Novel therapeutic options in anaplastic large cell lymphoma: molecular targets and immunological tools

Anaplastic large cell lymphoma (ALCL) is a CD30-positive, aggressive T-cell lymphoma, and about half of the patients with this disease harbor the t(2;5)(p21;q35) translocation. This chromosomal aberration leads to fusion of the NPM gene with the ALK tyrosine kinase, leading to its constitutive activation. To date, treatment options include polychemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone), which is sometimes combined with radiation in the case of bulky disease, leading to remission rates of ～80%. However, the remaining patients do not respond to therapy, and some patients experience chemo-resistant relapses, making the identification of new and better treatments imperative. The recent discovery of deregulated ALK in common cancers such as non-small cell lung cancer and neuroblastoma has reinvigorated industry interest in the development of ALK inhibitors. Moreover, it has been shown that the ALK protein is an ideal antigen for vaccination strategies due to its low expression in normal tissue. The characterization of microRNAs that are deregulated in ALCL will yield new insights into the biology of ALCL and open new avenues for therapeutic approaches in the future. Also, CD30 antibodies that have been tested in ALCL for quite a while will probably find a place in forthcoming treatment strategies.     

Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse

Niemann-Pick type C 1 (NPC1) disease is an autosomal recessive cholesterol transport defect resulting in a neurodegenerative process in patients mainly at an early age, although some patients may start with manifestation in adult. Since loss of myelin is considered as a main pathogenetic factor, the precise mechanism inducing dysmylination in NPC1 disease is still unclear. In the present study, a quantitative evaluation on the myelin protein and its regulatory factors of oligodendrocytes, such as SRY-related HMG-box 10 (Sox10), Yin Yang 1 factor (YY1) and myelin gene regulatory factor (MRF), in different parts of the brain and spinal cord was performed in NPC1-mutant mice. The results showed that NPC1 protein was expressed in oligodendrocytes and the amount of myelin protein was generally decreased in all parts of the brain and spinal cord in NPC1-mutant mice. Compared to wild type, the amount of Sox10 and YY1 was not different in NPC1-mutant mice, but MRF was significantly decreased, suggesting a possible mechanism perturbing differentiation of oligodendrocytes and the myelination process in the NPC1-mutant mouse.     

Glitazone-like action of glimepiride and glibenclamide in primary human adipocytes

Aim: Sulphonylureas (SUs) are among the most widely used oral hypoglycaemic drugs that stimulate insulin secretion. In addition, SUs have pleiotropic effects on other tissues. Conflicting findings have been reported regarding the effects of SUs on adipocytes. We have now investigated the actions of glimepiride and glibenclamide (=glyburide) in primary human adipocytes. Methods: Primary cultured human white pre‐adipocytes were differentiated in vitro according to a standard protocol. Lipid accumulation was assessed by Oil Red O staining and determination of triglyceride content; gene expression was measured by RT PCR and Western blotting. Results: Initially, we characterized the genes regulated during human pre‐adipocyte differentiation by performing global microarray analysis. Treatment with glimepiride and glibenclamide caused an increased accumulation of lipid droplets and triglycerides. In addition, genes involved in lipid metabolism were induced and chemokine expression was decreased. Interestingly, the effects of SUs were generally qualitatively and quantitatively similar to those of pioglitazone. In direct comparison, glibenclamide was more potent than glimepiride with respect to the induction of fatty acid binding protein 4 (FABP4) (EC₅₀ 0.32 vs. 2.8 µM), an important adipocyte marker gene. SU‐induced differentiation was virtually completely blocked by the peroxisome proliferator‐activated receptor γ (PPARγ)‐antagonist T0070907 but not affected by diazoxide, indicating PPARγ activation by SUs. Repaglinide had no effect on adipogenesis, although it causes insulin liberation like SUs. Conclusions: In primary human pre‐adipocytes, glibenclamide and glimepiride strongly induced differentiation, apparently by activating PPARγ. Thus, SUs but not repaglinide may be used to influence insulin resistance beyond their effect on insulin liberation.     

A new sulcus-corrected approach for assessing cerebellar volume in spinocerebellar ataxia

Precise volumetry of the cerebellum still remains challenging, due to thin sulci and gyri. We present a new fast and reliable sulcus-corrected approach for quantitative assessment of cerebellar atrophy, evaluated on patients with spinocerebellar ataxia (SCA). Thin-sliced T1-weighted magnetic resonance images (MPRAGE) were acquired in 11 genetically confirmed SCA6 patients and in a group of age-matched control subjects (n = 14). Post-processing involves a morphological image segmentation pipeline as a basis for a sulcus-corrected cerebellar volume measurement. Cerebellar volumes and intra-rater, inter-rater and scan-rescan reproducibility were quantified. Reliability of the measurements was validated using an anatomical preparation of the cerebellum. Repeatability coefficients (RC: intra-rater/inter-rater/scan-rescan) of the method were 1.07%/1.11%/1.35%. Absolute cerebellar volumes showed good agreement with the actual volume of the anatomical preparation. The cerebellar volume of the SCA 6 was 96.3 ± 12.1 ml (mean ± S.D.), which was significantly lower than the results of the corresponding control groups. The cerebellar volume correlated significantly to clinical dysfunction in SCA6. This is the first study to demonstrate the feasibility of a new sulcus-corrected approach to assess cerebellar volume. In contrast to currently used methods, this new approach may be more sensitive even to small atrophic changes affecting sulcal widening.     

Cerebellar Lingula Size and Experiential Risk Factors Associated with High Levels of Alcohol and Drug Use in Young Adults

Previous studies have reported cerebellar abnormalities or static ataxia associated with risk for chronic use of alcohol and drugs. Adverse childhood experience is another strong risk factor for later substance abuse. We therefore sought to ascertain the relationship between morphological phenotypes of the lingula (lobule I) of the anterior cerebellar vermis, and exposure to emotional (EM) versus physical (PM) maltreatment, on the degree of ongoing alcohol or drug use. The study design consisted of a cross-sectional in vivo neuroimaging study, utilizing retrospective assessment of maltreatment history and self-reports of alcohol and substance use. Study participants were 153 subjects (54 M/99F, 21.9 ± 2.2 years) selected for imaging from a database of 1,402 community participants 18–25 years of age, who completed a detailed online screening instrument and met rigorous inclusion/exclusion criteria. Subjects were exposed to only physical abuse or harsh corporal punishment (HCP; PM group, n = 37) and parental verbal abuse and/or witnessing domestic violence (EM group, n = 58) or had no history of maltreatment or axis I disorders (n = 58). The main outcome measures consisted of the gray matter volume of lobule I as measured by manual tracing, number and type of alcoholic beverages consumed during a drinking session, number of sessions per month, and monthly drug use, along with family history of drug and alcohol abuse. Lingula thickness was not attenuated by alcohol use or maltreatment history. However, increased lingula thickness was associated with greater consumption of drugs and hard liquor, particularly in physically maltreated subjects who consumed 2.5- and 2.7-fold more alcohol and used drugs 6.1- and 7.8-fold more frequently than controls or EM subjects, respectively. In conclusion, physical maltreatment was observed to interact with cerebellar morphology resulting in a strong association with alcohol and substance use. Lingula thickness may represent a novel, experientially sensitive, phenotypic risk factor for enhanced alcohol and drug use that perhaps modulates sensitivity to these agents.     

Short-course whole-brain radiotherapy (WBRT) for brain metastases due to small-cell lung cancer (SCLC)

Objective

Many patients with brain metastases due to SCLC have a poor survival prognosis. The most common treatment is whole-brain radiotherapy (WBRT). This retrospective study compares short-course WBRT with 5 × 4 Gy in 1 week to standard WBRT with 10 × 3 Gy in 2 weeks.

Methods

Forty-four SCLC patients receiving WBRT with 5 × 4 Gy were compared to 102 patients receiving 10 × 3 Gy for survival (OS) and local (intracerebral) control (LC). Seven further potential prognostic factors were investigated: age, gender, Karnofsky Performance Score (KPS), number of brain metastases, extracerebral metastases, interval from tumor diagnosis to WBRT, RPA (Recursive Partitioning Analysis) class.

Results

After 5 × 4 Gy, 12-month OS was 15%, versus 22% after 10 × 3 Gy (p = 0.69). On multivariate analysis, improved OS was associated with age ≤60 years (p = 0.013), KPS ≥70 (p < 0.001), <4 brain metastases (p = 0.011), and RPA class 1 (p < 0.001). 12-month LC was 34% after 5 × 4 Gy versus 25% after 10 × 3 Gy (p = 0.32). On multivariate analysis, improved LC was associated with KPS ≥70 (p < 0.001), <4 brain metastases (p = 0.027), and RPA class 1 (p < 0.001).

Conclusion

In patients with brain metastases due to SCLC, short-course WBRT with 5 × 4 Gy provided similar outcomes as 10 × 3 Gy and appears preferable, particularly for patients with poor estimated survival.     

XbaI polymorphism of the estrogen receptor alpha gene influences the effect of raloxifene on the endothelial function

Objectives

Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activation. We explored if polymorphisms of the ESR1 modify the effects of 6 months raloxifene treatment on endothelial function.

Methods

A total of 53 postmenopausal women, mean age 59.7 ± 6.2, finished the prospective clinical trial. The PvuII, XbaI, and P325P polymorphisms of the ESR1 gene were analyzed. In all subjects endothelium-dependent flow mediated dilatation (FMD) and cell adhesion molecules (CAM) ICAM-1, VCAM-1 and E-selectin were measured before and after 6 months of raloxifene treatment.

Results

There was no difference in FMD between the ESR1 genotypes, at baseline. After raloxifene treatment, the FMD was significantly greater in subjects with XX genotype of XbaI polymorphism compared to xx (p = 0.03) and borderline greater when compared to Xx genotype (p = 0.053). The FMD increased significantly with raloxifene treatment in women with Xx genotype of XbaI and Pp genotype of PvuII polymorphisms (p = 0.027 and p = 0.034, respectively). The P325P polymorphism did not influence the FMD after raloxifene. None of the ESR1 gene polymorphisms had any impact on the levels of CAM before or after the treatment. When analysing the whole group, a significant decrease in E-selectin (p < 0.001) and a small increase in ICAM-1 levels (p = 0.029) was observed with raloxifene treatment, but no influence on VCAM-1 levels or FMD overall was seen.

Conclusion

Our data suggest that XbaI and possibly PvuII polymorphisms of the ESR1 gene influence the impact of raloxifene treatment on endothelial function. This effect could be of pharmacogenomic and clinical importance.