SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC). PATIENTS AND METHODS: We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME. RESULTS: The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank] <0.001, P[trend] < 0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)]. CONCLUSIONS: SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

Safety of emergency, elective and day case operating during the winter period at East Suffolk and North Essex NHS Foundation Trust: lessons from the outcomes of 4,254 surgical patients from the first COVID-19 wave.

BACKGROUND: There is limited evidence on perioperative outcomes of surgical patients during the COVID-19 pandemic to inform continued operating into the winter period. METHODS: We retrospectively analysed the rate of 30-day COVID-19 transmission and mortality of all surgical patients in the three hospitals in our trust in the East of England during the first lockdown in March 2020. All patients who underwent a swab were swabbed on or 24 hours prior to admission. RESULTS: There were 4,254 patients and an overall 30-day mortality of 0.99%. The excess surgical mortality in our region was 0.29%. There were 39 patients who were COVID-19 positive within 30 days of admission, 12 of whom died. All 12 were emergency admissions with a length of stay longer than 24 hours. There were three deaths among those who underwent day case surgery, one of whom was COVID-19 negative, and the other two were not swabbed but not suspected to have COVID-19. There were two COVID-19 positive elective cases and none in day case elective or emergency surgery. There were no COVID-19 positive deaths in elective or day case surgery. CONCLUSIONS: There was a low rate of COVID-19 transmission and mortality in elective and day case operations. Our data have allowed us to guide patients in the consent process and provided the evidence base to restart elective and day case operating with precautions and regular review. A number of regions will be similarly affected and should perform a review of their data for the winter period and beyond.

Depression, anxiety and quality of life in subjects with atopic eczema in a population-based cross-sectional study in Germany.

BACKGROUND: Atopic eczema (AE) may be associated with several mental health problems. In Germany, existing data from selected patient cohorts may lead to misestimation of the problem. OBJECTIVES: We aimed to cross-sectionally determine associations of AE with depression, anxiety, quality of life (QoL) and social interactions in subjects from the population-based LIFE-Adult-Study. METHODS: Subjects underwent standardized interviews (medical history) and answered standardized questionnaires [Centre of Epidemiologic studies-Depression scale (CES-D), Generalized Anxiety Disorder (GAD-7), Lubben Social Network Scale (LSNS), Short Form Health Survey (SF-8)]. We compared data from subjects with AE with those from subjects with selected other chronic/disabling diseases (cardiovascular, diabetes, cancer) and adjusted for selected sociodemographic parameters. Multivariate binary logistic regression was used for categorical variables, linear regression for continuous variables. RESULTS: Out of 9104 adults included (57% female, median age 54 years), 372 (4.1%) had a history of AE. Compared with controls, subjects with AE showed higher scores for depressive symptoms (9.3% vs. 6.3%; P < 0.001) and anxiety (8.4% vs. 5.6%, P < 0.001). Odds ratio (OR) was 1.5 [CI 1.0; 2.3] (P = 0.031) for depression, which was comparable to OR in patients with a history of cancer (OR 1.6 [1-2.3], P = 0.001. OR for anxiety in AE was 1.5 [1.0; 2.2], P < 0.049, which was slightly higher than in diabetes mellitus (OR 1.2) and stroke (OR 1.4). Other than in diabetes and/or stroke, we did not find a significant association between AE and social isolation. QoL scores were lower in AE than in controls (mean 46.9 vs. 48.0, P < 0.001 for physical and 50.6 vs. 52.5, P < 0.001 for mental components). CONCLUSIONS: Subjects with AE showed higher values for depression and anxiety as well as lower QoL scores compared to controls. With regard to depression, odds in AE and cancer were hardly different. Medical care of AE patients should therefore include mental health evaluation and treatment if indicated.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

The association between an anxiety disorder and cancer in medical history.

BACKGROUND: Cancer patients can feel depression and anxiety any time after a cancer diagnosis. The Generalized Anxiety Disorder Scale (GAD-7) is an instrument for the assessment of anxiety. The main objective of this work was to compare general anxiety levels between cancer survivors and individuals without a history of cancer in a population-based study (LIFE-ADULT) with 10,000 participants. METHODS: All participants (18-80 years) completed the GAD-7 and other psychological and medical questionnaires. A score of 10 or greater for GAD-7 (of total 21) indicates a probable generalized anxiety disorder. RESULTS: 954 participants reported a diagnosis of cancer in their medical history. In the multivariate analysis an anxiety disorder was associated with prior cancer diagnosis (OR: 1.8; 95% CI [1.4-2.4]), age -every additional year- (OR: 0.983; [0.976-0.991]), female gender (OR: 1.8; [1.5-2.2]) and low socioeconomic status (OR: 2.0; [1.7-2.5]) all p < 0.001. There were no significant associations between general anxiety and other comorbidities, such as myocardial infarction (OR: 1.0; p = 0.948), stroke (OR: 1.4; p = 0.237) or diabetes (OR: 1.0; p = 0.326). There was also no significant difference in anxiety disorder among cancer survivors regarding the time passed since the initial cancer diagnosis (OR: 1.1; [0.6-1.9], p = 0.804 comparing 5-10 years after a diagnosis of cancer vs. ≤5 years and OR: 0.6; [0.4-1.1], p = 0.107 comparing >10 vs. ≤5 years). LIMITATIONS: This study has a cross-sectional character, therefore, causal conclusions cannot be drawn. CONCLUSION: Cancer survivors may require screening for anxiety disorders and long-term professional psychosocial support.

Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin's lymphoma trial group.

To study if obesity is a risk factor in elderly patients (>60 years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI < 18·5), 38% were normal weight (18·5 ≤ BMI < 25), 42% were overweight (25 ≤ BMI < 30) and 19% were obese (BMI ≥ 30). Event-free (EFS), progression-free (PFS) and overall survival (OS) according to BMI showed no significant differences for all and for male patients. EFS (P = 0·041), PFS (P = 0·038) and OS (P = 0·031) were significantly better for female non-obese patients. A multivariate analysis adjusted for International Prognostic Index risk factors confirmed these results, with the following hazard ratios (HR) for obesity (BMI ≥ 30) for EFS/PFS/OS: all patients - 1·4/1·4/1·4 (not significant); male patients - 1·2/1·2/1·0 (not significant) and female patients - 1·7 (P = 0·032)/1·9 (P = 0·022)/2·0 (P = 0·017). In conclusion, obesity is a risk factor that influences treatment outcome in elderly female patients with aggressive B-cell lymphoma treated with R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisolone). The inferior outcomes in obese female patients may be due to faster rituximab clearance in obese females.

Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients.

Male sex is associated with unfavourable pharmacokinetics and prognosis in elderly patients with diffuse large B-cell lymphoma (DLBCL). We investigated higher rituximab doses for elderly male DLBCL patients. Elderly patients (61-80 years) received 6 cycles CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisone at 14-day intervals) and were randomized to 8 cycles rituximab (males 500 mg/m2 , females 375 mg/m2 ) every 2 weeks or according to an upfront dose-dense schedule. In 268 (120 females, 148 males) no difference between the standard and the upfront dose-dense rituximab schedule was found (3-year PFS 72% vs. 74%; OS 74% vs. 77%; P = 0.651). The 500 mg/m2 dose of rituximab for male patients was associated with serum levels and exposure times slightly better than in females and a male/female hazard ratio of 0.9 for progression-free survival (PFS) and 0.8 for overall survival. For elderly males, 500 mg/m2 was not more toxic than 375 mg/m2 rituximab, but improved PFS by 32.5% (P = 0.039), with a trend for a (30%) better overall survival (P = 0.076) in a planned subgroup analysis adjusting for International Prognostic Index risk factors. We conclude that the higher rituximab dose for elderly male patients abrogated the adverse prognosis of male sex without increasing toxicity. In the era of personalized medicine, sex-specific pharmacokinetics and toxicities should be investigated for all drugs where these parameters impact on outcome.

Second generation cephalosporin antibiotic prophylaxis and Clostridium difficile infection in hip and knee arthroplasty.

Introduction The use of broad spectrum cephalosporin antibiotics has been discouraged by the Department of Health in England because of the link to increased Clostridium difficile infection rates. The aim of this study was to evaluate whether a local protocol that included the use of second generation cephalosporin (cefuroxime) antibiotics as a prophylactic agent was associated with increased risk of C difficile in elective hip and knee arthroplasty patients. Methods A retrospective intention-to-treat study was conducted. An infection control database of all cases of C difficile infection both in hospital and in the community was reviewed and cross-referenced against surgical records. A positive correlation was identified when a C difficile positive sample was documented within eight weeks of arthroplasty surgery. Results Only 1 case (0.02%) of C difficile positive diarrhoea was identified that correlated to the 8-week postoperative period following 4,488 arthroplasty procedures. Conclusions The use of cephalosporin antibiotic prophylaxis in the elective hip and knee arthroplasty setting does not appear to be associated with increased C difficile infection rates, achieving surgical site infection rates that are comparable with the national average.

Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency.

Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first. Months before tumor onset, normal Msh2-deficient tissue contained tumor precursor cells forming organoids with higher MSI, cystic growth and growth rates resembling temporarily those of tumor organoids. Consistently, Msh2-deficient tissue exhibited a tumor-like gene signature. Normal Msh2-deficient organoids showed increased inheritable transient cyst-like growth, which became independent of R-spondin. ISC transformation proceeded faster in vitro than in vivo independent of the underlying genotype but more under MMR deficiency. Transient cyst-like growth but not MSI was suppressed by aspirin. In summary, as highlighted by organoids, molecular alterations continuously proceeded long before tumor onset in MMR-deficient intestine, thus increasing its susceptibility for ISC transformation.

Does laminar flow ventilation reduce the rate of infection? an observational study of trauma in England.

AIMS: To determine whether there is any difference in infection rate at 90 days between trauma operations performed in laminar flow and plenum ventilation, and whether infection risk is altered following the installation of laminar flow (LF). PATIENTS AND METHODS: We assessed the impact of plenum ventilation (PV) and LF on the rate of infection for patients undergoing orthopaedic trauma operations. All NHS hospitals in England with a trauma theatre(s) were contacted to identify the ventilation system which was used between April 2008 and March 2013 in the following categories: always LF, never LF, installed LF during study period (subdivided: before, during and after installation) and unknown. For each operation, age, gender, comorbidity, socio-economic deprivation, number of previous trauma operations and surgical site infection within 90 days (SSI90) were extracted from England's national hospital administrative Hospital Episode Statistics database. Crude and adjusted odds ratios (OR) were used to compare ventilation groups using hierarchical logistic regression. Subanalysis was performed for hip hemiarthroplasties. RESULTS: A total of 803 065 trauma operations were performed during this time; 19 hospitals installed LF, 124 already had LF, 13 had PV and the type of ventilation was unknown in 28. Patient characteristics were similar between the groups. The rate of SSI90 was similar for always LF and PV (2.7% and 2.4%). For hemiarthroplasties of the hip, the rates of SSI90 were significantly higher for LF compared with PV (3.8% and 2.6%, OR 1.45, p = 0·001). Hospitals installing LF did not see any statistically significant change in the rate of SSI90. CONCLUSION: The results of this observational study imply that infection rate is similar when orthopaedic trauma surgery is performed in LF and PV, and is unchanged by installing LF in a previously PV theatre. Cite this article: Bone Joint J 2016;98-B:1262-9.

Patient-specific instrumentation versus conventional instrumentation in total knee arthroplasty.

PURPOSE: To compare patient-specific instrumentation (PSI) with conventional instrumentation in total knee arthroplasty (TKA) in terms of component alignment, operating time, and the learning curve required in a non-teaching hospital. METHODS: Records of 33 men and 29 women aged 50 to 88 (mean, 71) years who underwent TKA for osteoarthritis using PSI (n=31) or conventional instrumentation (n=31) by a single surgeon were reviewed. The choice of instrumentation was made by the patient; the surgeon did not express any preference and had not used PSI before. All patients used the same cemented, cruciate-retaining system. RESULTS: The PSI and conventional instrumentation groups were comparable in terms of age, body mass index (BMI), American Society of Anesthesiologists grade, pre- and post-operative haemoglobin level, and the need for blood transfusion. Compared with conventional instrumentation, PSI resulted in a smaller coronal femoral component angle (7.7º vs. 6.4º, p=0.003) and posterior tibial slope angle (6.4º vs. 3.2º, p=0.0001), and smaller variance of the respective angles (p=0.006 and p=0.003). In patients with a BMI ≥30, PSI still resulted in a smaller posterior tibial slope angle (5.8º vs. 3.1º, p=0.015) and variance of the angle (p=0.02). The mean tourniquet time was shorter in the PSI group in all patients (p=0.013) and in patients with BMI ≥30 kg/m2 (p=0.0008), and its variance was also smaller in the PSI group (p=0.0004). There was no learning curve required. CONCLUSION: PSI was simple to use, with no learning curve required. It can be used in non-teaching hospitals and in patients with a high BMI and in cases where the use of an intramedullary alignment guide would be problematic due to previous femoral trauma.

[Gene expression analyses and their possible clinical benefit in head and neck cancer]. / Genexpressionsanalysen und ihrmöglicher klinischer Nutzen inder Betrachtung der Kopf-Hals-Karzinome

Systems biology approaches for mutational (exome analysis and targeted sequencing) and gene expression analysis (transcriptome-wide gene expression profiling) represent a new and growing scientific field in head and neck oncology. In addition to medical biological expertise, bioinformatic assistance is increasingly required. For squamous cell head and neck cancer (HNSCC), the recent molecular genetic single-gene and signal pathway observations represent basic research. Important aspects of this have now been significantly enhanced by systems biology approaches, which have grown into relevant areas of translational clinical research. It is now known that HPV16 is associated with genetic alterations at various locations, but also that it functionally affects genes not altered in their base sequence at the level of methylation. In transcriptome analyses, various consortia found matching clusters of gene expression and HPV16 association with the spectrum of somatic mutations. The differential methylation of gene promoters discovered in HPV16-driven HNSCC proved predictive for survival­even in HNSCC patients without HPV detection. The authors present an overview of some translationally relevant findings and venture an outlook on possible future clinical developments.

Different biological risk factors in young poor-prognosis and elderly patients with diffuse large B-cell lymphoma.

Prognostically relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors are also valid in younger, poor-prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14, 21 and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (P=0.002). Combined overexpression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared with an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker.

Genomic and epigenomic co-evolution in follicular lymphomas.

Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL.

Return to theatre for elective hip and knee replacements: what is the relative importance of patient factors, surgeon and hospital?

The aim of this study was to define return to theatre (RTT) rates for elective hip and knee replacement (HR and KR), to describe the predictors and to show the variations in risk-adjusted rates by surgical team and hospital using national English hospital administrative data. We examined information on 260 206 HRs and 315 249 KRs undertaken between April 2007 and March 2012. The 90-day RTT rates were 2.1% for HR and 1.8% for KR. Male gender, obesity, diabetes and several other comorbidities were associated with higher odds for both index procedures. For HR, hip resurfacing had half the odds of cement fixation (OR = 0.58, 95% confidence intervals (CI) 0.47 to 0.71). For KR, unicondylar KR had half the odds of total replacement (OR = 0.49, 95% CI 0.42 to 0.56), and younger ages had higher odds (OR = 2.23, 95% CI 1.65 to 3.01) for ages < 40 years compared with ages 60 to 69 years). There were more funnel plot outliers at three standard deviations than would be expected if variation occurred on a random basis. Hierarchical modelling showed that three-quarters of the variation between surgeons for HR and over half the variation between surgeons for KR are not explained by the hospital they operated at or by available patient factors. We conclude that 90-day RTT rate may be a useful quality indicator for orthopaedics.

CHO(E)P-14 followed by alemtuzumab consolidation in untreated peripheral T cell lymphomas: final analysis of a prospective phase II trial.

The rate of long-term remissions after treatment of peripheral T cell lymphomas (PTCL) with standard CHOP-like protocols is unsatisfactory. A prospective multicenter phase II trial was initiated in untreated patients with PTCL of all International Prognostic Index-risk groups, evaluating alemtuzumab consolidation in patients with complete or good partial remission after CHO(E)P-14 induction. Twenty-nine (70.7 %) of the 41 enrolled patients received alemtuzumab consolidation (133 mg in total). The main grades 3-4 toxicities during alemtuzumab therapy were infections and neutropenia with one potentially treatment-related death. Complete responses were seen in 58.5 %, partial responses in 2.4 % and 29.3 % had progressive disease. After a median observation time of 46 months, 19 patients have died, 16 of them due to lymphoma and/or salvage therapy complications. Event-free and overall survival at 3 years in the whole intent to treat population are 32.3 and 62.5 %, respectively, and 42.4 and 75.1 % in the patients who received alemtuzumab. In conclusion, application of a short course of alemtuzumab after CHO(E)P-14 induction is feasible although complicated by severe infections. A current phase III trial, applying alemtuzumab as part of the initial chemotherapy protocol to avoid early progression, will further clarify its significance for the therapeutic outcome.

Comparison and modelling of pegylated or unpegylated G-CSF schedules in CHOP-14 regimen of elderly patients with aggressive B-cell lymphoma.

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials.

Graduated compression stockings in hip fractures.

INTRODUCTION: Hip fractures are the most common cause of acute admissions to orthopaedics units and in the UK approximately 70,000-75,000 hip fractures occur annually. Hip fractures carry a significant risk of developing a venous thromboembolism. The National Institute for Health and Clinical Excellence (NICE) estimated that the risk of developing a venous thromboembolism in patients with hip fractures who do not receive thromboprophylaxis is 43%. In their recent guidelines, NICE recommended that combined mechanical and pharmacological thromboprophylaxis should be offered to patients undergoing hip fracture surgery and mechanical prophylaxis should be commenced at admission. The aim of this review was to search for available evidence that could support using graduated compression stockings combined with low molecular weight heparin (LMWH) in hip fracture patients. METHODS: NICE guidelines and the reference list of the guidance were reviewed and a thorough literature search was performed on main electronic databases (MEDLINE(®), Embase™ and the Cochrane Library). RESULTS: A literature search was unable to find sufficient evidence to support the use of graduated compression stockings combined with LMWH in hip fracture settings. The guidelines are critically reviewed and the available evidence is discussed. CONCLUSIONS: The evidence supporting these recommendations is very limited and there is considerable concern regarding the safety and efficacy of the mechanical devices used in thromboprophylaxis. Further studies are needed urgently before specific guidelines can be agreed confidently for patients with hip fractures.

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) ± etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.