Allergy and risk of hematologic malignancies: Associations and mechanisms

Increasing evidence indicates that a dysregulated immune system, as the one found in allergic disorders, can affect survival of tumor cells. A possible association between allergies and risk of hematologic malignancies has been examined in several epidemiological studies; however, results were not always consistent.     

The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo

BACKGROUND AND PURPOSE

The mechanisms of paraquat (PQ)-induced toxicity are poorly understood and PQ poisoning is often fatal due to a lack of effective antidotes. In this study we report the effects of N-[2-(2-methoxy-6H-dipyrido{2,3-a:3,2-e}pyrrolizin-11-yl)ethyl]-2-furamide (NMDPEF), a melatonin-related inhibitor of quinone oxidoreductase2 (QR2) on the toxicity of PQ in vitro & in vivo.

EXPERIMENTAL APPROACH

Prevention of PQ-induced toxicity was tested in different cells, including primary pneumocytes and astroglial U373 cells. Cell death and reactive oxygen species (ROS) were analysed by flow cytometry and fluorescent probes. QR2 silencing was achieved by lentiviral shRNAs. PQ (30 mg·kg⁻¹) and NMDPEF were administered i.p. to Wistar rats and animals were monitored for 28 days. PQ toxicity in the substantia nigra (SN) was tested by a localized microinfusion and electrocorticography. QR2 activity was measured by fluorimetry of N-benzyldihydronicotinamide oxidation.

KEY RESULTS

NMDPEF potently antagonized non-apoptotic PQ-induced cell death, ROS generation and inhibited cellular QR2 activity. In contrast, the cytoprotective effect of melatonin and apocynin was limited and transient compared with NMDPEF. Silencing of QR2 attenuated PQ-induced cell death and reduced the efficacy of NMDPEF. Significantly, NMDPEF (4.5 mg·kg⁻¹) potently antagonized PQ-induced systemic toxicity and animal mortality. Microinfusion of NMDPEF into SN prevented severe behavioural and electrocortical effects of PQ which correlated with inhibition of malondialdehyde accumulation in cells and tissues.

CONCLUSIONS AND IMPLICATIONS

NMDPEF protected against PQ-induced toxicity in vitro and in vivo, suggesting a key role for QR2 in the regulation of oxidative stress.

LINKED ARTICLE

This article is commented on by Baltazar et al., pp. 44–45 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02017.x     

Nanoparticles in oncology: the new theragnostic molecules

Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems such as nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover, cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently, nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapy and diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context of the current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and application of nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findings with respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recent prospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system and apoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drug discovery.     

Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study

BACKGROUND:

A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)‐positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood‐brain barrier, has been associated with this increased risk.

METHODS:

The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4‐year period between 2004 and 2007.

RESULTS:

A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow‐up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2‐negative patients and HER2‐positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2‐positive status and trastuzumab treatment, high Ki‐67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis.

CONCLUSIONS:

To the authors' knowledge, this is the first population‐based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2‐positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab‐based therapy may lead to an “unmasking” of CNS disease recurrence that would otherwise remain clinically silent before a patient's death. Cancer 2011. © 2010 American Cancer Society.     

A randomized phase II trial of ridaforolimus,dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

Purpose

To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.

Methods

This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS).

Results

Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81–1.72; P = 0.565). Grade 3–5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.

Conclusions

R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

     

Thymus hyperplasia after resolution of hypercortisolism in ACTH-dependent Cushing's syndrome: the importance of thymic vein catheterization

Thymic hyperplasia has been described after the resolution of hypercortisolism from several etiologies, causing great diagnostic dilemmas. We describe a case where the catheterization of the thymic vein was essential for the differential diagnosis of a thymic enlargement in an adrenalectomized patient with ACTH-dependent Cushing's syndrome. The patient was a 48-year-old female with clinical and laboratorial data suggesting Cushing's disease. She underwent a transsphenoidal surgery with no tumor visualization and no remission of the syndrome. Histopathological studies disclosed a normal pituitary. She underwent a bilateral adrenalectomy and 8 months later a chest CT showed an increase of left thymic lobe, which was previously non-existent. After a negative (111)In-pentetreotide scintigraphy, the patient underwent simultaneous and bilateral catheterism of the petrosus sinuses and catheterization of the thymic and inominate veins and no ACTH gradient was shown among the sites of collection. She did not undergo thoracotomy and a follow-up was established. During the evolution, there was a spontaneous regression of the thymic lesion 38 months after the diagnosis. The ACTH gradient during the catheterization of thymic vein was essential for the differential diagnosis of the thymic enlargement tumor after hypercortisolism resolution in ACTH-dependent Cushing's syndrome, especially in this case, where the ACTH source was occult, thus avoiding an invasive surgical procedure for a benign entity with spontaneous resolution.     

Lipomas of oral cavity: case reports with review of literature

Lipomas represent about 1 to 5% of all neoplasms of the oral cavity. Although relatively common, few large series of intraoral lipomas and its variants are seen in the literature. Therefore, the author presents the four cases of intra-oral lipoma with one case of histological variant of lipoma, the fibrolipoma. All lesions were removed surgically with the intra-oral approach and none showed recurrence.     

Osteosclerotic myeloma with spinal leptomeningitis and severe polyneuropathy: A case report

Osteosclerotic myeloma is a rare plasma cell disorder often associated with a polyneuropathy. We describe a young patient with progressive polyneuropathy associated with vertebral bone marrow lesions and unusual meningeal infiltration at cauda level. The diagnosis of osteosclerotic myeloma was confirmed by bone marrow biopsy findings including the chromosome 13q14 deletion in 37% of the cells. Leptomeningeal involvement was demonstrated by spine magnetic resonance imaging with gadolinium administration and fat-suppression technique.