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Hematopathology: LC14-1 DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): STILL A PANDORA'S BOX?

September 5, 2014 By Manish Butte

Hematopathology: LC14-1 DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): STILL A PANDORA’S BOX?

Pathology. 2014 Oct;46 Suppl 2:S21

Authors: Pileri SA

Abstract
DLBCL is the most common lymphoid malignancy worldwide. It includes tumors that cannot be morphologically classified (NOS) and clinic-pathologic variants characterized by specific features (e.g., age, primary site, immunodeficiency, and/or relationship with infectious agents).Nowadays, the cell of origin and complex cytogenetic alterations deserve great attention by affecting the disease behavior and therapeutic decisions.Gene expression profiling (GEP) studies have subdivided DLBCL/NOS into two main categories, related to germinal center and activated blood B-lymphocytes. The former has a more favorable course also in thepresent immunochemotherapy era. The attempts to surrogate GEP by immunohistochemistry ensued in algorithms, none of which as effective as GEP. More recently, an approach based on 15 genes and Nanostring technology has revealed excellent accuracy, inter-lab reproducibility and affordable costs.Equally important is the search for double/triple hits involving BCL2, MYC and BCL6, which can be detected by FISH and confer protection against apoptosis and high proliferative activity. The search for the corresponding proteins does not represent an absolute surrogate of cytogenetics. However, BCL2/MYC double expression heralds a poor prognosis. Further relevant parameters are CD30 expression and EBV infection.Finally, next generation sequencing has highlighted a series of mutations that might represent the rationale for innovative-targeted therapies.

PMID: 25188094 [PubMed – as supplied by publisher]

Interstitial Lung Disease with Multiple Microgranulomas in Chronic Granulomatous Disease.

September 5, 2014 By Manish Butte

Interstitial Lung Disease with Multiple Microgranulomas in Chronic Granulomatous Disease.

J Clin Immunol. 2014 Sep 4;

Authors: Kawai T, Watanabe N, Yokoyama M, Nakazawa Y, Goto F, Uchiyama T, Higuchi M, Maekawa T, Tamura E, Nagasaka S, Hojo M, Onodera M

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. CGD patients also suffer from immune regulatory disorders, such as CGD-associated bowel inflammation with granuloma, which could be caused by excessive inflammation without demonstrable infection.
PURPOSE: We investigated the clinical manifestation of interstitial lung disease (ILD) resulting from excessive inflammation in X-linked CGD patients.
METHODS: Pulmonary CT images and testing of serum KL-6 levels were performed to assess ILD in the patients. For this study, patients with pulmonary lesions due to demonstrable infections were excluded from among ILD patients.
RESULTS: Among 33 CGD patients, four developed ILD; they had increased reticulo-nodular opacities on CT images and elevated serum KL-6 levels. Histopathological examinations revealed multiple homogeneous microgranulomas in the lesions of inflammatory cell infiltration. Mononuclear cells obtained from their pulmonary lesions produced higher amounts of inflammatory cytokines than the peripheral blood mononuclear cells of CGD patients, suggesting that the only infiltrating cells in the pulmonary lesions were activated and produced large amounts of inflammatory cytokines in ILD patients. Interestingly, an anti-inflammatory drug, such as a corticosteroid or thalidomide, but not anti-bacterial or anti-fungal drugs, improved CT image findings and reduced their KL-6 levels.
CONCLUSIONS: CGD patients’ daily exposures to inhaled antigens may induce excessive reactions with the production of inflammatory cytokines leading to the development of ILD with multiple microgranulomas, which could be due to an inadequate production of reactive oxygen species in CGD.

PMID: 25186973 [PubMed – as supplied by publisher]

Sheep CD34+ amniotic fluid cells have haematopoietic potential and engraft after autologous in utero transplantation.

September 5, 2014 By Manish Butte

Sheep CD34+ amniotic fluid cells have haematopoietic potential and engraft after autologous in utero transplantation.

Stem Cells. 2014 Sep 3;

Authors: Shaw SW, Blundell MP, Pipino C, Shangaris P, Maghsoudlou P, Ramachandra DL, Georgiades F, Boyd M, Thrasher AJ, Porada CD, Almeida-Porada G, Cheng PJ, David AL, De Coppi P

Abstract
Unmatched allogeneic in utero stem cell transplantation (IUSCT) produces poor engraftment unless the fetus has congenital immunodeficiency, probably because of maternal and fetal immune responses to injected cells. We studied the functional haematopoietic potential of transduced GFP+ sheep amniotic fluid (AF) stem cells, before and after autologous IUSCT. CD34+ cells were selected from first trimester sheep AF, transduced overnight and injected intravenously into NOD-SCID-gamma (NSG) mice. At 3 months primary recipient bone marrow (BM) was injected into secondary NSG recipients. GFP+ cells were detected in the haematopoietic organs and peripheral blood of primary and secondary recipients at 3 months. Autologous IUSCT (transduced GFP+CD34+AF) was performed in fetal sheep. Six months postnatally, lamb BM was injected into secondary NSG recipients. GFP+ cells were detected in the peripheral blood of primary and secondary recipients. This confirms the haematopoietic potential of AF stem cells supporting the concept of autologous IUSCT to treat congenital haematopoietic disease. Stem Cells 2014.

PMID: 25186828 [PubMed – as supplied by publisher]

Emerging roles of store-operated Ca²⁺ entry through STIM and ORAI proteins in immunity, hemostasis and cancer.

September 5, 2014 By Manish Butte

Emerging roles of store-operated Ca²⁺ entry through STIM and ORAI proteins in immunity, hemostasis and cancer.

Channels (Austin). 2013 Sep-Oct;7(5):379-91

Authors: Bergmeier W, Weidinger C, Zee I, Feske S

Abstract
Store-operated Ca(2+) entry (SOCE) is an important Ca(2+) influx pathway, which is defined by the fact that depletion of intracellular Ca(2+) stores, mainly the endoplasmic reticulum (ER), triggers the opening of Ca(2+) channels in the plasma membrane. The best characterized SOC channel is the Ca(2+) release-activated Ca(2+) (CRAC) channel, which was first described in cells of the immune system but has since been reported in many different cell types. CRAC channels are multimers of ORAI family proteins, of which ORAI1 is the best characterized. They are activated by stromal interaction molecules (STIM) 1 and 2, which respond to the depletion of intracellular Ca(2+) stores with oligomerization and binding to ORAI proteins. The resulting SOCE is critical for the physiological function of many cell types including immune cells and platelets. Recent studies using cell lines, animal models and primary cells from human patients with defects in SOCE have highlighted the importance of this Ca(2+) entry mechanism in a variety of pathophysiological processes. This review focuses on the role of SOCE in immunity to infection, allergy, hemostasis and cancer.

PMID: 23511024 [PubMed – indexed for MEDLINE]

Chronic granulomatous disease: why an inflammatory disease?

September 4, 2014 By Manish Butte

Chronic granulomatous disease: why an inflammatory disease?

Braz J Med Biol Res. 2014 Aug 29;0:0

Authors: Roxo-Junior P, Simão HM

Abstract
Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the phagocytic NADPH oxidase system. Patients can present with severe, recurrent infections and noninfectious conditions. Among the latter, inflammatory manifestations are predominant, especially granulomas and colitis. In this article, we systematically review the possible mechanisms of hyperinflammation in this rare primary immunodeficiency condition and their correlations with clinical aspects.

PMID: 25184375 [PubMed – as supplied by publisher]

Hizentra for the treatment of primary immunodeficiency.

September 4, 2014 By Manish Butte

Hizentra for the treatment of primary immunodeficiency.

Expert Rev Clin Immunol. 2014 Sep 3;:1-15

Authors: Wasserman RL

Abstract
Immunoglobulin (IgG) replacement therapy has been the cornerstone of treatment for primary immunodeficiency disease for nearly 60 years. During this time, research has continually refined the target IgG trough level and IgG replacement dosages to allow patients with primary immunodeficiency disease to achieve effective protection from infection. Manufacturers have also improved IgG formulations to allow patients to receive clinically beneficial dosages of IgG replacement with improved safety and tolerability. This review will introduce Hizentra(®), a highly concentrated (20%) IgG solution for subcutaneous (sc.) infusion, discuss its manufacturing process and pharmacokinetic profile and review its tolerability and efficacy data as evaluated in clinical trials. New highly concentrated sc. IgG products may improve patient quality of life and adherence to therapy because of the flexible dosing options, fewer infusion sites and less infusion time, compared with less concentrated sc. IgG products, resulting in favorable patient outcomes consistent with higher steady-state IgG levels.

PMID: 25182658 [PubMed – as supplied by publisher]

AAOA allergy primer: immunodeficiency.

September 4, 2014 By Manish Butte

AAOA allergy primer: immunodeficiency.

Int Forum Allergy Rhinol. 2014 Sep;4 Suppl 2:S74-8

Authors: Ryan MW

Abstract
BACKGROUND: Primary immunodeficiency is rare but should be considered in patients who present to the otolaryngologist with recurrent, severe, or treatment refractory infections.
METHODS: Recent literature and consensus statements on immunodeficiency were reviewed for clinically important information of relevance to otolaryngologists.
RESULTS: The most common and most relevant immunodeficiencies are humoral deficiencies with inadequate antibody production or an impairment in the production of specific antibody after antigen exposure. For otolaryngologists the most important immunodeficiencies include immunoglobulin A (IgA) deficiency, common variable immunodeficiency (CVID), and specific antibody deficiency. Simple screening tests can be used by the otolaryngologist to exclude the most common immunodeficiencies. The general treatment approach to patients with these immunodeficiencies includes airway hygiene, early and aggressive treatment of infections, immunization, and antibody replacement therapy.
CONCLUSION: By virtue of their scope of practice, otolaryngologists are in a position to recognize and initiate the diagnostic workup of patients with immunodeficiency. Patients with a diagnosed primary immunodeficiency are best managed in a multidisciplinary manner with close cooperation among the otolaryngologist, immunologist, and other specialists that are involved in treating these multisystem diseases.

PMID: 25182361 [PubMed – in process]

Primary ciliary dyskinesia diagnosed by electron microscopy in one case of Kartagener syndrome.

September 3, 2014 By Manish Butte

Primary ciliary dyskinesia diagnosed by electron microscopy in one case of Kartagener syndrome.

Rom J Morphol Embryol. 2014;55(2 Suppl):697-701

Authors: Rugină AL, Dimitriu AG, Nistor N, Mihăilă D

Abstract
Primary ciliary dyskinesia (PCD) is associated with abnormalities in the structure of a function of motile cilia, causing impairment of muco-ciliary clearence, with bacterial overinfection of the upper and lower respiratory tract (chronic oto-sino-pulmonary disease), heterotaxia (situs abnormalities), with÷without congenital heart disease, abnormal sperm motility with male infertility, higher frequency of ectopic pregnancy and female subfertility. The presence of recurrent respiratory tract infections in the pediatric age requires differentiation between primary immunodeficiency, diseases with abnormal mucus (e.g., cystic fibrosis) and abnormal ciliary diseases. This case was hospitalized for recurrent respiratory tract infections and total situs inversus at the age of five years, which has enabled the diagnosis of Kartagener syndrome. The PCD confirmation was performed by electron microscopy examination of nasal mucosa cells through which were confirmed dynein arms abnormalities. The diagnosis and early treatment of childhood PCD allows a positive development and a good prognosis, thus improving the quality of life.

PMID: 25178347 [PubMed – as supplied by publisher]

[Wiskott-Aldrich syndrome. A report of a new mutation.]

September 2, 2014 By Manish Butte

[Wiskott-Aldrich syndrome. A report of a new mutation.]

Rev Alerg Mex. 2014 Jul-Sep;61(3):219-23

Authors: Guillén-Rocha N, López-Rocha E, Danielian S, Segura-Méndez N, López-González L, Lugo-Reyes SO

Abstract
Wiskott-Aldrich syndrome was first reported clinically in 1937, and in 1954 the classic triad was identified: eccema, recurrent infections and thrombocytopenia with an X-linked transmission. Its incidence is estimated at 1 to 10 in one million live births per year. Wiskott Aldrich syndrome is caused by mutations in a gene in the short arm of chromosome X that encodes the Wiskott-Aldrich syndrome protein (WASp), which identification and sequencing was first performed in 1994, and since then about 300 mutations have been reported. This paper describes the case of a boy with Wiskott-Aldrich syndrome, with clinical and genetic diagnosis, with a considerable diagnostic delay attributable to an atypical presentation misdiagnosed as immune thrombocytopenia.

PMID: 25177856 [PubMed – as supplied by publisher]

[Adverse effects with ambulatory intravenous immunoglobulin administration in adult patients with common variable immunodeficiency.]

September 2, 2014 By Manish Butte

[Adverse effects with ambulatory intravenous immunoglobulin administration in adult patients with common variable immunodeficiency.]

Rev Alerg Mex. 2014 Jul-Sep;61(3):131-40

Authors: Rodríguez-Mireles KA, Galguera-Sauceda A, Gaspar-López A, López-Rocha EG, Campos-Romero F, Del Rivero-Hernández L, Amaya-Mejía A, Galindo-Pacheco L, O’Farril-Romanillos P, Segura-Méndez NH

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, affecting 1:25,000-75,000 people. It is characterized by the absence or decrease antibody production. Treatment for CVID consists on human immunoglobulin administration, and the intravenous route is the most common route for administration, at 400-800 mg/kg of weight every 3-4 weeks. Adverse effects associated with intravenous immunoglobulin (IVIg) use occur in 25% of all infusions, with severe adverse reactions presenting in less than 1% of all patients. Acute renal failure can occur as a severe adverse reaction, which presents 1-10 days after starting IVIg treatment. In our center we implemented an ambulatory scheme for IVIg administration, which allows its administration in an average of 3 hours, without severe adverse effects.
OBJECTIVES: To describe adverse effects and to evaluate the frequency of renal failure secondary to ambulatory IVIg administration in patients with common variable immunodeficiency.
MATERIAL AND METHOD: A descriptive and prospective study was done including adult patients con definitive diagnosis of common variable immunodeficiency, receiving IVIg at replacement dose every 3 weeks. All patients were evaluated with clinical exploration, somatometry, serum creatinine, albumin and urea determination, 24 hours creatinine clearance, glomerular filtration rate with CKD-EPI, and immediate renal function associated with accumulated IVIg. Results were analyzed with descriptive statistics.
RESULTS: We determined adverse effects in 25 patients with common variable immunodeficiency (15 women and 10 men, average age 36.7 years), during a 10 months period (January-September 2013). During this period 284 IVIg infusions were administered using our scheme, frequency of adverse effects were 12.9%, with 5.2% of early adverse effects and 7.7% late adverse effects, all being mild to moderate, in some cases required analgesic and/or antihistamine administration, without having to stop the IVIg infusion. In the renal function study 19 patients were included (12 women and 7 men, average age 36 years, average weigh 58.74 kg and average height 1.60 m), evaluated from January 2009 to October 2013. Average serum creatinine was 0.76 ± 0.18 mg/dL, average serum urea was 28.6 ± 7.6 mg/dL, none patient presenting acute renal failure. Glomerular filtration rate was determined with CKD-EPI formula, and the average was 116 ± 34 mL/min/1.73 m2, finding chronic renal failure in 4 patients. Average 24 hours creatinine clearance was 98.64 ± 22 mL/min/1.73 m2, with chronic renal failure data in 6 patients.
CONCLUSIONS: There were no severe adverse effects with this ambulatory IVIg scheme (anaphylaxis, acute renal failure). We did not find data of acute renal failure secondary to IVIg administration in this population, but we did find data of chronic renal failure secondary to IVIg administration through 24 hours creatinine clearance in 6 patients. No relation was found between accumulated IVIg dose in the last 5 years and decreased glomerular filtration rate. Another benefit worth of mentioning with this scheme is the reduction in costs for the health institution and to the patient.

PMID: 25177848 [PubMed – as supplied by publisher]