Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

Proapoptotic signaling activity of the anti-CD40 monoclonal antibody dacetuzumab circumvents multiple oncogenic transformation events and chemosensitizes NHL cells.

Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The objective of this study was to elucidate the signal transduction-based antitumor mechanism(s) of action for the anti-CD40 monoclonal antibody dacetuzumab (SGN-40) in NHL. We report that dacetuzumab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuzumab-mediated CD40 signaling constitutively activated the nuclear factor-κB and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. In a second mechanism, dacetuzumab signaling induced the expression of the proapoptotic p53 family member TAp63α and downstream proteins associated with the intrinsic and extrinsic apoptotic machinery. Dacetuzumab was synergistic in combination with DNA-damaging chemotherapeutic drugs, correlating with TAp63α upregulation. Furthermore, dacetuzumab augmented the activity of rituximab in combination with multiple chemotherapies in the xenograft models of NHL. The ability of dacetuzumab signaling to circumvent oncogenic events and potentiate the activity of chemotherapy regimens provides a unique therapeutic approach to NHL.

Lactoferrin binds CpG-containing oligonucleotides and inhibits their immunostimulatory effects on human B cells.

Unmethylated CpG dinucleotide motifs in bacterial DNA, as well as oligodeoxynucleotides (ODN) containing these motifs, are potent stimuli for many host immunological responses. These CpG motifs may enhance host responses to bacterial infection and are being examined as immune activators for therapeutic applications in cancer, allergy/asthma, and infectious diseases. However, little attention has been given to processes that down-modulate this response. The iron-binding protein lactoferrin is present at mucosal surfaces and at sites of infection. Since lactoferrin is known to bind DNA, we tested the hypothesis that lactoferrin will bind CpG-containing ODN and modulate their biological activity. Physiological concentrations of lactoferrin (regardless of iron content) rapidly bound CpG ODN. The related iron-binding protein transferrin lacked this capacity. ODN binding by lactoferrin did not require the presence of CpG motifs and was calcium independent. The process was inhibited by high salt, and the highly cationic N-terminal sequence of lactoferrin (lactoferricin B) was equivalent to lactoferrin in its ODN-binding ability, suggesting that ODN binding by lactoferrin occurs via charge-charge interaction. Heparin and bacterial LPS, known to bind to the lactoferricin component of lactoferrin, also inhibited ODN binding. Lactoferrin and lactoferricin B, but not transferrin, inhibited CpG ODN stimulation of CD86 expression in the human Ramos B cell line and decreased cellular uptake of ODN, a process required for CpG bioactivity. Lactoferrin binding of CpG-containing ODN may serve to modulate and terminate host response to these potent immunostimulatory molecules at mucosal surfaces and sites of bacterial infection.

Mitotic phosphorylation of Golgi reassembly stacking protein 55 by mitogen-activated protein kinase ERK2.

The role of the mitogen-activated protein kinase kinase (MKK)/extracellular-activated protein kinase (ERK) pathway in mitotic Golgi disassembly is controversial, in part because Golgi-localized targets have not been identified. We observed that Golgi reassembly stacking protein 55 (GRASP55) was phosphorylated in mitotic cells and extracts, generating a mitosis-specific phospho-epitope recognized by the MPM2 mAb. This phosphorylation was prevented by mutation of ERK consensus sites in GRASP55. GRASP55 mitotic phosphorylation was significantly reduced, both in vitro and in vivo, by treatment with U0126, a potent and specific inhibitor of MKK and thus ERK activation. Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope. These results are the first demonstration of GRASP55 mitotic phosphorylation and indicate that the MKK/ERK pathway directly phosphorylates the Golgi during mitosis.

Assessing the psychosocial impact of the ICD: a national survey of implantable cardioverter defibrillator health care providers.

The implantable cardioverter defibrillator (ICD) provides a survival advantage over antiarrhythmic medications for patients with life-threatening ventricular arrhythmias. However, the effect of ICD therapy on quality-of-life and psychosocial functioning are not as well understood. Health care providers (e.g., physicians, nurses) can serve as a valuable source of information related to these ICD outcomes. The purpose of this study was to investigate health care provider perceptions regarding: (1) the quality-of-life and psychosocial functioning of their ICD recipients, (2) the concerns or problems reported by ICD recipients, and (3) the degree of provider comfort in managing these concerns. The final sample of health care providers (n = 261) rated ICD recipients' global quality-of-life and psychosocial functioning, and specific concerns about health care, lifestyle, special population adjustment, marital and family adjustment, and emotional well-being. With regard to quality-of-life, health care providers reported that the majority of ICD recipients were functioning better (38%) or about the same (47%) than before implantation. However, health care providers reported that 15% of recipients experienced worse quality-of-life postimplantation. Similarly, health care providers indicated that 10%-20% of ICD recipients experienced worse emotional functioning and strained family relationships. Moreover, issues related to driving, dealing with ICD shocks, and depression were the most common ICD recipient concerns. Significant differences were noted between physicians and nurses/other health care professionals on a wide range of psychosocial issues. Health care providers generally reported the most comfort dealing with traditional medical issues (i.e., patient adherence), and the least comfort in managing emotional well-being issues (e.g., depression and anxiety). These results suggest that routine attention to ICD quality-of-life and psychosocial outcomes is indicated for health care providers who care for ICD recipients.

Identification of novel MAP kinase pathway signaling targets by functional proteomics and mass spectrometry.

Functional proteomics provides a powerful method for monitoring global molecular responses following activation of signal transduction pathways, reporting altered protein posttranslational modification and expression. Here we combine functional proteomics with selective activation and inhibition of MKK1/2, in order to identify cellular targets regulated by the MKK/ERK cascade. Twenty-five targets of this signaling pathway were identified, of which only five were previously characterized as MKK/ERK effectors. The remaining targets suggest novel roles for this signaling cascade in cellular processes of nuclear transport, nucleotide excision repair, nucleosome assembly, membrane trafficking, and cytoskeletal regulation. This study represents an application of functional proteomics toward identifying regulated targets of a discrete signal transduction pathway and demonstrates the utility of this discovery-based strategy in elucidating novel MAP kinase pathway effectors.

Despite structural similarities between gp91phox and FRE1, flavocytochrome b558 does not mediate iron uptake by myeloid cells.

Superoxide (O2-) generated by the phagocyte reduced nicotinamide adenine dinucleotide phosphate oxidase is dependent on electron transfer by flavocytochrome b558 (flavocytochrome b), a transmembrane heterodimer that forms the redox center of the oxidase at the plasma or phagosomal membrane. The larger of its two subunits, gp91phox, is homologous to the yeast iron reductase subunit FRE1, and these two proteins share many structural and functional characteristics. Because FRE1 is required for iron uptake in yeast, we hypothesized that flavocytochrome b might serve a similar function in human phagocytes and thus provide a mechanism for the transferrin-independent iron acquisition observed in myeloid cells. To determine whether flavocytochrome b was required for iron uptake, we compared iron acquisition by polymorphonuclear neutrophils (PMNs) or Epstein-Barr virus (EBV)-transformed B lymphocytes derived from individuals with X-linked chronic granulomatous disease (CGD) with iron acquisition by normal cells. Our results indicate that all cells acquired iron to the same extent and that uptake could be significantly enhanced in the presence of the trivalent metal gallium. The gallium enhancement of iron uptake observed in PMNs or in EBV-transformed B lymphocytes derived from healthy individuals was mirrored by those derived from individuals deficient in flavocytochrome b. Furthermore, both normal and CGD-derived EBV-transformed B lymphocytes had similar iron reductase activity, suggesting that flavocytochrome b is not a biologically significant iron reductase. In contrast to previously suggested hypotheses, these results show conclusively that flavocytochrome b is not necessary for cellular iron acquisition, despite structural and functional similarities between yeast iron reductases and flavocytochrome b.

Self-diagnostics and home monitoring: exploring new business opportunities.

The world is still shrinking. Advances in telecommunications are turning the concept of a global community into a reality. In the medical industry, this has translated into increased self-diagnostics and home monitoring. This article discusses a number of strategies for successful product positioning amidst technical revolution.

Examining the psychosocial impact of implantable cardioverter defibrillators: a literature review.

BACKGROUND: The implantable cardioverter defibrillator (ICD) has proven to be superior to medications in treating potentially life-threatening ventricular arrhythmias, resulting in reduced mortality rates. Despite the number of patients receiving this therapy, its psychosocial impact is not well understood. HYPOTHESIS: The purposes of this paper are (1) to review the available literature documenting the psychosocial impact of the ICD on patients, (2) to hypothesize possible mechanisms for this psychosocial impact, and (3) to suggest clinical risk profiles and indications for psychological consultation. METHODS: Electronic and library searches (e.g., MEDLINE, PsychLit) were used to gather studies examining the psychosocial impact of the ICD. Only studies investigating psychosocial outcomes (e.g., psychological distress, quality of life, social and role functioning), either prospectively or cross-sectionally, were admitted into the review. No literature reviews or secondary sources were included. RESULTS AND CONCLUSIONS: Current research suggests that ICD-specific fears and symptoms of anxiety (e.g., excessive worry, physiological arousal) are the most common psychological symptoms experienced by ICD recipients, with approximately 13-38% of recipients experiencing diagnosable levels of anxiety. Depressive symptoms are reported at rates that are generally consistent with other cardiac populations. Although the incidence of psychological disorders appears to be similar to that found in general cardiac populations, specific ICD-related concerns such as fear of shock, fear of device malfunction, fear of death, and fear of embarrassment have been identified. Selected psychological theories such as classical conditioning, learned helplessness, and a cognitive appraisal model help to explain the occurrence of psychological symptoms post implantation. Psychosocial adjustment risk profiles indicate that young ICD recipients and those with high discharge rates may experience the most adjustment difficulties.

Market drivers: preparing for the future.

Developing a market strategy is a complex task. Analysts need to identify a diverse range of issues and correctly assess their impact. This article uses political, economic, social and technology analysis to assess the market drivers that are affecting all medical device companies. The wide-ranging implications of the euro are also examined.

Evidence for the existence of a surface receptor for ferriclactoferrin and ferrictransferrin associated with the plasma membrane of the protozoan parasite Leishmania donovani.

Previous work has demonstrated the ability of the promastigote form of the protozoan parasite Leishmania chagasi to utilize iron chelated to lactoferrin and transferrin for growth and metabolism. We have obtained evidence suggesting that the promastigote form of the parasite possesses specific binding sites for lactoferrin and transferrin. Lactoferrin binding appears to be: 1) independent of whether or not the protein contains iron; 2) not inhibited by transferrin; and 3) independent of whether the organism is in log or stationary phase of growth. Transferrin binding is: 1) markedly greater if the protein is iron loaded; 2) inhibited by the presence of lactoferrin; and 3) independent of whether the organism is in log or stationary growth phase. Preliminary ligand blot analyses are consistent with the presence of a protein or proteins which bind lactoferrin and/or transferrin. The relationship to these binding sites to those described in other protozoan species requires further investigation.

Managed care: has the revolution arrived?

Managed Care has been predicted to become the single most important issue by the end of the century. Is there any evidence to suggest that this is happening? In this article, the author reviews recent health-care cost containment initiatives and merger and acquisition activity. A profile of the market in the United States and evidence of policy changes in the United Kingdom also illustrate the trends.

Managed care--evolution or revolution?

What are the key influences on today's highly competitive health care market? Are they relevant to medical devices and will they affect device manufacturers? This article attempts to answer these key questions and suggests that Managed Care will become the single most important issue in the next five years.

Mass spectrometric analysis of 40 S ribosomal proteins from Rat-1 fibroblasts.

Although sequences of most mammalian ribosomal proteins are available, little is known about the post-translational processing of ribosomal proteins. To examine their post-translational modifications, 40 S subunit proteins purified from Rat-1 fibroblasts and their peptides were analyzed by liquid chromatography coupled with electrospray mass spectrometry. Of 41 proteins observed, 36 corresponded to the 32 rat 40 S ribosomal proteins with known sequences (S3, S5, S7, and S24 presented in two forms). The observed masses of S4, S6-S8, S13, S15a, S16, S17, S19, S27a, S29, and S30 matched those predicted. Sa, S3a, S5, S11, S15, S18, S20, S21, S24, S26-S28, and an S7 variant showed changes in mass that were consistent with N-terminal demethionylation and/or acetylation (S5 and S27 also appeared to be internally formylated and acetylated, respectively). S23 appeared to be internally hydroxylated or methylated. S2, S3, S9, S10, S12, S14, and S25 showed changes in mass inconsistent with known covalent modifications (+220, -75, +86, +56, -100, -117, and -103 Da, respectively), possibly representing novel post-translational modifications or allelic sequence variation. Five unidentified proteins (12,084, 13,706, 13,741, 13,884, and 34, 987 Da) were observed; for one, a sequence tag (PPGPPP), absent in any known ribosomal proteins, was determined, suggesting that it is a previously undescribed ribosome-associated protein. This study establishes a powerful method to rapidly analyze protein components of large biological complexes and their covalent modifications.

FDA: friend or foe?

Delays in FDA product approvals have weakened the US medical device market. Reduced investment returns and the erosion of industry's confidence in FDA procedures have slowed the introduction of new products and threatened the market's potential for growth. This article examines the background to those issues and describes FDA's attempts to overcome its procedural shortcomings.

Correlative measurement of anterior margin of the anulus for surgical planning.

STUDY DESIGN: This study was a retrospective anatomic correlation of intervertebral disc dimensions with current surgical guidelines. OBJECTIVES: To develop safer guidelines for disc instrumentation. SUMMARY OF BACKGROUND DATA: Anterior perforation of the anulus fibrosus and injury to intra-abdominal structures is a known complication of lumbar discectomy. Coplanar magnetic resonance imaging of the lumbar intervertebral discs could decrease the rate of complication using axial 11-weighted scans. METHODS: Three measurements through the intervertebral discs of the lumbar spine were taken in 50 patients. These were correlated with current surgical guidelines for lumbar instrumentation. RESULTS: Most of the measurements exceeded the current suggested guidelines for instrumentation at 3 cm. CONCLUSIONS: Current guidelines for introduction of instruments into the lumbar disc spaces should be reevaluated. Appropriate measurements should be made on an individual basis.