalcaemia is managed with aggressive rehydration with saline and furosemide and commencement of bisphosphonates, or alternatively changing to a more potent bisphosphonate if already on treatment.

Bisphosphonates—Bone pain, hypercalcaemia and pathological fractures are a major cause of morbidity and mortality in patients with myeloma. Long term bisphosphonates have been used increasingly to prevent these problems. Meta‐analysis of trial data concluded that adding bisphosphonates reduces vertebral fractures and pain, but not mortality. Treatment with clodronate, pamidronate or zoledronate is therefore recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident. There have been no published randomised trials comparing oral with intravenous bisphosphonates although currently this is being addressed in the UK MRC Multiple Myeloma IX trial which compares clodronate with zoledronic acid. At present the choice between oral and intravenous bisphosphonate is a matter of patient and physician preference.17,18

Renal impairment—This occurs in up to 30% of patients at presentation and up to 50% of patients at some stage of the illness. The pathogenesis is multifactorial; light chain damage direct to the distal tubules, dehydration, sepsis, hypercalcaemia, hyperuricaemia and the use of nephrotoxic medications such as non‐steroidal anti‐inflammatory drugs. Patients are advised to keep well hydrated at all stages of the disease, drinking 3 litres of water per day, and avoiding potentially nephrotoxic agents. If renal failure does ensue, renal biopsy is desirable to guide management. The biopsy will identify those patients with acute tubular necrosis which may naturally resolve over time, amyloid and light chain deposition disease which does not respond to measures other than disease control, or cast nephropathy which may improve with rapid reduction of light chain concentration. Plasma exchange has been undertaken in cast nephropathy, however published trials have shown conflicting results. It is therefore appropriate that new patients are treated within a trial setting, such as the current UK MERIT trial (NCRN trial portfolio ISRCTN 37161699; http://www.ncrn.org.uk/portfolio). In patients with established renal failure, dialysis should be offered where appropriate.7,19

Anaemia—This is present in two thirds of patients at presentation and becomes more common with recurrent or progressive disease; it usually responds to control of the underlying myeloma. Traditionally, anaemia has been managed by transfusions of packed red cells although recombinant erythropoietin is being used increasingly. Studies have reported decreased transfusion requirements, increased haemoglobin concentrations and patient‐assessed improved quality of life. Current recommendations suggest a trial of erythropoietin in patients on chemotherapy and those with symptomatic anaemia, with the aim of decreasing transfusion requirements.20,21

Infections—The risk of infection is increased as a consequence of both disease and treatment. Contributory factors include the M‐protein, immune paresis and disturbed B cell function. Steroids remain the mainstay of chemotherapy treatment but are associated with viral and fungal infections and the chemotherapy itself may produce variable degrees of neutropenia. A range of approaches are required, including 24 h access to specialist care and prompt intravenous broad spectrum antibiotic treatment for any febrile myeloma patient. Vaccination against Streptococcus pneumonia and Haemophilus influenzae, and prophylactic intravenous immunoglobulin in patients in plateau phase experiencing recurrent significant infections, may be helpful.

Hyperviscosity—Symptomatic patients are managed with plasma exchange followed by prompt institution of chemotherapy.

AL amyloidosis—Approximately 15% of patients with myeloma will develop AL amyloidosis with complications including cardiac failure, renal failure and neuropathy. There are recently published comprehensive UK guidelines for the evaluation and management of all AL amyloidosis patients including those with co‐existent myeloma.22

MYELOMA BIOLOGY AND SPECIFIC THERAPY

In contrast to other haematological malignancies such as acute leukaemia and chronic myeloid leukaemia, until recently it has been difficult to identify the molecular events which underlie MGUS and myeloma. This was mainly due to the difficulty in performing cytogenetic analysis in these slowly proliferating tumours. Many of these difficulties have been resolved with the advent of or improvement in techniques such as: isolation and purification of plasma cells; interphase FISH cytogenetics; and the recognition of chromosomal translocations involving the immunoglobulin heavy chain switch region. From these studies it is emerging that cytogenetic abnormalities such as translocations are common in both MGUS (46%), myeloma (55–73%), and plasma cell leukaemia (85%). Within plasma cell dyscrasias there appear to be two pathways involved in pathogenesis. Approximately half of cases have a karyotype that is non‐hyperdiploid with a high incidence of both chromosome 13 loss, and an IgH switch region translocation involving one of five recurring partner chromosomal loci; 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET), 16q23 (c‐maf) and 20q11 (mafB). The remaining tumours have a hyperdiploid karyotype with multiple chromosome trisomies. The translocations result in altered expression of oncogenes. There is an almost universal finding of increased expression of a cyclin D gene in MGUS and myeloma. Cyclin D overexpression may arise directly from the translocation involving the IgH switch region and either 11q13 or 6p21 partner loci; however, the mechanism of overexpression in hyperdiploid tumours or other translocations is unexplained. It is clear that certain karyotype aberrations, such as loss of chromosome 13 material and translocations involving 4p16 and 16q22, predict a poor outcome and response to treatment. It is likely that in the future myeloma may be further classified on the basis of primary chromosomal translocation and cyclin expression, with more aggressive and/or experimental therapies being offered to those in the poorest prognostic group.23

Useful websites

Medical information

http://www.bcshguidelines.com

http://www.asheducationbook.org

Patient information

http://www.lrf.org.uk

http://www.myeloma.org.uk

http://www.cancerbackup.org.uk

In current practice myeloma remains largely a disease of the elderly, with approximately 15% of patients aged less than 60 years and fewer than 2% of cases arising in patients under 40 years old. This age distribution has implications for the types of treatment offered. Excluding a very few selected young patients aged less than 50 years for whom an allogeneic stem cell transplant may offer the prospect of cure, for the majority of patients current treatment is not curative and is aimed at prolonging good quality life. The optimal approach to achieving this is high dose therapy and autologous stem cell transplantation (HDT), an approach which is usually reserved for patients aged less than 65 years or those aged less than 70 with an excellent performance status. All other patients are treated with oral therapies.7,22
The treatment of patients eligible for HDT will consist of 4–6 months of cyclical combination chemotherapy via a central indwelling catheter. In the UK perhaps the most widely used regimen is a continuous 4 day intravenous infusion of vincristine and doxorubicin along with 4 day blocks of oral dexamethasone at a dose of 40 mg/day. This regimen termed VAD is associated with a 60–70% response rate. Related infusional regimens using cyclophosphamide, vincristine, adriamycin and prednisolone (C‐VAMP) are also widely used though there has been no randomised comparison with VAD.25,26 Two key points to note are: VAD is chosen in preference to oral alkylating agents such as melphalan as a pre‐HDT chemotherapy regimen as it achieves rapid cytoreduction without prejudicing stem cell mobilisation. Many authorities consider that dexamethasone is the effective agent in these regimens and in many US centres high dose dexamethasone alone is used as initial chemotherapy.27 Since the introduction of thalidomide into myeloma chemotherapy regimens (described more fully below), US centres are increasingly using the combination of thalidomide and dexamethasone as induction therapy. Following initial chemotherapy patients will then undergo chemotherapy mobilised peripheral blood stem cell collection (PBSC) followed by high dose therapy using intravenous melphalan and PBSC rescue. The evidence base for HDT therapy is derived from four prospective randomised trials comparing conventional chemotherapy (CC) with HDT. A French multicentre study IFM90 randomised 200 patients and noted a median event‐free survival for CC of 18 months and HDT 28 months, and overall survival for CC of 44 months and HDT 57 months. The other studies confirmed an improved outcome in their HDT arm though clearly the HDT approach is not curative and inevitably all patients will relapse.7,28,29
Patients ineligible for HDT are treated with oral chemotherapy. Early Medical Research Council trials in the 1970s established oral melphalan and prednisolone (MP) as an effective regimen. Subsequent meta‐analysis showed that this combination is as effective as other regimens including intravenous chemotherapy. Consequently standard oral chemotherapy remains as cycles of oral MP administered until the patient achieves a maximum response plus a further 3 months.30,31
Inevitably all patients will relapse; if the duration of first plateau phase is greater than 6–12 months then re‐treating with the same first line therapy may be effective. However, for many patients there is a need for new treatments. Two new agents are acquiring a role in the management of relapsed myeloma: thalidomide and bortezomib. There is greater experience with thalidomide. Thalidomide is an orally bioavailable glutamic acid derivative; among its biological activities it inhibits production of tumour necrosis factor α (TNFα) and angiogenic cytokines. On the basis of the known dependence of malignant plasma cells on bone marrow supporting cells and observed increased angiogenesis in marrow biopsies from myeloma cases, empirical therapy of myeloma using thalidomide was undertaken, and these initial studies showed that myeloma is responsive to thalidomide.32 Current practice is to use thalidomide for patients who relapse early after initial chemotherapy. Published studies of thalidomide as a single agent report a response rate of 30% or combined with dexamethasone a response rate of 60%.33,34 Current relapse/refractory protocols use thalidomide combined with dexamethasone and cyclophosphamide. Thalidomide does have a significant side effect profile with frequent or severe problems being sedation, peripheral neuropathy, constipation and, when used in conjunction with dexamethasone, a high incidence of thromboembolic events. In view of the teratogenic effects of thalidomide, where required barrier forms of contraception are essential and care must be taken to ensure that the drug is only taken by the individual for whom it is prescribed. In view of the efficacy of thalidomide in relapsed/refractory myeloma, ongoing trials are addressing the question whether thalidomide should play a role in first line treatment of myeloma. Indeed, in the USA, outside clinical trials thalidomide and dexamethasone is now widely used as a first line therapy.

Key references

Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. Br J Haematol 2006;134:573–89.

Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol 2006;132:410–51.

Child JA, Morgan GJ, Davies FE, et al. High‐dose chemotherapy with hematopoietic stem‐cell rescue for multiple myeloma. N Engl J Med2003;348:1875–83.

Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single‐agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492–4.

Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood2004;103:20–32.

SUMMARY

Identifying a paraprotein is a frequent finding in medical practice, with MGUS the most common clonal plasma cell disorder in the general population. It is essential to distinguish MGUS from asymptomatic and symptomatic myeloma as the natural history is so varied. For patients with symptomatic myeloma the disorder remains incurable; there are, however, well‐defined treatment protocols which have been shown to prolong good quality life. These include high dose therapy for patients under the age of 65 (age 70 if excellent performance status) and oral melphalan for the older patient. Supportive therapies including bisphosphonates and erythropoietin decrease morbidity and improve quality of life. There is a clear therapeutic benefit from thalidomide in myeloma and a current question under study is what role thalidomide may have in the future as part of first line therapy for symptomatic myeloma.

MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS AFTER THE REFERENCES)

In individuals >50 years old, the incidence of paraproteinaemia is 3.2%.

In any individual with a circulating paraprotein, the finding of immunoglobulin light chains in the urine establishes the diagnosis of myeloma.

In MGUS the presence of an abnormal serum free light chain ratio predicts an increased risk of progression to myeloma.

High dose chemotherapy and autologous stem cell transplantation may cure a proportion of patients with asymptomatic myeloma.

In patients with symptomatic myeloma the use of bisphosphonates is recommended only for those with radiological evidence of bone lytic lesions.

ACKNOWLEDGEMENTS

We are grateful to Dr Amin Rahemtulla for constructive comments on this article.

Abbreviations

CC – conventional chemotherapy
CLL – chronic lymphocytic leukaemia
C‐VAMP – cyclophosphamide, vincristine, adriamycin and prednisolone
HDT – high dose therapy
IPI – international prognostic index
LPL/WM – lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia
MGUS – monoclonal gammopathy of undetermined significance
MP – melphalan and prednisolone
NHL – non‐Hodgkin’s lymphoma
PBSC – peripheral blood stem cell collection
ROTI – related organ or tissue impairment
VAD – vincristine and doxorubicin

Answers

(1)T, (2) F, (3) T, (4) F, (5) F

Footnotes

Competing interests: None declared

Article information

Postgrad Med J. 2007 Apr; 83(978): 217–223.

doi: 10.1136/pgmj.2006.054627

PMCID: PMC2600027

PMID: 17403946

Lucy Cook and Donald H C Macdonald

Lucy Cook, Donald H C Macdonald, Department of Haematology, Imperial College, London, UK

Correspondence to: Dr Donald Macdonald
Room 1L05, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK; d.h.macdonald@imperial.ac.uk

Received 2006 Oct 24; Accepted 2007 Jan 5.

Copyright © 2007 The Fellowship of Postgraduate Medicine

This article has been cited by other articles in PMC.

Articles from Postgraduate Medical Journal are provided here courtesy of BMJ Publishing Group

References

  1. Kyle R A, Therneau T M, Rajkumar S V. et al Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med20063541362–1369. [PubMed]

  2. Landgren O, Gridley G, Turesson I. et al Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood2006107904–906. [PMC free article][PubMed]

  3. Kyle R A, Rajkumar S V. Monoclonal gammopathy of undetermined significance. Br J Haematol2006134573–589. [PubMed]

  4. Oscier D, Fegan C, Hillmen P. et alGuidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004125294–317. [PubMed]

  5. Jaffe E S, World Health OrganizationPathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon and Oxford: IARC Press, Oxford University Press (distributor), 2001

  6. Merlini G, Stone M J. Dangerous small B‐cell clones. Blood20061082520–2530. [PubMed]

  7. Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol 2006132410–451. [PubMed]

  8. Lamboley V, Zabraniecki L, Sie P. et al Myeloma and monoclonal gammopathy of uncertain significance associated with acquired von Willebrand’s syndrome. Seven new cases with a literature review. Joint Bone Spine 20026962–67. [PubMed]

  9. Ropper A H, Gorson K C. Neuropathies associated with paraproteinemia. N Engl J Med19983381601–1607. [PubMed]

  10. Kyle R A, Therneau T M, Rajkumar S V. et al A long‐term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002346564–569. [PubMed]

  11. Blade J, Lopez‐Guillermo A, Rozman C. et al Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 199281391–394. [PubMed]

  12. Cesana C, Klersy C, Barbarano L. et al Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002201625–1634. [PubMed]

  13. Mead G P, Carr‐Smith H D, Drayson M T. et al Serum free light chains for monitoring multiple myeloma. Br J Haematol 2004126348–354. [PubMed]

  14. Rajkumar S V, Kyle R A, Therneau T M. et al Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005106812–817. [PMC free article] [PubMed]

  15. Hjorth M, Holmberg E, Rodjer S. et al Impact of active and passive exclusions on the results of a clinical trial in multiple myeloma. The Myeloma Group of Western Sweden. Br J Haematol 19928055–61. [PubMed]

  16. Riccardi A, Mora O, Tinelli C. et alLong‐term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 2000821254–1260. [PMC free article] [PubMed]

  17. Djulbegovic B, Wheatley K, Ross J. et al Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev2002CD003188 [PubMed]

  18. McCloskey E V, MacLennan I C, Drayson M T. et al A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998100317–325. [PubMed]

  19. Knudsen L M, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 200065175–181. [PubMed]

  20. Gabrilove J L, Cleeland C S, Livingston R B. et al Clinical evaluation of once‐weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three‐times‐weekly dosing. J Clin Oncol2001192875–2882. [PubMed]

  21. Glaspy J, Bukowski R, Steinberg D. et al Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997151218–1234. [PubMed]

  22. Guidelines Working Group of UK Myeloma Forum , British Committee for Standards in Haematology, British Society for Haematology Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol2004125681–700. [PubMed]

  23. Hideshima T, Bergsagel P L, Kuehl W M. et al Advances in biology of multiple myeloma: clinical applications. Blood 2004104607–618. [PubMed]

  24. Soutar R, Lucraft H, Jackson G. et alGuidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. Br J Haematol2004124717–726. [PubMed]

  25. Abrahamson G M, Bird J M, Newland A C. et al A randomized study of VAD therapy with either concurrent or maintenance interferon in patients with newly diagnosed multiple myeloma. Br J Haematol 199694659–664. [PubMed]

  26. Raje N, Powles R, Kulkarni S. et al A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C‐VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol 199797153–160. [PubMed]

  27. Kumar S, Lacy M Q, Dispenzieri A. et al Single agent dexamethasone for pre‐stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant 200434485–490. [PubMed]

  28. Attal M, Harousseau J L, Stoppa A M. et al A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med199633591–97. [PubMed]

  29. Child J A, Morgan G J, Davies F E. et al High‐dose chemotherapy with hematopoietic stem‐cell rescue for multiple myeloma. N Engl J Med20033481875–1883. [PubMed]

  30. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol1998163832–3842. [PubMed]

  31. Galton D A, Peto R. A progress report on the Medical Research Council’s therapeutic trial in myelomatosis. Br J Haematol196815319–320. [PubMed]

  32. Richardson P G, Mitsiades C S, Hideshima T. et al Novel biological therapies for the treatment of multiple myeloma. Best Pract Res Clin Haematol200518619–634. [PubMed]

  33. Barlogie B, Desikan R, Eddlemon P. et al Extended survival in advanced and refractory multiple myeloma after single‐agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 200198492–494. [PubMed]

  34. Palumbo A, Giaccone L, Bertola A. et al Low‐dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 200186399–403. [PubMed]

  35. Mazumder A, Jagannath S. Thalidomide and lenalidomide in multiple myeloma. Best Pract Res Clin Haematol 200619769–780. [PubMed]

  36. Richardson P G, Barlogie B, Berenson J. et al A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 20033482609–2617. [PubMed]

  37. Richardson P G, Schlossman R, Hideshima T. et al New treatments for multiple myeloma. Oncology (Williston Park). 2005;19: 1781–92; discussion 1792, 1795–87, [PubMed]

The potential role of curcumin (diferuloylmethane) in plasma cell dyscrasias/paraproteinemia


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727780/

Biologics : Targets & Therapy

The potential role of curcumin (diferuloylmethane) in plasma cell dyscrasias/paraproteinemia

Terry Golombick and Terry Diamond
Additional article information

Abstract

Plasma cell dyscrasias, most commonly associated with paraproteinemia, are a diverse group of diseases. Monoclonal gammopathy of undefined significance (MGUS) can precede multiple myeloma, a progressive neoplastic disease. MGUS occurs in association with a variety of other diseases and currently no treatment is recommended but rather “watchful waiting”. Given that the size of the M-protein is a risk factor for disease progression, early intervention with the aim of reducing the paraprotein load would provide an innovative therapeutic tool. Preliminary results from our pilot study show a drop of between 5% and 30% serum paraprotein in patients taking curcumin compared with patients on placebo. Curcumin is a diferuloylmethane present in extracts of the rhizome of the Curcuma longa plant. As a natural product, this has exciting potential in the treatment of plasma cell dyscrasias.

Keywords: plasma cell dyscrasias, MGUS, myeloma, curcumin, paraproteinemia

A paraprotein is a monoclonal immunoglobulin or immunoglobulin light chain (Bence Jones protein) present in blood or urine and arising from clonal proliferation of mature B cells, most commonly plasma cells or B-lymphocytes. Alternative terms include monoclonal protein or M-band.
Plasma cell dyscrasias, most commonly associated with paraproteinemia, are a diverse group of diseases which includes multiple myeloma, Waldenstrom’s macro-globulinemia, heavy chain disease, monoclonal gammopathy of undefined significance (MGUS), and immunocytic amyloidosis. The incidence of plasma cell dyscrasias is age-related, with 1% of persons over age 25 and 4% of those over age 70. Paraproteinemia is also associated with the non-Hodgkin lymphoma disorders CLL (chronic lymphocytic leukemia) and LPL (lymphoplasmacytic lymphoma).
MGUS or monoclonal gammopathy of undefined significance, can precede multiple myeloma and is typified by a serum M-protein value of <30 g/L, fewer than 10% plasma cells in the bone marrow, no or a small amount of M protein in the urine, and absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency related to the plasma-cell proliferative process (Kyle and Rajkumar 2005). MGUS occurs in association with a variety of other diseases and currently no treatment is recommended; rather that patients should be observed for change in clinical and immunochemical status at 4–6 month intervals.
Overall the risk of progression of MGUS to myeloma or related disorder is 1% per year. Although the prevalence of MGUS increases with advancing age, after adjustment for the level of the M-protein, the annual risk of progression to myeloma or a related cancer is not affected by age or the duration of MGUS. Younger patients are more likely to have progression to cancer during their lifetime because they are at risk for longer (Cook and Macdonald 2007). It is currently not possible to predict the course in any individual patient, and clinically symptomatic myeloma may not evolve for as long as 20 years. Myeloma is a progressive neoplastic disease and is often associated with multiple osteolytic lesions, hypercalcemia, anemia, renal damage, and increased susceptibility to bacterial infections. Myeloma is associated with a high mortality.
Parameters which are currently used to identify those patients at highest risk of developing disease progression are: the size of the M-protein, the type of M-protein with IgA and IgM paraproteins having a higher risk compared with IgG paraproteins, the percentage of bone marrow plasma cells, and an abnormal serum-free light chain ratio. Given the uncertainty of disease progression with MGUS, early intervention with the aim of reducing the paraprotein load would provide an innovative therapeutic tool.
Curcuma longa or turmeric is a tropical plant native to southern and southeastern tropical Asia. It is a perennial herb belonging to the ginger family. The most active component in turmeric is curcumin (Aggarwal et al 2005). Curcumin is a diferuloylmethane present in extracts of the rhizome of the Curcuma longa plant.
This non-nutritive phytochemical is pharmacologically safe, considering that it has been consumed as a dietary spice, at doses up to 100 mg/day, for centuries. Recent phase 1 clinical trials indicate that people can tolerate a dose as high as 8 g/day with no adverse effects (Sharma et al 2004).
A Medline search revealed over 1500 publications describing various activities of this polyphenol. Curcumin has been shown to suppress proliferation of a wide variety of tumor cells; to down-regulate transcription factors NF-KB, AP-1, and early growth response gene-1; to suppress the expression of cyclooxygenase-2, lipoxygenase, NO synthase, matrix metalloproteinase-9, urokinase-type plasminogen activator, tumor necrosis factor, chemokines, cell surface adhesion molecules and cyclin D1; to inhibit the expression of growth factor receptors (such as epidermal growth factor receptor and human epidermal growth factor receptor 2); and to inhibit the activity of JNK, protein tyrosine kinases, and several other protein serine/threonine kinases. This polyphenol has antioxidant and anti-inflammatory activity and has been found to suppress tumor initiation, promotion and metastasis. Numerous reports suggest that curcumin has chemopreventive and chemotherapeutic effects. Curcumin has been shown to inhibit the proliferation of a wide variety of tumor cells, including multiple myeloma cells through the down-regulation of interleukin-6.
Nine different studies of the safety and efficacy of curcumin in humans have been reported (see Aggarwal et al 2005). Over the past several years, numerous studies have been funded by the National Institutes of Health to investigate the role of curcumin and its derivatives in treatment of patients with cancer. Additionally, M.D. Anderson Cancer Center at the University of Texas is involved in pre-clinical and clinical research of the anti-cancer mechanism and application of curcuminoids in conditions including lung, breast, multiple myeloma, pancreatic, myelodysplatic syndrome, colon, prostate, head, and neck cancers.
How curcumin produces its therapeutic effects is not fully understood. It has been suggested that the effects are in part through the antioxidant and anti-inflammatory action of curcumin. It appears likely that curcumin mediates its effects through other mechanisms as well.
We are conducting a single blind randomized controlled pilot study on 25 patients with paraproteinemia. Entry criteria included patients defined as having MGUS ie, the presence of a serum paraprotein (greater than 8 g/L and less than 40 g/L) with the exclusion of multiple myeloma. These patients are being monitored for a 6 month period of curcumin or placebo therapy. Curcumin or placebo is being administered orally as a 2 grams twice daily regimen. After one week on curcumin, there has been a drop of between 5% and 30% serum paraprotein in some patients, compared to controls (see figures). After 3 months of curcumin therapy, these reduced levels have remained suppressed. These exciting findings have prompted a double-blind, randomized, controlled trial. The benefits of the fall in paraprotein is uncertain. How long these reduced levels will remain suppressed and what the clinical benefits are, remain to be seen. As a natural product, it has exciting potential in the treatment of plasma cell dyscrasias.

Figure 1

Curcumin: Paraprotein levels (g/L).

Figure 2

Control: Paraprotein levels.

Article information

Biologics. 2008 Mar; 2(1): 161–163.

Published online 2008 Mar.

PMCID: PMC2727780

PMID: 19707439

Terry Golombick and Terry Diamond

Department of Endocrinology, St George Hospital, Kogarah, Australia

Correspondence: Terry Golombick, Department of Endocrinology, St George Hospital, Kogarah, Australia, Tel + 62 2 9350 2767, Fax + 62 2 9350 3966, Email ua.vog.wsn.htlaeh.shaises@kcibmolog.yrret

Copyright © 2008 Golombick and Diamond, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Articles from Biologics : Targets & Therapy are provided here courtesy of Dove Press

References

Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Br J Haematol. 2006;34:573–89. [PubMed]

Cook L, Macdonald DHC. Management of paraproteinaemia. Post-grad Med J. 2007;83:217–23.[PMC free article] [PubMed]

Aggarwal BB, Kumar A, Aggarwal MS, et al. Curcumin Derived from Turmeric Curcuma longa: a spice for All Seasons. In: Bagchi D, editor. Phytopharmaceuticals in Cancer Chemoprevention. 2005. pp. 349–87.

Sharma RA, Euden SA, Platton SL, et al. Phase 1 clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin Cancer Res. 2004;10:6847–54.[PubMed]

Romania’s Revolution, Then And Now | Radio Free Europe / Radio Liberty


https://www.rferl.org/a/romania-revolution-then-and-now/29660285.html

Click on the pic to go to the story!

Great performances: Watch “”Sibelius: Symphony No.5 Leonard Bernstein Sibelius, Symphonie Nr 5 Es Dur op 82 Leonard Bernstein” on YouTube


Sibelius, Symphonie Nr 5 Es Dur op 82 Leonard Bernstein, Wiener Philharmoniker

00.00 : Part 1 : Tempo molto moderato – Allegro moderato (ma poco a poco stretto) –
Vivace molto – Presto – Più Presto
14.12 : Part 2 : Andante mosso, quasi allegretto – Poco a poco stretto – Tranquillo – Poco
a poco stretto – Ritenuto al tempo I
22.38 : Part 3 : Allegro molto – Misterioso – Un pochettino largamente – Largamente
assai – Un pochettino stretto

Background ( https://en.wikipedia.org/wiki/Symphony_No.5%28Sibelius%29?wprov=sfla1):

The Symphony No. 5 in E-flat major, Op. 82, by Jean Sibelius is a symphony in three movements that typically lasts around 33 minutes.

Quick facts: Symphony No. 5, Key …
History
Sibelius was commissioned to write this symphony by the Finnish government in honour of his 50th birthday, which had been declared a national holiday. The symphony was originally composed in 1915. It was revised first in 1916 and then again in 1919.

During the composition phase, Sibelius wrote in his diary: “It is as if God Almighty had thrown down pieces of a mosaic for heaven’s floor and asked me to find out what was the original pattern.”

The original version was premiered by Sibelius himself with the Helsinki Philharmonic Orchestra on his own 50th birthday, 8 December 1915. The second version (only part of which has survived) was first performed by the Orchestra of Turun Soitannollinen Seura in Turku exactly one year later. The final version, which is the most commonly performed today, was premiered by Sibelius conducting the Helsinki Philharmonic Orchestra on 24 November 1919.

The 1910s were a decade of change for the symphonic form which had existed for over two centuries. Meanwhile, various landmark works in other genres had presented further radical developments. In 1909 Schoenberg continued pushing for more dissonant and chromatic harmonies in his Five Pieces for Orchestra, Op. 16. From 1910–1913 Igor Stravinsky premiered his innovative and revolutionary ballets, Petrushka and The Rite of Spring (Le Sacre du Printemps). Ravel and Debussy were at work developing and performing their Impressionistic music. Though having spent nearly 30 years in the public spotlight, Jean Sibelius found his works receiving poor reviews for the first time with the 1911 premiere of his Fourth Symphony and, as James Hepokoski theorized, the composer “was beginning to sense his own eclipse as a contending modernist.”

These events perhaps brought Sibelius to a point of crisis in his career, maybe forcing him to choose between changing his style to fill the more modern desires of audiences or continue composing as he felt best fit.
The first version of this symphony kept his orchestral style (consonant sonorities, woodwind lines in parallel thirds, rich melodic development, etc.) while further developing his structural style. Hepokoski calls this structural development “sonata deformation” or the change and development of sonata form itself. The success of this change is reflected in the popularity of the Fifth Symphony to the present day.

The first version of the Fifth Symphony still has much in common with the more modernist Fourth Symphony as it features some bitonal passages; the version from 1919 seems to be more straightforward and classical. Sibelius commented on his revision: “I wished to give my symphony another – more human – form. More down-to-earth, more vivid.”

Instrumentation
The symphony is scored for 2 flutes, 2 oboes, 2 clarinets, 2 bassoons, 4 horns, 3 trumpets, 3 trombones, timpani, and strings.

Structure
This symphony is unusual in its structure:

Tempo molto moderato – Allegro moderato (ma poco a poco stretto) – Vivace molto – Presto – Più Presto (in E-flat major)
Andante mosso, quasi allegretto – Poco a poco stretto – Tranquillo – Poco a poco stretto – Ritenuto al tempo I (in G major)
Allegro molto – Misterioso – Un pochettino largamente – Largamente assai – Un pochettino stretto (in E-flat major)
Among the multi-movement symphonies by Sibelius, this is the only one where all the movements are in major keys.

The form of the symphony is symmetrical when it comes to tempo: the first movement starts in a slow tempo but ends with the fast “scherzo”. The second movement is a neither slow nor fast movement; it forms a calm “intermezzo”. Then follows the third movement, which begins in a fast tempo but ends slowly. The duration is approximately 32 minutes.

(from Wikipedia: https://en.wikipedia.org/wiki/Symphony_No.5%28Sibelius%29?wprov=sfla1)

Category
Music
License
Standard YouTube License
Music
“Sibelius: Symphony No.5

A music full of love, the everliving music of Antonin Dvorak: Watch “The most Romantic Music by Antonin Dvorak. American Suite in A, opus 98b.” on YouTube


A music full of love, the everliving music of Antonin Dvorak