Morphine: double-faced roles in the regulation of tumor development

Morphine, a highly potent analgesic, is one of the most effective drugs for the treatment of severe pain associated with cancer. It directly acts on the central nervous system to relieve pain, but also cause secondary complications, such as addiction, respiratory depression and constipation due to its activities on peripheral tissues. Besides pain relief, morphine is of great importance on cancer management with its effect on tumor development being the subject of debate for many years with some contradictory findings. Morphine has shown both tumor growth-promoting and growth-inhibiting effects in many published research studies. And various signaling pathways have been suggested to be involved in these effects of morphine. Based on a thorough literature review, we summarized the double-faced effects of morphine in tumor development, including tumor cell growth and apoptosis, metastasis, angiogenesis, immunomodulation and inflammation. And we attempted to optimize morphine administration in cancer patients to attenuate its tumor growth-promoting effects.     

Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma

The majority of anaplastic large cell lymphomas (ALCL) are associated with chromosomal abnormalities affecting the anaplastic lymphoma kinase (ALK) gene which result in the expression of hybrid ALK fusion proteins in the tumor cells. In most of these tumors, the hybrid gene comprises the 5' region of nucleophosmin (NPM) fused in frame to the 3' portion of ALK, resulting in the expression of the chimeric oncogenic tyrosine kinase NPM-ALK. However, other variant rearrangements have been described in which ALK fuses to a partner other than NPM. Here we have identified the moesin (MSN) gene at Xq11-12 as a new partner of ALK in a case of ALCL which exhibited a distinctive membrane-restricted pattern of ALK labeling. The hybrid MSN-ALK protein had a molecular weight of 125 kd and contained an active tyrosine kinase domain. The unique membrane staining pattern of ALK is presumed to reflect association of moesin with cell membrane proteins. In contrast to other translocations involving the ALK gene, the ALK breakpoint in this case occurred within the exonic sequence coding for the juxtamembrane portion of ALK. Identification of the genomic breakpoint confirmed the in-frame fusion of the whole MSN intron 10 to a 17 bp shorter juxtamembrane exon of ALK. The breakpoint in der(2) chromosome showed a deletion, including 30 bp of ALK and 36 bp of MSN genes. These findings indicate that MSN may act as an alternative fusion partner for activation of ALK in ALCL and provide further evidence that oncogenic activation of ALK may occur at different intracellular locations.     

EBV-positive immunodeficiency lymphoma after alemtuzumab-CHOP therapy for peripheral T-cell lymphoma

Chemotherapy with alemtuzumab and the combination of cyclophosphamide, adriamycin, oncovin, and prednisone (CHOP) has become experimental trial therapy for aggressive T-cell lymphoma. Several multicenter phase 3 trials will incorporate this scheme. As part of an ongoing phase 2 trial in which we recently treated 20 patients with 8 cycles of CHOP every 2 weeks with 3 additional doses of 30 mg alemtuzumab per cycle, we observed the development of Epstein-Barr virus (EBV)-positive lymphoproliferative disease, after completion of the immunochemotherapy in 3 patients with peripheral T-cell lymphoma. Because the occurrence of EBV-positive lymphoproliferative disease is rare after alemtuzumab monotherapy, such as is given for chronic lymphocytic leukemia, we think that early reporting of this potential side effect is warranted. It may be caused by intrinsic T-cell defects in patients with T-cell lymphoma, or by the combination of alemtuzumab with CHOP chemotherapy.     

Serum interleukin-6 has no discriminatory role in paraproteinaemia nor a prognostic role in multiple myeloma.

We determined interleukin-6 (IL-6) levels in the serum of 212 well-defined patients with newly diagnosed paraproteinaemia and evaluated its discriminatory value and prognostic role in multiple myeloma (MM). Results were compared with serum neural cell adhesion molecule and beta-2-microglobulin, both established prognostic MM markers. Paraproteinaemia-related diagnoses were: MM (60), other haematological diseases (46), solid tumours (35), autoimmune diseases (17) and monoclonal gammopathy of unknown significance (MGUS) (54). The range of IL-6 levels in all diagnostic groups overlapped widely and did not serve as a discriminatory marker in newly diagnosed paraproteinaemia even when patients with infection or fever (42) were excluded. In MM high IL-6 levels (>/= 50 pg/ml) were not associated with a shorter survival (P = 0.24). We compared our results with 20 published studies on serum IL-6 in paraproteinaemia and/or MM. IL-6 data have to be related to the assay used (bio- or immunoassay) and to the status of MM (newly diagnosed, during therapy, progressive disease). We conclude that serum IL-6 is not specific for paraproteinaemia-related diseases and will not serve as a reliable discriminatory or prognostic marker in paraproteinaemia and MM.     

How pediatricians can respond to the psychosocial implications of disasters. American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health, 1998-1999

Natural and human-caused disasters, violence with weapons, and terrorist acts have touched directly the lives of thousands of families with children in the United States.1 Media coverage of disasters has brought images of floods, hurricanes, and airplane crashes into the living rooms of most American families, with limited censorship for vulnerable young children. Therefore, children may be exposed to disastrous events in ways that previous generations never or rarely experienced. Pediatricians should serve as important resources to the community in preparing for disasters, as well as acting in its behalf during and after such events.     

First-time anterior shoulder dislocations: should they be arthroscopically stabilised?

The glenohumeral joint is inherently unstable because the large humeral head articulates with the small shadow glenoid fossa. Traumatic anterior dislocation of the shoulder is a relatively common athletic injury, and the high frequency of recurrent instability in young athletes after shoulder dislocation is discouraging to both the patient and the treating physician. Management of primary traumatic shoulder dislocation remains controversial. Traditionally, treatment involves initial immobilisation for 4–6 weeks, followed by functional rehabilitation. However, in view of the high recurrence rates associated with this traditional approach, there has been an escalating interest in determining whether immediate surgical intervention can lower the rate of recurrent shoulder dislocation, improving the patient’s quality of life. This review article aims to provide an overview of the nature and pathogenesis of first-time primary anterior shoulder dislocations, the widely accepted management modalities, and the efficacy of primary surgical intervention in first-time primary anterior shoulder dislocations.     

GWAS with longitudinal phenotypes: performance of approximate procedures

Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165–180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single-nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power.