68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors

Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same NET patients.

Activation of the unfolded protein response in human acute myeloid leukemia

There is accumulating evidence for the involvement of the unfolded protein response (UPR) in the pathogenesis of many tumor types in humans. This is particularly the case in rapidly growing solid tumors in which the demand for oxygen and nutrients can exceed the supply until new tumor-initiated blood vessels are formed. In contrast, the role of the UPR during leukemogenesis remains largely unknown. Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disorder characterized by the accumulation of somatic mutations in hematopoietic progenitor cells that alter the physiological regulation of self-renewal, survival, proliferation, or differentiation. The CCAAT/enhancer-binding protein alpha (CEBPA) gene is a key myeloid transcription factor and a frequent target for disruption in AML. In particular, translation of CEBPA mRNA can be specifically blocked by binding of the chaperone calreticulin (CALR), a well-established effector of the UPR, to a stem loop structure within the 5' region of the CEBPA mRNA. The relevance of this mechanism was first elucidated in certain AML subtypes carrying the gene rearrangements t(3;21) or inv(16). In our recent work, we could demonstrate the induction of key effectors of the UPR in leukemic cells of AML patients comprising all subtypes (according to the French-American-British (FAB) classification for human AML). The formation of the spliced variant of the X-box binding protein (XBP1s) was detectable in 17.4% (17 of 105) of AML patients. Consistent with an activated UPR, this group had significantly increased expression of the UPR target genes CALR, the 78 kDa glucose-regulated protein (GRP78), and the CCAAT/enhancer-binding protein homologous protein (CHOP). Consistently, in vitro studies confirmed that calreticulin expression was upregulated via activation of the ATF6 pathway in myeloid leukemic cells. As a consequence, CEBPA protein expression was inhibited in vitro as well as in leukemic cells from patients with activated UPR. We therefore propose a model of the UPR being involved in leukemogenesis through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation and cell-cycle deregulation which represent key features of the leukemic phenotype. From a more clinical point of view, the presence of activated UPR in AML patient samples was found to be associated with a favorable disease course.

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX

The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed.

Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors

Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.

High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade

Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sézary syndrome, and 13 non-mycosis fungoides/Sézary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS(G13D) mutation; one Sézary syndrome and one CD30(+) CTCL harbored a NRAS(Q61K) amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRAS(Q61K) mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRAS(Q61K) mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors.

[Sarcomas and mixed mesodermal tumors of the uterus]

Malignant mesodermal tumors of the uterus are an inhomogenous group of uterine malignancies with different pathogenesis, clinical presentation and prognosis. These rare tumors represent approximately 1 % of all uterine malignancies. The aggressive carcinosarcomas or mixed muellerian tumors are defined by mixed malignant epithelial and malignant mesodermal histopathology and are of the same precursor cell origin like endometrial cancer. Thus, carcinosarcomas were reclassified by the FIGO as an aggressive type of endometrial cancer and treated like type II endometrial cancer. Adenosarcomas are also mixed tumors with benign epithelial proliferation and malignant mesodermal cell growth, have a good prognosis and represent less than 5 % of all mesodermal uterine malignancies. Besides carcinosarcomas, the pure mesodermal leiomyosarcomas are the most common mesodermal malignancies. Patients with leiomyosarcamos are usually perimenopausal, and although more than half of the patients present with symptoms, diagnosis occurs incidentally in most cases in final histopathologic workup of an excised putative myoma or uterus. Adequate anamnesis, gynecologic examination and careful imaging by transvaginal ultrasound in the preoperative setting might hint to correct differential diagnosis in many cases. Overall the prognosis of uterine leiomyomas is poor. Malignancies of the endometrial stroma are very rare and divided in two subgroups, the mostly estrogen receptor positive endometrial stromal sarcoma, which occur preferably in premenopausal women and show a favorable prognosis, and the very aggressive undifferentiated endometrial sarcomas. The more rare undifferentiated endometrial sarcomas occur in postmenopausal women and most patients die in the first two years after diagnosis. Risk stratification of preoperative differential diagnosis requires improvements and the correct histopathologic workup of mesodermal uterine malignancies is still a challenge for pathologists.

Xenotransplantation of cryopreserved ovarian tissue from patients with ovarian tumors into SCID mice--no evidence of malignant cell contamination

This study examined the possible presence of malignant cells in ovarian cortex from patients with ovarian tumors after xenografting of the ovarian tissue into severe combined immunodeficiency mice. None of the mice presented symptoms of reintroduced malignancy nor did microscopic and immunohistochemical evaluation of the grafts raise any suspicion of residual malignant disease.

Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study

It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents.

Impact of random and systematic recall errors and selection bias in case--control studies on mobile phone use and brain tumors in adolescents (CEFALO study)

Whether the use of mobile phones is a risk factor for brain tumors in adolescents is currently being studied. Case--control studies investigating this possible relationship are prone to recall error and selection bias. We assessed the potential impact of random and systematic recall error and selection bias on odds ratios (ORs) by performing simulations based on real data from an ongoing case--control study of mobile phones and brain tumor risk in children and adolescents (CEFALO study). Simulations were conducted for two mobile phone exposure categories: regular and heavy use. Our choice of levels of recall error was guided by a validation study that compared objective network operator data with the self-reported amount of mobile phone use in CEFALO. In our validation study, cases overestimated their number of calls by 9% on average and controls by 34%. Cases also overestimated their duration of calls by 52% on average and controls by 163%. The participation rates in CEFALO were 83% for cases and 71% for controls. In a variety of scenarios, the combined impact of recall error and selection bias on the estimated ORs was complex. These simulations are useful for the interpretation of previous case-control studies on brain tumor and mobile phone use in adults as well as for the interpretation of future studies on adolescents.

Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo

Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo.

MR imaging of parotid tumors: typical lesion characteristics in MR imaging improve discrimination between benign and malignant disease

The surgical approach to parotid tumors is different for benign and malignant neoplasms, but the clinical symptoms do not correlate well with histology. Difficulties in tumor classification also arise in imaging modalities, in which sonography has the lowest and MR imaging, the highest accuracy. The purpose of this study was to review our experience using conventional MR imaging of the neck in the evaluation of parotid tumors and to evaluate which MR imaging findings are best able to predict malignant histology.

Identification of venous variants in the pineal region with three-dimensional preoperative magnetic resonance imaging navigation in patients harbouring tumors in this area: significance for surgical approach to the lesion

The purpose of this study was to identify the anatomy of pineal region venous complex using neuronavigation software when distorted by the presence of a space-occupying lesion and to describe the anatomical relationship between lesion and veins. Moreover we discuss its influence on the choice of the surgical strategy.

The phosphoinositide 3-kinase signaling pathway as a therapeutic target in grade IV brain tumors

Brain tumors comprise a wide variety of neoplasia classified according to their cellular origin and their morphological and histological characteristics. The transformed phenotype of brain tumor cells has been extensively studied in the past years, achieving a significant progress in our understanding of the molecular pathways leading to tumorigenesis. It has been reported that the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is frequently altered in grade IV brain tumors resulting in uncontrolled cell growth, survival, proliferation, angiogenesis, and migration. This aberrant activation can be explained by oncogenic mutations in key components of the pathway or through abnormalities in its regulation. These alterations include overexpression and mutations of receptor tyrosine kinases (RTKs), mutations and deletions of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene, encoding a lipid kinase that directly antagonized PI3K activity, and alterations in Ras signaling. Due to promising results of preclinical studies investigating the PI3K/AKT pathway in grade IV brain tumors like glioblastoma and medulloblastoma, the components of this pathway have emerged as promising therapeutic targets to treat these malignant brain tumors. Although an arsenal of small molecule inhibitors that target specific components of this signaling pathway is being developed, its successful application in the clinics remains a challenge. In this article we will review the molecular basis of the PI3K/AKT signaling pathway in malignant brain tumors, mainly focusing on glioblastoma and medulloblastoma, and we will further discuss the current status and potential of molecular targeted therapies.