Hypersensitivity reactions to anticancer agents: Data mining of the public version of the FDA adverse event reporting system, AERS

Background

Cancer-testis antigens (CTAs) are suitable targets for cancer-specific immunotherapy. The aim of the study is to investigate the expression of CTAs in intrahepatic cholagiocarcinoma (IHCC) and evaluate their potential therapeutic values.

Methods

Eighty-nine IHCC patients were retrospectively assessed for their expression of CTAs and HLA Class I by immunohistochemistry using the following antibodies: MA454 recognizing MAGE-A1, 57B recognizing multiple MAGE-A (MAGE-A3/A4), E978 recognizing NY-ESO-1, and EMR8-5 recognizing HLA class I. The clinicopathological and prognostic significance of individual CTA markers and their combination were further evaluated.

Results

The expression rates of MAGE-A1, MAGE-A3/4 and NY-ESO-1 were 29.2%, 27.0% and 22.5%, respectively. The concomitant expression of CTAs and HLA class I antigen was observed in 33.7% of the IHCC tumors. We found that positive MAGE-3/4 expression correlated with larger tumor size (≥ 5 cm), tumor recurrence and poor prognosis. Moreover, we identified 52 cases (58.4%) of IHCC patients with at least one CTA marker expression, and this subgroup displayed a higher frequency of larger tumor size and a shorter survival than the other cases. Furthermore, expression of at least one CTA marker was also an independent prognostic factor in patients with IHCC.

Conclusion

Our data suggest that specific immunotherapy targeted CTAs might be a novel treatment option for IHCC patients.     

Use of imaging in the follow-up of workers exposed to lung carcinogens: practices in occupational medicine and its determinants

We studied occupational physicians' (OPs) practices of referrals for imaging of workers occupationally exposed to lung/pleural carcinogens and the factors associated with them. This cross-sectional telephone survey of 379 OPs practicing in Southeastern France showed that 81% of them referred exposed patients for chest radiographs, 33.5% for computed tomography (CT), and 16.1% for neither. Making no referral was positively associated with believing cancer risks are lower in one's own geographic sector than elsewhere and negatively associated with keeping employee risk records up-to-date. Referrals for CT were positively associated with work at in-house occupational health services (OHS), and completing employee exposure histories often/always. Both the OHS type and factors that may shape OPs' awareness of cancer risks in their sector appear to influence imaging referral practices. Occupational physicians would benefit from guidelines clarifying benefits and risks associated with imaging in such patients. An effort to harmonize regulatory provisions and guidelines also appears necessary.     

Definitive and palliative radiotherapy for cervix cancer in the elderly

The elderly population is increasing in number. Aggressive therapeutic intervention in this patient group may not always be possible because of age, the presence of co-morbidity, and poor functional status. Hence, individualized management of cervix cancer (CC) in the elderly is often practiced. Because of the preceding consideration, the cases of 79 women 65 years of age and older with CC treated with radiation over the last 20 years were reviewed. The cases were classified into two groups--those who were aggressively irradiated (group 1: 43 patients) and those managed less intensively for palliation (group 2: 36 patients). Local tumor control, complications, and survival were assessed. There were fewer extremely aged (> or = 75 years of age) women (p = 0.006) with advanced stage disease (p = 0.012) in group 1 than in group 2. Also, group 1 women experienced fewer treatment failures (p < 0.0003) and more of them were alive and well at last follow-up (p < 0.005) than those from group 2. The median survival periods for groups 1 and 2 were 60 months and 11 months, respectively (p < 0.0001); the corresponding 5-year crude survival rates were 54% and 19%, respectively (p = 0.002). Two women required remedial surgery for bowel obstruction/perforation after irradiation, and one patient sustained chronic radiation cystitis.     

Complementary and contrasting roles of NK cells and T cells in pediatric umbilical cord blood transplantation

UCBT has been used for almost 25 years to treat a variety of malignant and nonmalignant childhood diseases. The biological properties of NK cells and T cells and their implication in engraftment, immune reconstitution, OIs, leukemic relapse, and GvHD have been explored in the context of UCBT. These studies have established that lymphocytes have a major impact on the outcome of UCBT and that NK cells and T cells play complementary and contrasting roles in immune reconstitution and the GvL effect. Therefore, novel strategies to improve the outcome of UCBT recipients, including immunotherapeutic regimens, should be based on key immunologic features of UCB T lymphocytes and NK cells.     

DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process

Prostate cancer metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer, frequently resulting in significant morbidity and mortality. As the underlying mechanisms are not fully characterized, understanding the biological mechanisms that govern prostate cancer metastases to bone at the molecular level should lead to the determination of new potential therapeutic targets. Receptor activator of NFkappaB ligand (RANKL)/RANK/Osteoprotegerin (OPG) are the key regulators of bone metabolism both in normal and pathological condition, including prostate cancer bone metastases. In the present study, we demonstrated that human prostate cancer cell lines, DU145 and PC3 express biologically functional RANK. Indeed, soluble human RANKL (shRANKL, 100 ng/ml) treatment induced ERK 1/2, p38 and IkappaB phosphorylations in these cells. shRANKL administration also promoted DU145 and PC3 prostate cancer cell invasion in vitro. Whereas human OPG (hOPG) administration alone (100 ng/ml) had no marked effect, combined association of both agents abolished the RANKL-induced DU145 cell invasion. As RANKL had no direct effect on DU145 cell proliferation, the observed effects were indeed related to RANKL-induced cell migration. DU145 human prostate cancer cells promoted osteoclastogenesis of osteoclast precursors generated from mouse bone marrow. Moreover, DU145 cells produced soluble factor(s) that up-regulate the proliferation of MC3T3-E1 pre-osteoblasts through the activation of the ERK 1/2 and STAT3 signal transduction pathways. This stimulation of pre-osteoblast proliferation resulted in an increased local RANKL expression that can activate both osteoclasts/osteoclast precursors and prostate cancer cells, thus facilitating prostate cancer metastasis development in bone. We confirm that RANKL is a factor that facilitates metastasis to bone by acting as an activator of both osteoclasts and RANK-positive prostate cancer cells in our model. Furthermore, the present study provides the evidence that blocking RANKL-RANK interaction offer new therapeutic approach not only at the level of bone resorbing cells, but also by interfering with RANK-positive prostate cancer cells in the prostate cancer bone metastasis development.     

Interactions of infectious symptoms and modifiable risk factors in sudden infant death syndrome. The Nordic Epidemiological SIDS study

The aim of the study was to investigate the effect of infection on sudden infant death syndrome (SIDS) and to analyse whether modifiable risk factors of SIDS, prone sleeping, covered head and smoking act as effect modifiers. In a consecutive multicentre case-control study of SIDS in Denmark, Norway and Sweden, questionnaires on potential risk factors for SIDS were completed by parents of SIDS victims, and for at least two controls matched for gender, age and place of birth. All SIDS cases were verified by an autopsy. The study comprised 244 SIDS cases and 869 controls, analysed by conditional logistic regression. Significantly more cases than controls presenting symptoms of infectious diseases during the last week and/or last day were treated with antibiotics and had been seen by a physician. The finding is consistent with the hypothesis of an infectious mechanism in SIDS induced by local microorganism growth and toxin or cytokine production, and also adds further support to a possible association between infection and SIDS by loss of protective mechanisms, such as arousal. The risk of SIDS among infants with the combined presence of infectious symptoms and either of the other modifiable risk factors, prone sleeping, head covered or parental smoking, was far greater than the sum of each individual factor. These risk factors thus modify the dangerousness of infection in infancy.     

Defects in CD54 and CD86 up-regulation by plasmacytoid dendritic cells during pregnancy

Physiological modulation of the immune system is required for foetal tolerance during pregnancy. However, this immune regulation might lead to impaired self-defence against pathogens. Indeed, pregnant women are more susceptible to newly encountered viruses comparing to non-pregnant women, as exemplified by the prevalence of severe complications in pregnant women infected with the pandemic influenza virus in 2009. Plasmacytoid dendritic cells (pDCs) are specialized dendritic cells that recognise viral antigens and initiate both innate and adaptive immune responses. We therefore sought to determine whether the number and/or the functions of peripheral blood pDCs are regulated during pregnancy. pDC maturation and interferon (IFN)-α production were analysed in response to Toll-like receptor (TLR) stimulation of peripheral blood mononuclear cells from pregnant and non-pregnant women. Our results reveal that pDC frequency is slightly decreased, while the IFN-α production in response to TLR stimulation increases during pregnancy. Interestingly, the up-regulation of the co-stimulatory receptors CD54 (ICAM1) and CD86 is significantly decreased in pDCs from pregnant women as compared to controls, suggesting a possible impact on T-cell responses. In conclusion, we propose that the modulation of CD54 and CD86 expression on peripheral blood pDCs during pregnancy might decrease the initiation of adaptive antiviral immune responses.