Factors associated with second-line triplet therapy in routine care in relapsed/refractory multiple myeloma.

WHAT IS KNOWN AND OBJECTIVE: Second-line therapy (SLT) trials in relapsed/refractory multiple myeloma (RRMM) report superior outcomes with triplet combinations. We sought to determine factors associated with triplet SLT in routine practice. METHODS: A retrospective cohort with claims for MM between 01/01/2008 and 03/31/2015 was grouped by 1-2 ("doublet") or 3+ ("triplet") agent therapy. Charlson comorbidity index (CCI) and disability status; CRAB symptoms (hypercalcaemia, renal/bone disease, anaemia); and relapse risk were determined. RESULTS: Among 623 patients, the triplet group (n=146 [23%]) was younger (65.2 vs 69.8 years) and more likely to have high-risk relapse (67% vs 50%), CRAB symptoms (94.5% vs 81.1%), triplet first-line treatment (75% vs 51%) and frontline stem cell transplant (38% vs 20%) (P<0.001 for all). In multivariate analyses, CRAB symptoms (OR: 3.22, 95% CI: 1.47, 7.10), high-risk relapse (OR: 1.71, 95% CI: 1.12, 2.62) and prior triplet therapy (OR: 2.16, 95% CI: 1.38, 3.40), but neither CCI nor disability, were associated with triplet SLT. A trend towards triplets among younger patients (<65 vs >75 years, OR: 1.73, 95% CI: 0.99, 3.04) was observed. WHAT IS NEW AND CONCLUSION: The majority of patients did not receive triplet regimens. Treatment selection with triplet therapy for RRMM should carefully consider comorbidities and patient-specific characteristics.

Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force.

Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

High resolution anoscopy may be useful in achieving reductions in anal cancer local disease failure rates.

Anal cancer is uncommon, with an incidence rate of 0.5-1.0 per 100,000 of the population but incidence rates have been steadily increasing over the last 3 decades. Biological and epidemiological evidence have been mounting and demonstrate that anal cancer has many similarities to cervical cancer, especially in regard to its aetiology. High-resolution anoscopy (HRA) of the anal region ­ analogous to colposcopy of the cervix, is a technique that is not well-known in the medical and surgical fraternity. Evidence to support the use of HRA for detection and treatment in the surveillance of AIN exists and strongly suggests that it is beneficial, resulting in reduced rates of cancer progression. Pilot data from our study showed a local disease failure rate of 1.73 per 1000 patient-months compared with a published rate of 9.89 per 1000 patient-months. This demonstrates a 5.72-fold reduction in local disease failure rates of patients with T1-T3 tumours; the data therefore suggests that use of HRA for detection and treatment in surveillance of anal cancer patients will help prevent local regional relapse at the anal site. There is an urgent need for a large, randomised controlled clinical trial to definitively test this hypothesis.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

The role of body mass index in survival outcome for lymphoma patients: US intergroup experience.

BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

Use of virulence determinants and seropathotypes to distinguish high- and low-risk Escherichia coli O157 and non-O157 isolates from Europe.

The presence of 10 virulence genes was examined using polymerase chain reaction (PCR) in 365 European O157 and non-O157 Escherichia coli isolates associated with verotoxin production. Strain-specific PCR data were analysed using hierarchical clustering. The resulting dendrogram clearly separated O157 from non-O157 strains. The former clustered typical high-risk seropathotype (SPT) A strains from all regions, including Sweden and Spain, which were homogenous by Cramer's V statistic, and strains with less typical O157 features mostly from Hungary. The non-O157 strains divided into a high-risk SPTB harbouring O26, O111 and O103 strains, a group pathogenic to pigs, and a group with few virulence genes other than for verotoxin. The data demonstrate SPT designation and selected PCR separated verotoxigenic E. coli of high and low risk to humans; although more virulence genes or pulsed-field gel electrophoresis will need to be included to separate high-risk strains further for epidemiological tracing.

An assessment of the impact of behavioural cognitions on function in patients partaking in a trial of early home-based progressive resistance training after total hip replacement surgery.

BACKGROUND: Control cognitions have been directly related to positive engagement with rehabilitation regimes. The impact of such cognitions on recovery following surgery is not well understood. PURPOSE: To assess whether perceived control cognitions predict function 9-12 months following total hip replacement (THR). METHODS: Prospective cohort study performed as part of a randomised controlled trial. Behavioural cognitions (BC) (recovery locus of control (RLOC); perceived external behavioural control (PEBC))) and subjective functional outcome measures (Oxford hip score (OHS) and a reduced version of the Western Ontario and McMasters University Osteoarthritis Function scale (rWOMAC PF)) were administered pre-operatively and up to 12 months post-operatively to 50 patients randomised to home-based progressive resistance training (N = 26) or standard rehabilitation (N = 24), post-THR. Regression analysis investigated variance in functional scores. RESULTS: Group randomisation had no effect on BC. RLOC and OHS (6 months) correlated significantly with 12-month OHS, with 6-month OHS predicting 62.3% of the variance in 12-month OHS. 12-month rWOMAC PF was determined by each of its three previous assessments (pre-operative 8.8%, 6 weeks 17.8% and 6 months 67.3%). Variance in functional gain at 12 months (OHS and rWOMAC PF) was explained by pre-operative OHS and rWOMAC PF (63.7% and 63.8%, respectively). CONCLUSIONS: BC had no impact on functional outcome in this population. Subjectively assessed function at 12 months, as well as the levels of functional gain over time, was best explained by the patients' earlier functional status. Implications for Rehabilitation It is important to assess psychological factors such as poor pre-operative mental health and pain catastrophising in patients undergoing joint replacement surgery as these factors have an adverse effect on subjective patient outcomes. Pre-operative behavioural cognitions appear to have no impact on subjective functional outcome at 12 months post-THR. The pre-existing functional status of the patient appears to be most predictive of subjective function at 12 months post-THR, implying that perhaps earlier surgery may be optimal before the onset of a decline in function.

Investigating the cognitive precursors of emotional response to cancer stress: re-testing Lazarus's transactional model.

OBJECTIVES: Lazarus's Transactional Model of stress and coping underwent significant theoretical development through the 1990s to better incorporate emotional reactions to stress with their appraisal components. Few studies have robustly explored the full model. This study aimed to do so within the context of a major life event: cancer diagnosis. DESIGN: A repeated measures design was used whereby data were collected using self-report questionnaire at baseline (soon after diagnosis), and 3- and 6-month follow-up. METHODS: A total of 160 recently diagnosed cancer patients were recruited (mean time since diagnosis = 46 days). Their mean age was 64.2 years. Data on appraisals, core-relational themes, and emotions were collected. Data were analysed using both Spearman's correlation tests and multivariate regression modelling. RESULTS: Longitudinal analysis demonstrated weak correlation between change scores of theoretically associated components and some emotions correlated more strongly with cognitions contradicting theoretical expectations. Cross-sectional multivariate testing of the ability of cognitions to explain variance in emotion was largely theory inconsistent. CONCLUSIONS: Although data support the generic structure of the Transactional Model, they question the model specifics. Larger scale research is needed encompassing a wider range of emotions and using more complex statistical testing. STATEMENT OF CONTRIBUTION: WHAT IS ALREADY KNOWN ON THIS SUBJECT?: • Stress processes are transactional and coping outcome is informed by both cognitive appraisal of the stressor and the individual's emotional response (Lazarus & Folkman, 1984). • Lazarus (1999) made specific hypotheses about which particular stress appraisals would determine which emotional response, but only a small number of these relationships have been robustly investigated. • Previous empirical testing of this theory has been limited by design and statistical limitations. WHAT DOES THIS STUDY ADD?: • This study empirically investigates the cognitive precedents of a much larger range of emotional outcomes than has previously been attempted in the literature. • Support for the model at a general level is established: this study demonstrates that both primary and secondary appraisals, and core-relational themes are important variables in explaining variance in emotional outcome. • The specific hypotheses proposed by Lazarus (1999) are not, however, supported: using data-driven approaches we demonstrate that equally high levels of variance can be explained using entirely different cognitive appraisals than those hypothesized.

Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy.

BACKGROUND: The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS: The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS: In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS: Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.

Common, important, and unmet needs of cancer outpatients.

PURPOSE: To maximize patient well-being, health and social care should, whenever possible, address individual patient needs. The present study aims firstly, to identify prevalent, salient and unmet needs amongst cancer outpatients, and secondly, to explore socio-demographic and clinical influences on expressed need. METHODS: One-hundred and ten outpatients registered at a UK cancer treatment centre completed a self-report questionnaire measuring the presence, salience and degree to which 80 need items were met. Six broad cancer sites were represented: urology, colorectal, breast, gynaecology, haematology, and head and neck. RESULTS: The mean number of needs reported was 27. The top five needs concerned the treatment, care and health information patients receive from healthcare professionals, all of which were rated as well met. Least met needs included receiving genetic information, information about lifestyle changes, help with worries about spread or recurrence, and parking near treatment centres. Salient needs showed greater variation across the sample and were often unmet, for example the need for genetic information, and the need for information about symptoms/indicators of recurrence. Gender (female), age (younger), having an informal caregiver, and cancer site all affected aspects of need; whereas time since diagnosis and type of treatment did not. CONCLUSIONS: Acknowledging these influences on patient need could help guide patient-centred support services with potential gains to patient satisfaction and well-being.

Malassezia: is it a pulmonary pathogen in the stem cell transplant population?

Malassezia furfur is a yeast that can cause a variety of infections, most commonly in normal hosts, and also in immunocompromised hosts. This yeast typically colonizes the skin, and is the causative agent of tinea versicolor. However, in immunocompromised hosts, it can more commonly cause catheter-related fungemia or folliculitis. Pulmonary infections from Malassezia have not been commonly recognized. Unlike many other common opportunistic fungal infections in immunocompromised hosts, neutropenia and the use of broad-spectrum antibiotics do not appear to be significant risk factors for Malassezia infections in the stem cell transplant (SCT) population. Additionally, disseminated infection, despite fungemia, is uncommon. A series of patients who underwent SCT at the University of Minnesota between 2004 and 2006 were reviewed for the occurrence of suspected Malassezia infections in the post-transplant period. Four cases of possible pulmonary M. furfur infection were identified in our SCT recipients. The clinical characteristics of these patients, the infections, treatment, and outcome are described. In addition, we discuss the possible pathogenicity of this yeast in the pulmonary setting.

Closing gaps in the human genome with fosmid resources generated from multiple individuals.

The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.

Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.

The study presented here was performed in order to create a rule that identifies subjects at high risk for invasive candidiasis in the intensive care setting. Retrospective review and statistical modelling were carried out on 2,890 patients who stayed at least 4 days in nine hospitals in the USA and Brazil; the overall incidence of invasive candidiasis in this group was 3% (88 cases). The best performing rule was as follows: Any systemic antibiotic (days 1-3) OR presence of a central venous catheter (days 1-3) AND at least TWO of the following-total parenteral nutrition (days 1-3), any dialysis (days 1-3), any major surgery (days -7-0), pancreatitis (days -7-0), any use of steroids (days -7-3), or use of other immunosuppressive agents (days -7-0). The rate of invasive candidiasis among patients meeting the rule was 9.9%, capturing 34% of cases in the units, with the following performance: relative risk 4.36, sensitivity 0.34, specificity 0.90, positive predictive value 0.01, and negative predictive value 0.97. The rule may identify patients at high risk of invasive candidiasis.

Recurrent duplication-driven transposition of DNA during hominoid evolution.

The underlying mechanism by which the interspersed pattern of human segmental duplications has evolved is unknown. Based on a comparative analysis of primate genomes, we show that a particular segmental duplication (LCR16a) has been the source locus for the formation of the majority of intrachromosomal duplications blocks on human chromosome 16. We provide evidence that this particular segment has been active independently in each great ape and human lineage at different points during evolution. Euchromatic sequence that flanks sites of LCR16a integration are frequently lineage-specific duplications. This process has mobilized duplication blocks (15-200 kb in size) to new genomic locations in each species. Breakpoint analysis of lineage-specific insertions suggests coordinated deletion of repeat-rich DNA at the target site, in some cases deleting genes in that species. Our data support a model of duplication where the probability that a segment of DNA becomes duplicated is determined by its proximity to core duplicons, such as LCR16a.

A preliminary study into stress in palliative care: optimism, self-efficacy and social support.

Caring for the terminally ill is a demanding, but rewarding area of health care. Stressors unique to this working environment--dealing with patient death rather than cure, and supporting entire family units, for example--put caregivers at risk from stress related illness. This study investigated the buffering effects of optimism, self-efficacy and social support against two measures of stress within the palliative setting. Comparisons were made between volunteer (n = 18) and professional (n = 18) caregivers across three caregiving settings. Data were collected retrospectively about personal control variables; use of and satisfaction with, social support; and, perceived general and occupational specific stress levels. Differences in reported stress levels were found both between settings (NHS, hospice and community-based) and between caregiver type (salary status and occupational category). Optimism was more strongly and consistently associated with low levels of perceived stress than was self-efficacy. Satisfaction with social support was highest among paid workers, and in terms of buffering stress in the whole sample, appeared mediated by optimism. Worksite interventions targeting caregiver self-efficacy and optimism are recommended as a potential source of stress management within this population.

High-throughput genotyping of intermediate-size structural variation.

The contribution of large-scale and intermediate-size structural variation (ISV) to human genetic disease and disease susceptibility is only beginning to be understood. The development of high-throughput genotyping technologies is one of the most critical aspects for future studies of linkage disequilibrium (LD) and disease association. Using a simple PCR-based method designed to assay the junctions of the breakpoints, we genotyped seven simple insertion and deletion polymorphisms ranging in size from 6.3 to 24.7 kb among 90 CEPH individuals. We then extended this analysis to a larger collection of samples (n=460) by application of an oligonucleotide extension-ligation genotyping assay. The analysis showed a high level of concordance ( approximately 99%) when compared with PCR/sequence-validated genotypes. Using the available HapMap data, we observed significant LD (r2=0.74-0.95) between each ISV and flanking single nucleotide polymorphisms, but this observation is likely to hold only for similar simple insertion/deletion events. The approach we describe may be used to characterize a large number of individuals in a cost-effective manner once the sequence organization of ISVs is known.

[Pathogenetic implications of lipid spectrum in some infectious diseases].

AIM: To estimate concentrations of blood serum lipids and erythrocytic membranes in the conditions of intoxication syndrome. MATERIAL AND METHODS: Lipids were studied in the serum and erythrocytic membranes of 48 patients with oropharyngeal diphtheria and 67 patients suffering from hemorrhagic fever with renal syndrome (HFRS) in different forms and severity of the disease. RESULTS: Various correlations were found between structural and serum lipids. This is pathogenetically important for characterizing biomembranes and variants of activation of lipid metabolism in conditions of intoxication syndrome in diphtheria and HFRS. CONCLUSION: At the height of diphtheria and HFRS organization of biomembrane phospholipids conformation creates conditions for cell disorganization.

A genome-wide survey of structural variation between human and chimpanzee.

Structural changes (deletions, insertions, and inversions) between human and chimpanzee genomes have likely had a significant impact on lineage-specific evolution because of their potential for dramatic and irreversible mutation. The low-quality nature of the current chimpanzee genome assembly precludes the reliable identification of many of these differences. To circumvent this, we applied a method to optimally map chimpanzee fosmid paired-end sequences against the human genome to systematically identify sites of structural variation > or = 12 kb between the two species. Our analysis yielded a total of 651 putative sites of chimpanzee deletion (n = 293), insertions (n = 184), and rearrangements consistent with local inversions between the two genomes (n = 174). We validated a subset (19/23) of insertion and deletions using PCR and Southern blot assays, confirming the accuracy of our method. The events are distributed throughout the genome on all chromosomes but are highly correlated with sites of segmental duplication in human and chimpanzee. These structural variants encompass at least 24 Mb of DNA and overlap with > 245 genes. Seventeen of these genes contain exons missing in the chimpanzee genomic sequence and also show a significant reduction in gene expression in chimpanzee. Compared with the pioneering work of Yunis, Prakash, Dutrillaux, and Lejeune, this analysis expands the number of potential rearrangements between chimpanzees and humans 50-fold. Furthermore, this work prioritizes regions for further finishing in the chimpanzee genome and provides a resource for interrogating functional differences between humans and chimpanzees.