Use of intravenous immunoglobulin in the treatment of immune-mediated demyelinating diseases of the nervous system

Intravenous immunoglobulins (IVIg) are used in treatment of a broad spectrum of diseases. Immunoglobulin replacement therapy is the standard treatment for immunodeficiencies with compromised humoural immunity. Use of this method as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities. Limited quantitative availability due to dependence on human donors as a source of IVIg, coupled with high treatment costs, make necessary a highly responsible and evidence-based approach with these agents. Discussion of the indications and currently valid recommendations on use of IVIg in treatment of immunomediated demyelinating diseases of the nervous system is based on existing clinical studies. We describe further neurological indications for use of IVIg as well as mechanisms of action and adverse effects of its use.     

MYC High Level Gene Amplification Is a Distinctive Feature of Angiosarcomas after Irradiation or Chronic Lymphedema

Angiosarcomas (AS) are rare vascular malignancies that arise either de novo as primary tumors or secondary to irradiation or chronic lymphedema. The cytogenetics of angiosarcomas are poorly characterized. We applied array-comparative genomic hybridization as a screening method to identify recurrent alterations in 22 cases. Recurrent genetic alterations were identified only in secondary but not in primary AS. The most frequent recurrent alterations were high level amplifications on chromosome 8q24.21 (50%), followed by 10p12.33 (33%) and 5q35.3 (11%). Fluorescence in situ hybridization analysis in 28 primary and 33 secondary angiosarcomas (31 tumors secondary to irradiation, 2 tumors secondary to chronic lymphedema) confirmed high level amplification of MYC on chromosome 8q24.21 as a recurrent genetic alteration found exclusively in 55% of AS secondary to irradiation or chronic lymphedema, but not in primary AS. Amplification of MYC did not predispose to high grade morphology or increased cell turnover. In conclusion, despite their identical morphology, secondary AS are genetically different from primary AS and are characterized by a high frequency of high level amplifications of MYC. This finding may have implications both for the diagnosis and treatment of these tumors.Angiosarcomas (AS) are rare sarcomas with morphological and functional properties of endothelial cells.¹ AS represent <1% of all sarcomas.² Roughly 35% of cases arise in the skin, 25% in soft tissue and the rest in various other locations including breast, liver, spleen, and bone.¹ The prognosis of AS has generally been considered to be poor with unpredictable clinical behavior. However, several publications clearly showed that prognosis depends on the primary site with a particularly poor prognosis for tumors arising in liver, spleen, heart, and bone with a 5-year-survival rate of 0%, as compared with approximately 50% for skin and soft tissue AS.^3,4 Other factors with an adverse impact on prognosis are older age, tumor necrosis, and epitheloid features.⁵ Tumors can arise either de novo (primary AS, pAS) or as secondary conditions in patients with long standing lymphedema^6,7 or after irradiation⁸ (secondary AS; sAS), especially in female patients irradiated for breast cancer. In fact, sAS of the breast is by far the most frequent radiation-induced sarcoma in women treated with radiation therapy as part of their initial treatment,⁹ with a more than 1000-fold increased relative risk¹⁰ as compared with the general population. It has been calculated that the standardized incidence ratio in irradiated breast cancer patients to develop AS is 26 compared with 3.8 to develop any other sarcoma⁹ over a latency period of 5 to 10 years. Of note, the latency period of sAS has been reported to be much shorter than in other radiation-induced sarcomas, which is generally >10 years.^11–14 Relatively little is known about the genetic changes in postradiation sarcomas in general^15–18 and in sAS in particular, where published genetic studies are limited to case reports or small case collections.^19–28 Probably due to the small case numbers, available data have so far failed to show consistent recurrent chromosomal abnormalities. In this report, we studied clinicopathologic and molecular genetic features in 61 primary and secondary AS from multiple international institutions.     

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients

Background:

Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy.

Methods:

Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status.

Results:

In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01).

Conclusions:

TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30–40% of CRC patients, may represent a new avenue of investigation for targeted therapy.