Activity of Crizotinib (PF02341066), a Dual Mesenchymal-Epithelial Transition (MET) and Anaplastic Lymphoma Kinase (ALK) Inhibitor,in a Non-small Cell Lung Cancer Patient with De Novo MET Amplification

Crizotinib is a dual MET and ALK inhibitor. Currently, clinical development of crizotinib is focused primarily on ALK rearranged non-small cell lung cancer (NSCLC). Here we report an NSCLC patient with de novo MET amplification but no ALK rearrangement who achieved a rapid and durable response to crizotinib indicating is also a bona fide MET inhibitor.     

Asymptomatic profound sinus bradycardia (heart rate ≤45) in non-small cell lung cancer patients treated with crizotinib

Crizotinib, a dual MET/ALK inhibitor, is now in advanced clinical development for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We have observed several patients who developed profound but asymptomatic sinus bradycardia (HR ≤45) during the course of crizotinib treatment. Herein, we describe the clinical characteristics of three separate patients enrolled in the A8081001 trial (NCT00585195) who developed asymptomatic profound sinus bradycardia with their accompanying electrocardiogram tracings.     

Small cell lung cancer

Small cell lung cancer accounts for approximately 15% of bronchogenic carcinomas. It is the cancer most commonly associated with various paraneoplastic syndromes, including the syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic cerebellar degeneration, and Lambert-Eaton myasthenic syndrome. Because of the high propensity of small cell lung cancer to metastasize early, surgery has a limited role as primary therapy. Although the disease is highly sensitive to chemotherapy and radiation, cure is difficult to achieve. The combination of platinum and etoposide is the accepted standard chemotherapeutic regimen. It is also the accepted standard therapy in combination with thoracic radiotherapy (TRT) for limited-stage disease. Adding TRT increases absolute survival by approximately 5% over chemotherapy alone. Thoracic radiotherapy administered concurrently with chemotherapy is more efficacious than sequential therapy. Furthermore, the survival benefit is greater if TRT is given early rather than late in the course of chemotherapy. Regardless of disease stage, no relevant survival benefit results from increased chemotherapy dose intensity or dose density, altered mode of administration (eg, alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy. Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival. In Japan and some other Asian countries, the combination of irinotecan and cisplatin is the standard chemotherapeutic regimen. Clinical trials using thalidomide, gefitinib, imatinib, temsirolimus, and farnesyltransferase inhibitors have not shown clinical benefit. Other novel agents such as bevacizumab have shown promising early results and are being evaluated in larger trials.     

Concordance of cancer patients’ function, symptoms, and supportive care needs

Purpose  

Although patients’ function, symptoms, and supportive care needs are obviously related, a better understanding of these relationships could improve patient management.     

Benign intrascrotal lipoblastoma in a child

Lipoblastoma of the scrotum is a rare clinical entity in children. It represents one of several differential diagnoses of scrotal masses that include malignant tumors. Surgical extirpation is mandatory. We present a rare case.     

Comparative case series of exostoses and osteomas of the internal auditory canal

Exostoses and osteomas are benign bony lesions of the auditory canal. Although common in the external auditory canal, they are rare and difficult to distinguish in the internal auditory canal (IAC). In this literature review and case presentation, we define radiologic and histologic criteria to differentiate exostoses from osteomas of the IAC. Two patients with exostoses and 1 patient with an osteoma of the IAC are described here. Patient 1 presented with disabling vertigo and was found to have bilateral exostoses with nerve impingement on the right. After removal of the right-sided exostoses via retrosigmoid craniotomy, the patient had complete resolution of her symptoms over 1 year. Patient 2 presented with bilateral pulsatile tinnitus and vertigo and was found to have bilateral IAC exostoses. Patient 3 presented with hearing loss and tinnitus, and a unilateral IAC osteoma was ultimately discovered. Because of the mild nature of their symptoms, patients 2 and 3 were managed without surgery. We show that IAC osteomas can be differentiated from exostoses by radiographic evidence of bone marrow in high-resolution computed tomography scans, or by the presence of fibrovascular channels on histologic analysis. Management of these rare entities is customized on the basis of patient symptoms.     

Evaluation of a web-based palliative care pain management module for housestaff

The objectives of this study were to determine internal medicine residents' knowledge of outpatient palliative care pain management, describe the association of level of training with knowledge, and evaluate the impact on knowledge of a web-based, interactive, evidence-based educational module. We developed the module using established educational principles, based on review of other educational materials, guidelines, and the medical literature. The module included pretest and post-test questions, case studies, didactic sections, and web links. Six hundred twelve housestaff in 35 training programs in 19 states completed the module during the 2005–2006 academic year (196 [32.0%] postgraduate year [PGY]-1, 200 [32.7%] PGY-2, and 216 [35.3%] PGY-3). The mean pretest score was 54.4% (range 31.1%–84.6%); scores were lowest for specific pain management knowledge questions, including appropriate titration of breakthrough opioid doses (mean 31.1% correct) and appropriate initial use of opioids (40.7% correct). Pretest scores were not significantly different by level of training (52.2% for PGY-1 and 56.7% for PGY-3). The mean post-test score was 72.8%, a statistically significant increase from the pretest overall (P < 0.001) and for seven of the 10 learning objectives (P < 0.001). These findings indicate that housestaff lacked knowledge in many areas of palliative care pain management, and knowledge did not increase with time spent in residency. The large increase in test scores after the module suggests that this may be an effective component of a comprehensive palliative care curriculum.     

LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer

Promoter hypermethylation is one of the common mechanisms leading to gene silencing in various human cancers. Using a combination of pharmacologic unmasking and microarray techniques, we identified 59 candidate hypermethylated genes, including LOXL1, a lysyl oxidase-like gene, in human bladder cancer cells. We further showed that LOXL1 and LOXL4 are commonly silenced genes in human bladder cancer cells, and this silence is predominantly related to promoter methylation. We also found LOXL1 and LOXL4 gene methylation and loss of expression in primary bladder tumors. In addition, somatic mutations were identified in LOXL4, but not in LOXL1 in bladder cancer. Moreover, reintroduction of LOXL1 and LOXL4 genes into human bladder cancer cells leads to a decrease of colony formation ability. Further studies indicated that the overexpression of LOXL1 and LOXL4 could antagonize Ras in activating the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, our current study suggests for the first time that lysyl oxidase-like genes can act as tumor suppressor genes and exert their functions through the inhibition of the Ras/ERK signaling pathway in human bladder cancer.     

Autism and Vaccination—The Current Evidence

PURPOSE.  The purpose of this article is to review relevant background literature regarding the evidence linking thimerosal-containing vaccine and the measles, mumps, and rubella vaccine to autism.
CONCLUSIONS.  Rigorous scientific studies have not identified links between autism and either thimerosal-containing vaccine or the measles, mumps, and rubella vaccine.
PRACTICE IMPLICATIONS.  Nurses are often in the position of providing advice regarding vaccines in their formal practice areas as well as in their daily lives. Families need current and credible evidence to make decisions for their children. Excellent vaccine information resources are available online.