Selection Of Patients For Therapy Research Articles

Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Medications for Attention Deficit/Hyperactivity Disorder

Over the past decade, concerns have been raised regarding the safety of a variety of psychotropic medications in children and adolescents, the appropriate selection of patients for therapy, and the indications for cardiovascular monitoring. In 1999, concerns over potential cardiovascular effects of psychotropic drugs, especially tricyclic antidepressants1,2 but including stimulants, prompted the American Heart Association (AHA) scientific statement “Cardiovascular Monitoring of Children and Adolescents Receiving Psychotropic Drugs.”3 At that time, no specific cardiovascular monitoring was recommended for the use of stimulant medications. Since that time, a constellation of circumstances have come together, necessitating a second look at this complicated issue. These circumstances include an increased awareness of the presence of attention deficit/hyperactivity disorder (ADHD) in the general population and in children with preexisting cardiac conditions; public concerns about the side effects and toxicities of medications, especially psychotropic medications in children; and regulatory factors and warnings issued by the US Food and Drug Administration (FDA) and by the pharmaceutical industry in response to the FDA. This writing group was convened in response to FDA concerns with regard to the safety of the ADHD drugs and with regard to the identification of children with underlying cardiovascular abnormalities. At a time when there is much discussion of the side effects of drugs and of the use of psychotropic drugs in children in the media and lay literature, it is particularly important for the medical profession to play a significant role in critically evaluating the use of stimulant medication in children, including those who may have undiagnosed heart disease and those who are known to have heart disease. The writing group for “Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Medications for Attention Deficit/Hyperactivity Disorder” reviewed the literature relevant to this topic since the last publication of the AHA scientific …

The Role of Complement Inhibition in PNH

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, debilitating, acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient. PNH results in the death of approximately half of affected individuals, mainly through thrombotic complications, and until recently had no specific therapy. In 2007 eculizumab, an anti-complement antibody targeting the C5 complement component was approved for PNH by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Eculizumab is very effective in the treatment of intravascular hemolysis and all its sequelae, which include most of the symptoms and complications of PNH. Eculizumab has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH, namely thrombosis and renal failure, should have a significant impact on survival. However, the development of eculizumab presents new challenges in PNH, such as how to avoid complications of therapy, how to overcome some of the problems associated with treatment and who to select for treatment, as only a proportion of patients with a PNH clone will benefit. This article will review the evidence behind the use of eculizumab in PNH, the effect it will have on the complications of the disease, the most appropriate selection of patients for therapy, the optimal management and the potential complications of the therapy.

Impact of Antibiotic Treatment on Bacterial Resistance Rates from Patients with Hospital-Acquired Infection

We assessed the impact of antibiotic administration prior to sample collection on the bacterial resistance rates from patients with nosocomial infection. Every individual susceptibility report was assessed in real time at the bedside of the patient by a team composed of infectious diseases and internal medicine specialists as well as clinical microbiologists for clinical significance and appropriateness of the specimen. The report also stated the kind, source and origin of the infection, history of administration of any antibiotic during the last month prior to sample collection. To evaluate the impact of previous antibiotic administration, resistance rates were calculated separately among the group of patients with and without history of antibiotic treatment. A crude univariate analysis was performed to assess the significance of the differences between groups for every species-antibiotic pair. Patients who had received ciprofloxacin showed significantly higher rates of Escherichia coli resistant to ciprofloxacin, broad-spectrum cephalosporins and gentamicin. A higher rate of methicillin-resistant Staphylococcus aureus was observed in patients who were given gentamicin. A stratified analysis showed that the previous antibiotic administration continued to be a risk factor for increased resistance rates regardless of the hospital ward or the source of the infection.This study demonstrates the influence of previous antibiotic administration on bacterial resistance rates although this fact is barely taken into account by the laboratory when constructing the cumulative susceptibility data. Real time clinical validation of the individual susceptibility reports, performed by a multidisciplinary team prior to the data entering, might be a suitable approach to get more reliable susceptibility rates to guide the rational selection of antimicrobial empirical therapy in patients with hospital-acquired infections who have been given antimicrobial treatment prior to specimen collection.

MR Imaging in Hyperthermia

There is growing clinical evidence that the combination of radiation therapy and hyperthermia, when delivered at moderate temperatures (40°–45°C) for sustained times (30–90 minutes), is of benefit with regard to palliative relief of cancer, tumor response, local control, and survival. Adequate measurement of the temperature distribution achieved with the hyperthermia is a key element in successful therapy. Thermal dosimetry, even invasive dosimetry, is a complex topic when applied to the heterogeneous tissue of a tumor and associated organ systems. Imaging in hyperthermia therapy is performed primarily for estimation and control of temperature. Magnetic resonance (MR) imaging has unique parameter dependences that make it possible to monitor hyperthermia therapy by detection of proton resonant frequency changes or diffusion coefficient changes. In addition, MR imaging can be used to assess vascular parameters that not only allow selection of suitable patients for therapy but may also allow demonstration of response to therapy. Finally, as the use of thermally sensitive liposomes for delivery of chemotherapeutic agents is developed, MR imaging may allow determination of local drug dose. © RSNA, 2007

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Hepatitis B Virus and HIV Coinfection: Results of a Survey on Treatment Practices and Recommendations for Therapy

The management of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection is challenged by the selection of patients for therapy, options for antiviral medications, and inconsistency in published treatment guidelines. A survey was sent to 161 sites in a multicenter HIV clinical trials group to assess HBV screening, criteria for initiation of therapy, and treatment choices for patients coinfected with HBV and HIV. Of 161 sites, 78 completed the survey (response rate, 48.4%). Of these sites, 98.7% screened for HBV infection, 86% vaccinated HIV-infected patients who were not immune to HBV infection, and 79% made treatment decisions without referral to a hepatologist or gastroenterologist. Treatment recommendations varied; 42% of the sites initiated therapy when patients' levels of alanine aminotransferase and aspartate aminotransferase were elevated and HBV DNA level was >10(5) copies/mL, whereas 49% of the sites initiated therapy in the presence of any detectable HBV DNA level. Antiviral treatment choices for patients who were not concurrently receiving antiretroviral therapy were lamivudine plus tenofovir, adefovir, or interferon. Patients concurrently receiving antiretroviral therapy received lamivudine plus tenofovir preferentially, followed by tenofovir plus emtricitabine, adefovir, or interferon. Ninety-one percent of the sites screened for hepatocellular carcinoma. The majority of HIV-infected patients were screened and vaccinated for HBV infection and underwent surveillance for hepatocellular carcinoma. Decisions regarding the performance of liver biopsy, threshold to initiate therapy, and criteria to discontinue therapy varied, reflecting inconsistencies in available treatment guidelines. Treatment decisions reflected concerns regarding future drug resistance in patients who are naive to antiretroviral therapy and the emergence of drug resistance in patients receiving antiretroviral therapy.

Standards and standardization in mastocytosis: Consensus Statements on Diagnostics, Treatment Recommendations and Response Criteria

Although a classification for mastocytosis and diagnostic criteria are available, there remains a need to define standards for the application of diagnostic tests, clinical evaluations, and treatment responses. To address these demands, leading experts discussed current issues and standards in mastocytosis in a Working Conference. The present article provides the resulting outcome with consensus statements, which focus on the appropriate application of clinical and laboratory tests, patient selection for interventional therapy, and the selection of appropriate drugs. In addition, treatment response criteria for the various clinical conditions, disease-specific symptoms, and specific pathologies are provided. Resulting recommendations and algorithms should greatly facilitate the management of patients with mastocytosis in clinical practice, selection of patients for therapies, and the conduct of clinical trials.

ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib

Abnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recently approved for pancreatic cancer treatment, but there are no reliable predictors of patient response. Expression of additional ErbB receptors seems to influence tumor response to EGFR-targeted therapy. We analyzed the influence of ErbB3 expression on pancreatic cancer cell response to erlotinib treatment. Proliferation assays of five human pancreatic cancer cell lines were performed following treatment with erlotinib. Expression and phosphorylation profiles of ErbB receptors and downstream adaptor protein (Akt, ERK1/2, STAT3, mTOR) were evaluated following stimulation with EGF or neuregulin-β. The formation of EGFR homodimers and EGFR-ErbB3 heterodimers, necessary to enable ErbB3 downstream signaling, was demonstrated by chemical cross-linking assays. The effects of RNA inhibition of ErbB3 on sensitivity to erlotinib treatment were evaluated in AsPC-1 pancreatic cancer cells. Erlotinib inhibited Akt phosphorylation and proliferation of all the ErbB3-expressing cell lines but did not affect mTOR activation. Cross-linking studies confirmed the presence of EGFR-ErbB3 heterodimers in pancreatic cancer cells. Only the ErbB3-deficient MIA PaCa-2 cells displayed persistent Akt activation and ongoing proliferation in spite of erlotinib treatment. siRNA–mediated inhibition of ErbB3 expression in AsPC-1 cells resulted in acquired resistance to erlotinib treatment. Pancreatic cancer cells which lack ErbB3 do not display activation of the ErbB3-PI3K-Akt cascade induced by EGFR/ErbB3 heterodimers and become less critically dependent on EGFR signaling and therefore resistant to erlotinib. Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted therapy patient selection.

Molecular Tumour Profiling for Detection of Biomarkers in Renal Cell Tumours

Objectives For renal cell tumours, biomarkers for diagnosis, prognostic evaluation, and therapy management are badly needed. This paper describes the development of new biomarkers for clinical use based on molecular tumour profiling of renal tumours. Methods High-throughput techniques for DNA, RNA, and protein analysis, as well as conventional comparative genomic hybridisation and immunochemistry, were used for complex characterisation of specific subtypes of renal cell tumours. Furthermore, ProteinChip technology was performed on serum samples to identify specific biomarkers useful for detection and monitoring of patients. Results On the basis of the specific genetic pattern of each subtype of renal cell tumours, a genetic test for routine diagnostics was developed. Furthermore, expression profiling resulted in a new tumour marker for clear-cell renal cell carcinoma (RCC): CD70. Specific serum protein profiles of RCC patients were defined by performing protein analysis of serum samples, and serum amyloid A1 (SAA1) was identified as a specific serum marker of clear-cell RCC. Protein analysis of tumour tissue and serum is helpful for selection of patients for therapy and for therapy monitoring. Conclusions Ongoing studies on molecular and cellular biology show that differentiation between RCC subtypes with different prognosis, as well as therapeutic options and response rates, seems possible. Furthermore, on the basis of molecular profiles of tumour tissues and body fluids, development of specific therapies and selection for each individual patient become possible.

Nectin-1 Is a Marker of Thyroid Cancer Sensitivity to Herpes Oncolytic Therapy

The prognosis for patients diagnosed with anaplastic thyroid cancer is dismal, with a median survival time of only 6 months. Novel therapies are needed for these and other thyroid cancers that are refractory to conventional therapy. Our goals were to assess the ability of an attenuated, replication-competent, oncolytic herpes virus (NV1023) to enter and lyse human thyroid cancers and determine whether herpes simplex virus receptor expression is a determinant of NV1023 efficacy. A panel of 12 human thyroid cancer cell lines including anaplastic, medullary, follicular, and papillary cancers were exposed to NV1023 and assessed for susceptibility to viral entry and oncolysis. The expression of herpes simplex virus glycoprotein D receptors nectin-1 and herpes virus entry mediator was assessed by quantitative fluorescence-activated cell sorter and correlated with NV1023 entry and oncolysis. There was significant variation in the ability of NV1023 to enter thyroid cancer cells as measured by lacZ expression. Thyroid cancer nectin-1 expression correlated strongly with NV1023 entry. Nectin-1 transfections and antibody receptor blocking studies validated the importance of nectin-1 for NV1023 entry. Follicular cancers were least sensitive to NV1023 oncolysis. All anaplastic, medullary, and papillary cancers tested exhibited greater than 85% cytotoxicity 7 d after exposure to NV1023 at multiplicity of infection 1, although oncolysis was variable at multiplicity of infection 0.01. Significant correlations between nectin-1 expression and NV1023 oncolysis were identified using Pearson's coefficients. NV1023 causes significant cytotoxicity of anaplastic, medullary, and papillary thyroid cancers. Nectin-1 is a novel marker of thyroid cancer sensitivity to herpes oncolytic therapy that might guide patient selection for therapy.

Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference

The classification, scoring systems, and response criteria for myelodysplastic syndromes (MDS) have recently been updated and have become widely accepted. In addition, several new effective targeted drugs for patients with MDS have been developed. The current article provides a summary of updated and newly proposed markers, criteria, and standards in MDS, with special reference to the diagnostic interface and refinements in evaluations and scoring. Concerning the diagnostic interface, minimal diagnostic criteria for MDS are proposed, and for patients with unexplained cytopenia who do not fulfill these criteria, the term ‘idiopathic cytopenia of uncertain significance’ (ICUS) is suggested. In addition, new diagnostic and prognostic parameters, histopathologic and immunologic determinants, proposed refinements in scoring systems, and new therapeutic approaches are discussed. Respective algorithms and recommendations should facilitate diagnostic and prognostic evaluations in MDS, selection of patients for therapies, and the conduct of clinical trials.

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.

Molecular classification of breast cancer: implications for selection of adjuvant chemotherapy

Adjuvant chemotherapy improves survival of patients with stage I-III breast cancer but it is being increasingly recognized that the benefit is not equal for all patients. Molecular characteristics of the cancer affect sensitivity to chemotherapy. In general, estrogen-receptor-negative disease is more sensitive to chemotherapy than estrogren-receptor-positive disease. Large-scale genomic analyses of breast cancer suggest that further molecular subsets may exist within the categories defined by hormone receptor status. It is hoped that the new molecular classification schemes might improve patient selection for therapy. Before any new molecular classification (or predictive test) is adopted for routine clinical use, however, several criteria need to be met. There must be an agreed and reproducible method by which to assign molecular class to a new case. Cancers that belong to different molecular classes must show differences in disease outcome and treatment efficacy that affect management and treatment selection. Also desirable are results from prospective clinical trials that demonstrate improved patient outcome when the new test is used in decision-making, compared with the current standard of care. This Review describes the current limitations and future promises of gene-expression-based molecular classification of breast cancer and how it might impact on selection of adjuvant therapy for individual patients.

Genomic Approaches to Lung Cancer

The last decade has seen remarkable success in clinical targeting of activated oncogenes in cancer. We have applied gene expression profiling, high-density single-nucleotide polymorphism arrays, and systematic resequencing of genes to identify novel oncogenes and signaling pathways in lung cancer that might represent therapeutic targets. Systematic resequencing of tyrosine kinase genes has led to the discovery of somatic mutations in the epidermal growth factor receptor (EGFR) gene in lung adenocarcinomas. These mutations range in frequency from 10% in Caucasian to 40% in East Asian patients. Lung cancer-derived EGFR mutations are oncogenic and are tightly associated with clinical response to the EGFR kinase inhibitors erlotinib and gefitinib. Furthermore, gene expression profiling has been shown to classify patients according to their clinical outcome, indicating that the application of this technique may help in guiding patient selection for therapy in the future. Finally, genome-wide analyses of copy number gains and losses were successfully applied to detect gene amplifications and deletions. Taken together, the application of genomics technologies has led to important discoveries with clinical implications in lung cancer that might help to improve clinical care for patients suffering from this highly fatal tumor.

Sphincter of Oddi dysfunction: Managing the patient with chronic biliary pain

Sphincter of Oddi dysfunction (SOD) is a syndrome of chronic biliary pain or recurrent pancreatitis due to functional obstruction of pancreaticobiliary flow at the level of the sphincter of Oddi. The Milwaukee classification stratifies patients according to their clinical picture based on elevated liver enzymes, dilated common bile duct and presence of abdominal pain. Type I patients have pain as well as abnormal liver enzymes and a dilated common bile duct. Type II SOD consists of pain and only one objective finding, and Type III consists of biliary pain only. This classification is useful to guide diagnosis and management of sphincter of Oddi dysfunction. The current gold standard for diagnosis is manometry to detect elevated sphincter pressure, which correlates with outcome to sphincterotomy. However, manometry is not widely available and is an invasive procedure with a risk of pancreatitis. Non-invasive testing methods, including fatty meal ultrasonography and scintigraphy, have shown limited correlation with manometric findings but may be useful in predicting outcome to sphincterotomy. Endoscopic injection of botulinum toxin appears to predict subsequent outcome to sphincterotomy, and could be useful in selection of patients for therapy, especially in the setting where manometry is unavailable.

Molecularly-targeted therapies for non-small cell lung cancer

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.

Recent developments in advanced urothelial cancer

Metastatic or unresectable urothelial cancer of the urinary bladder has traditionally been treated with systemic chemotherapy, which is most often platinum-based. The long-term survival data and the associated toxicities from this form of therapy have spurred continuing interest in finding novel treatment options for this malignancy. Recently, trials of new chemotherapy combinations, many incorporating platinum analogs or deleting platinum entirely, have been reported. None has yet been shown to be superior to cisplatin-based regimens. In addition, recent advances in imaging and laboratory technologies have provided new avenues to understand urothelial cancer behavior and prognosis. These advances provide optimism for improvements in the diagnosis, staging, and ultimately, selection of therapy for patients with urothelial cancer. This review will summarize recent developments (circa 2004) in the diagnosis and management of advanced bladder cancer.

Antiviral agents in HBeAg-negative liver disease0

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis is characterized by persistent or intermittent hepatitis B virus (HBV) replication with a high lifetime incidence of cirrhosis and hepatocellular carcinoma. Antiviral therapy, which aims to suppress viral replication, may be achieved in as many as 70% to 90% of patients treated with 1 year of lamivudine and 51% to 74% of patients treated with 1 year of adefovir dipivoxil (ADV). However, the short-term therapeutic advantage of lamivudine is offset by the high incidence of drug-resistant mutations, which approaches 60% at 48 months. Both lamivudine and ADV have been associated with a high rate of virologic relapse following drug withdrawal and a low rate of hepatitis B surface antigen (HBsAg) clearance. Although interferon alpha is associated with HBsAg loss in up to 10% of treated patients, its side-effect profile precludes its use in patients with advanced liver disease. Thus, selection of antiviral therapy for patients with HBeAg-negative liver disease requires individualization based on disease severity, drug efficacy, and resistance profile.

Emerging Role of Erlotinib (OSI-774) in Non–Small-Cell Lung Cancer

Erlotinib (OSI-774; Tarceva™) is a novel, specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), recently approved by the US Federal Drug Administration for patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) after failure of ≥ 1 prior chemotherapy regimen. The approval was based on the improvement in survival with erlotinib assessed in a randomized, double-blind, placebo-controlled trial (BR.21).1 The median overall survival was 6.7 months in the erlotinib group compared with 4.7 months in the placebo group (hazard ratio, 0.73; 95% CI, 0.61-0.86; P < 0.001). The most common adverse events in patients receiving erlotinib were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively. This supplement describes the data available to date on erlotinib in NSCLC. The interest of clinicians and basic scientists was sparked by the impressive response to EGFR TKIs in some patients with NSCLC. This led to the discovery of EGFR mutations in the tyrosine kinase domain that appear to predict response with these agents.2,3 Although the data are of great interest, EGFR mutations do not fully explain the clinical benefit that patients derive from EGFR-targeted therapies. Nevertheless, this is an exciting and promising development in the history of treating lung cancer that demands further investigation, as described by Perea and Hidalgo. It is only a matter of time until we will be able to prescribe tailor-made therapies for our patients with lung cancer. Calvo and Rowinsky have put this data into perspective. Patients who have the mutation are most likely to respond to treatment and are likely to be female, lifetime nonsmokers, of Asian ethnic origin, and have adenocarcinoma histology. Treatment with erlotinib or gefinitib should not be withheld from patients who do not match this profile; although survival benefits have been noted in subgroups of patients who do not have mutations, the magnitude of benefit may be reduced, as discussed in the article by Herbst and Sandler. Performance status (PS) is the single most important prognostic indicator of survival in lung cancer, yet there has been no standard of care for patients with poor PS. Although these patients do derive benefit from chemotherapy, erlotinib has presented evidence of significant improvement in survival in the BR.21 trial.1 Of the 488 patients treated with erlotinib, 26% had PS 2 and 9% had a PS of 3. A trial of erlotinib versus chemotherapy has been initiated in this subset of patients. Perez-Soler has reviewed phase II data with erlotinib. He states that it is an active and well-tolerated agent in second- and thirdline settings. Among pretreated patients, erlotinib response does not correlate with the number of previous chemotherapy regimens, but patients who had received docetaxel as second-line therapy had a higher objective response rate. In patients with bronchoalveolar carcinoma (BAC), erlotinib response correlates most highly with a history of nonsmoking and adenocarcinoma histology with BAC features. Seven of 8 responders had activating mutations of the EGFR. Among elderly untreated patients without BAC, the erlotinib response rate to date is 13.3%. Anecdotal reports of swift and durable responses in patients with BAC treated with EGFR TKIs prompted further investigation. Trials of single-agent gefinitib and erlotinib in patients with BAC have yielded promising results,4,5 as described by Patel. One third of patients with BAC never smoked, compared with approximately 10% of other lung cancer histologies, and BAC occurs more frequently in women than in men. Patients diagnosed with early-stage BAC live longer than patients with other histologic subtypes of NSCLC. When BAC becomes metastatic to extrapulmonary sites, its prognosis is similar to that of general adenocarcinoma. Targeted agents, primarily the EGFR inhibitors, have led to a new era in the treatment of patients with NSCLC. Qualitative and quantitative survival benefit has been demonstrated with erlotinib as a single agent for patients with advanced NSCLC. The discovery of mutations in the EGFR has opened the door to proper selection of patients for therapy with EGFR inhibitors.

Determinants of rapamycin sensitivity in breast cancer cells.

Rapamycin inhibits the serine-threonine kinase mammalian target of rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Although rapamycin analogues show activity in clinical trials, only some of the treated patients respond. The purpose of this study is to identify determinants of rapamycin sensitivity that may assist the selection of appropriate patients for therapy. Breast cancer cell lines representing a spectrum of aberrations in the mTOR signaling pathway were tested for rapamycin sensitivity. The expression and phosphorylation state of multiple components of the pathway were tested by Western blot analysis, in the presence and absence of rapamycin. Cell proliferation was significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell lines. The ratio of total protein levels of 4E-BP1 to its binding partner eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In contrast, overexpression of S6K1, and phosphorylated Akt independent of phosphatase and tensin homologue deleted from chromosome 10 status, were associated with rapamycin sensitivity. Targeting S6K1 and Akt with small interfering RNA and dominant-negative constructs, respectively, decreased rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, indicating that its ability to inhibit the mTOR pathway is not sufficient to confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in rapamycin-resistant cells. Overexpression of S6K1 and expression of phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in breast cancer patients. Furthermore, changes in cyclin D1 levels provide a potential pharmacodynamic marker of response to rapamycin.