Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.     

Safety and tolerability of lamotrigine for bipolar disorder.

Tolerability and safety are important considerations in optimising pharmacotherapy for bipolar disorder. This paper reviews the tolerability and safety of lamotrigine, an anticonvulsant recommended in the 2002 American Psychiatric Association guidelines as a first-line treatment for acute depression in bipolar disorder and one of several options for maintenance therapy. This paper reviews the tolerability and safety of lamotrigine using data available from a large programme of eight placebo-controlled clinical trials of lamotrigine enrolling a total of nearly 1800 patients with bipolar disorder. This review is the first to collate all the safety information from these clinical trials, including data from four unpublished studies. The results these trials in which 827 patients with bipolar disorder were given lamotrigine as monotherapy or adjunctive therapy for up to 18 months for a total of 280 patient-years of exposure demonstrated that lamotrigine is well-tolerated with an adverse-event profile generally comparable with that of placebo. The most common adverse event with lamotrigine was headache. Lamotrigine did not appear to destabilise mood and was not associated with sexual adverse effects, weight gain, or withdrawal symptoms. Few patients experienced serious adverse events with lamotrigine, and the incidence of withdrawals because of adverse events was low. Serious rash occurred rarely (0.1% incidence) in the clinical development programme including both controlled and uncontrolled clinical trials. These findings - considered in the context of data showing lamotrigine to be effective for bipolar depression - establish lamotrigine as a well-tolerated addition to the psychotropic armamentarium.     

T cell vaccinology: Exploring the known unknowns

The objective of modern vaccine development is the safe generation of protective long-term immune memory, both prophylactic and therapeutic. Live attenuated vaccines generate potent cellular and humoral immunity 0005, 0010 and 0015, but numerous problems exist with these vaccines, ranging from production and storage issues to adverse reactions and reversion to virulence. Subunit vaccines are safer, more stable, and more amenable to mass production. However the protection they produce is frequently inferior to live attenuated vaccines and is typically confined to humoral, and not cellular immunity. Unfortunately, there are presently no subunit vaccines available clinically that are effective at eliciting cellular responses let alone cellular memory [4]. This article will provide and overview of areas of investigation that we see as important for the development of vaccines with the capacity to induce robust and enduring cellular immune responses.     

The treatment and care of mentally ill offenders in Victoria,Australia

This article explains, examines and evaluates the effectiveness of the legislative scheme for the provision of psychiatric services to forensic patients in Victoria.¹ The term “forensic patients” is used to describe people who have mental illness and who have come into contact with the criminal justice system.² This includes people who receive treatment for mental illness in jail, in psychiatric in‐patient services, or in the community. New initiatives were introduced by Victoria's Mental Health Act in 1986 and 1990, and in the Sentencing Act 1991.³ The aims of the reforms are to provide the best possible care and treatment for people with mental illness, and to give sentencing judges and magistrates a range of dispositional options when dealing with mentally ill people who appear before the criminal courts. This encompasses the often conflicting aims of providing treatment and care, and protecting the public. It also involves a number of agencies whose roles are explained and examined.     

Community-Dwelling,Older Women's Perspectives on Therapeutic Life Review: A Qualitative Analysis

The purpose of this study was to elicit the participants' perspective of a Therapeutic Life Review intervention program delivered by a home care worker. Following the intervention by the home care worker, 13 of the 14 older women receiving home care services were interviewed to examine their experiences. Qualitative data analysis revealed five themes: (1) Someone was there to listen to my story, (2) It was a special time, (3) A valued interaction with the home care worker developed, (4) Remembering was meaningful and pleasurable, and (5) Integration with one's lived experiences was healing. Three case scenarios illustrate the lives of these older women.     

Consensus on melanonychia nail plate dermoscopy

This statement, focused on melanonychia and nail plate dermoscopy, is intended to guide medical professionals working with melanonychia and to assist choosing appropriate management for melanonychia patients. The International Study Group on Melanonychia was founded in 2007 and currently has 30 members, including nail experts and dermatopathologists with special expertise in nails. The need for common definitions of nail plate dermoscopy was addressed during the Second Meeting of this Group held in February 2008. Prior to this meeting and to date (2010) there have been no evidence-based guidelines on the use of dermoscopy in the management of nail pigmentation.     

Red Blood Cell Alloimmunization Mitigation Strategies

Hemolytic transfusion reactions due to red blood cell (RBC) alloantibodies are a leading cause of transfusion-associated death. In addition to reported deaths, RBC alloantibodies also cause significant morbidity in the form of delayed hemolytic transfusion reactions. These alloantibodies may also cause morbidity in the form of anemia, with compatible RBC units at times being unable to be located for highly alloimmunized patients, or in the form of hemolytic disease of the newborn. Thus, preventing RBC alloantibodies from developing in the first place, or mitigating the dangers of existing RBC alloantibodies, would decrease transfusion-associated morbidity and mortality. A number of human studies have evaluated the impact on RBC alloimmunization rates of providing partially phenotypically or genotypically matched RBCs for transfusion, and a number of animal studies have evaluated the impact of single variables on RBC alloimmunization. The goal of this review is to take a comprehensive look at existing human and animal data on RBC alloimmunization, focusing on strategies that may mitigate this serious hazard of transfusion. Potential factors that impact initial RBC alloimmunization, on both the donor and recipient sides, will be discussed. These factors include, but are not limited to, exposure to the antigen and an ability of the recipient's immune system to present that antigen. Beyond these basic factors, coexisting “danger signals,” which may come from the donor unit itself or which may be present in the recipient, also likely play a role in determining which transfusion recipients may become alloimmunized after RBC antigen exposure. In addition, to better understanding factors that influence the development of RBC alloantibodies, this review will also briefly discuss strategies to decrease the dangers of existing RBC alloantibodies.