The epidermal growth factor receptor (EGFR) and its ligands figure prominently in the biology of gliomas, the most common tumors of the central nervous system (CNS). Although their histologic classification seems to be straightforward, these tumors constitute a heterogeneous class of related neoplasms. They are associated with a variety of molecular abnormalities affecting signal transduction, transcription factors, apoptosis, angiogensesis, and the extracellular matrix. Under normal conditions, these same interacting factors drive CNS growth and development. We are now recognizing the diverse molecular genetic heterogeneity that underlies tumors classified histologically into three distinct grades. This recognition is leading to new therapeutic strategies targeted directly at specific molecular subtypes. In this article, we will review the role of EGFR and related molecular pathways in the genesis of the normal CNS and their relationship to glial tumorigenesis. We will discuss barriers to effective treatment as they relate to anatomic specialization of the CNS. We will also consider the ways in which specific EGFR alterations common to glioma reflect outcomes following treatment with targeted therapies, all with an eye towards applying this understanding to improved patient outcomes. Epidermal growth factor (EGF) was identified by embryologistStanley Cohen in the early 1960s and its receptor (EGFR) was identified a decade later (1, 2). During that time and in the decades that followed, a family of related factors and their receptors were identified. The complex intracellular effects that follow activation of these receptors were subsequently elaborated. Together, this would prove to be of critical importance in our understanding of both normal growth and development and neoplastic transformation. This review will focus on the role of these receptor-ligand interactions in primary brain tumor biology. We will briefly discuss their importance in the development of normal brain and the implication of those roles for tumorigenesis. Following a review of specific abnormalities in brain tumors, we will conclude with a summary of brain tumor therapies that include EGFR-mediated signaling in their rationale. Receptor-Ligand InteractionsThe EGFR was the first of the human EGF receptor (HER) family members to be discovered. The HER family proteins are members of the receptor tyrosine kinase (RTK) superfamily. The platelet-derived growth factor receptor (PDGFR), another RTK family member, is also important in brain tumor biology. The ligands for the HER family receptors are also diverse. They include the EGF family and the structurally related neuregulin family. Both are produced by many cell types, including neurons and glia. All of the ligands function via autocrine and/ or paracrine signaling. The EGF family includes EGF, transforming growth factor-a (TGF-a), heparin-binding EGF, amphiregulin, betacellulin, and epiregulin (3).The neuregulin (NRG) family consists of the protein products derived from the alternat...
The subventricular zone (SVZ) lines the lateral ventricles and represents the origin of neural and some cancer stem cells. Tumors contacting the SVZ may be more invasive with higher potential to recruit migratory progenitor cells. Our specific aim was to determine whether SVZ involvement in glioblastoma multiforme (GBM) is associated with a higher recurrence rate and shorter overall survival. MR imaging and clinical data from 91 patients with GBM treated at our institution were retrospectively reviewed. Tumors were classified as type I if the contrast-enhancing lesion contacted both the SVZ and cortex on pre-operative MRI, type II if only the SVZ was involved, type III if only cortex was involved, and type IV if the lesion did not contact either the SVZ or cortex. Progression-free survival (PFS) and overall survival were estimated based on Kaplan-Meier calculations. When comparing type I tumors with types II-IV, only 39% of patients with type I tumors were free of recurrence and alive at 6 months, significantly fewer than for all other types combined (67%; P = .01). PFS at 6 months was also less, at only 47% among patients with SVZ-positive tumors, compared with 69% in the SVZ-negative group (P = .002). Patients with SVZ involvement also demonstrated a more rapid time to progression, compared with those not involving the SVZ (P = .003). Patients with GBM involving the SVZ have decreased overall survival and PFS, which may have prognostic and therapeutic implications.
Purpose To evaluate optimal contrast kinetics thresholds for measuring functional tumor volume (FTV) by breast magnetic resonance imaging (MRI) for assessment of recurrence-free survival (RFS). Materials and Methods In this Institutional Review Board (IRB)-approved retrospective study of 64 patients (ages 29–72, median age of 48.6) undergoing neoadjuvant chemotherapy (NACT) for breast cancer, all patients underwent pre-MRI1 and postchemotherapy MRI4 of the breast. Tumor was defined as voxels meeting thresholds for early percent enhancement (PEthresh) and early-to-late signal enhancement ratio (SERthresh); and FTV (PEthresh, SERthresh) by summing all voxels meeting threshold criteria and minimum connectivity requirements. Ranges of PEthresh from 50% to 220% and SERthresh from 0.0 to 2.0 were evaluated. A Cox proportional hazard model determined associations between change in FTV over treatment and RFS at different PE and SER thresholds. Results The plot of hazard ratios for change in FTV from MRI1 to MRI4 showed a broad peak with the maximum hazard ratio and highest significance occurring at PE threshold of 70% and SER threshold of 1.0 (hazard ratio = 8.71, 95% confidence interval 2.86–25.5, P < 0.00015), indicating optimal model fit. Conclusion Enhancement thresholds affect the ability of MRI tumor volume to predict RFS. The value is robust over a wide range of thresholds, supporting the use of FTV as a biomarker.
Small-cell lung cancer (SCLC) is an aggressive, malignant neoplasm with a 5-year survival of less than 10%. This poor survival rate is related to a high propensity for recurrence and a high rate of metastases. Metastases initially occur in the lymph nodes and thereafter in other organs such as the lung itself, liver, adrenal glands, brain, bone, and bone marrow. The mechanisms of metastases have been better understood recently and are described in this review. Receptor tyrosine kinases (RTKs) have been identified as important therapeutic targets in non-small-cell lung cancer (such as the EGF-receptor). We have begun to identify RTKs in SCLC and have shown that c-Kit and c-Met are expressed and functional in SCLC. RTKs have also been shown to be important in the metastasis of cancer cells. The roles of RTKs in the mechanism of metastasis are detailed in this review, with special emphasis on downstream signal transduction from RTK signaling.
Differences in ethnic background appear to influence women's understanding of mammography, compliance with recall, and preference for early detection of breast cancer.
We report two cases of invasive lobular carcinoma of the breast that were initially missed on first mammographic interpretation because of an uncommon, easily overlooked, and unreported imaging presentation. The abnormality in the cases manifested as an apparent decrease in breast glandular tissue volume when compared with the patients' previous mammograms, observed as “shrinking” of the breast on mammography. Invasive lobular carcinoma is considered one of the most difficult subtypes of breast cancer to identify on mammography because the changes that occur are often nonspecific and subtle. Microcalcifications that are usually associated with breast masses on imaging are rarely seen in this subtype of breast cancer. Although magnetic resonance imaging and computer-aided detection have somewhat improved the detection of invasive lobular carcinoma, radiologic and clinical detection remains a challenge.
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