A computational model of neurodegeneration in Alzheimer's disease.

Disruption of mental functions in Alzheimer's disease (AD) and related disorders is accompanied by selective degeneration of brain regions. These regions comprise large-scale ensembles of cells organized into systems for mental functioning, however the relationship between clinical symptoms of dementia, patterns of neurodegeneration, and functional systems is not clear. Here we present a model of the association between dementia symptoms and degenerative brain anatomy using F18-fluorodeoxyglucose PET and dimensionality reduction techniques in two cohorts of patients with AD. This reflected a simple information processing-based functional description of macroscale brain anatomy which we link to AD physiology, functional networks, and mental abilities. We further apply the model to normal aging and seven degenerative diseases of mental functions. We propose a global information processing model for mental functions that links neuroanatomy, cognitive neuroscience and clinical neurology.

Effectiveness of The Wikipedia Collaboration of Dental Schools' Training Programme: a new Paradigm for Teaching and Learning of Evidence-Based Dentistry.

BACKGROUND: The Wikipedia Collaboration of Dental Schools (WCODS) is a student-led initiative that aims to publish high quality scientific, evidence-based dental content on the Wikipedia online encyclopaedia by equipping its members to use research, critical appraisal and writing skills to create accurate content. In 2019, the Collaboration launched a standardised training programme developed by Wikimedia-trained committee members, academic dental school staff and the Cochrane Oral Health global community. OBJECTIVE: To evaluate the effectiveness of this training programme in ensuring WCODS editors follow the processes underpinning Evidence-Based Dentistry (EBD). METHOD: A cohort of dental students and staff (n=136) from six dental schools in the UK and Malaysia took part in a standardised and structured training programme at the annual WCODS training meeting. Participants' abilities and their perceived levels of confidence in carrying out critical analysis of the literature were measured using pre- and post-training surveys, and competency assessments. RESULTS: Participants' skills in conducting literature searches, critical appraisal of the findings and creating and editing a Wikipedia page improved after training. CONCLUSION: The training programme provided participants with the skill set and confidence to apply best practice to create and edit Wikipedia entries. This Collaboration intends to recruit more contributors to improve global oral health literacy using the free online Wikipedia encyclopaedia.

Changes in Ventricular and Cortical Volumes following Shunt Placement in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: While changes in ventricular and extraventricular CSF spaces have been studied following shunt placement in patients with idiopathic normal pressure hydrocephalus, regional changes in cortical volumes have not. These changes are important to better inform disease pathophysiology and evaluation for copathology. The purpose of this work is to investigate changes in ventricular and cortical volumes in patients with idiopathic normal pressure hydrocephalus following ventriculoperitoneal shunt placement. MATERIALS AND METHODS: This is a retrospective cohort study of patients with idiopathic normal pressure hydrocephalus who underwent 3D T1-weighted MR imaging before and after ventriculoperitoneal shunt placement. Images were analyzed using tensor-based morphometry with symmetric normalization to determine the percentage change in ventricular and regional cortical volumes. Ventricular volume changes were assessed using the Wilcoxon signed rank test, and cortical volume changes, using a linear mixed-effects model (P < .05). RESULTS: The study included 22 patients (5 women/17 men; mean age, 73 [SD, 6] years). Ventricular volume decreased after shunt placement with a mean change of -15.4% (P < .001). Measured cortical volume across all participants and cortical ROIs showed a mean percentage increase of 1.4% (P < .001). ROIs near the vertex showed the greatest percentage increase in volume after shunt placement, with smaller decreases in volume in the medial temporal lobes. CONCLUSIONS: Overall, cortical volumes mildly increased after shunt placement in patients with idiopathic normal pressure hydrocephalus with the greatest increases in regions near the vertex, indicating postshunt decompression of the cortex and sulci. Ventricular volumes showed an expected decrease after shunt placement.

"I guess it looks worse to me, it doesn't look like there's been a problem solved but obviously there is": a qualitative exploration of children's and their parents' views of silver diamine fluoride for the management of carious lesions in children.

BACKGROUND: Despite growing evidence to support the use of silver diamine fluoride (SDF) for managing carious lesions, and the increased interest in SDF worldwide, uptake in the UK remains limited. This study explored parents' and children's views and acceptability of SDF for the management of carious lesions in children. METHODS: Eleven semi-structured face-to-face interviews were conducted with 11 parent-child dyads recruited from patients attending Dundee Dental Hospital and School. Interviews were transcribed verbatim, coded and thematically analysed. RESULTS: Previous dental experience varied across all child participants. Of the 11 children, five had undergone general anaesthesia (GA) for multiple primary tooth extractions. Two had received SDF treatment. Child participants expressed concerns about being picked on by their peers, if they had discoloured anterior teeth. Younger children appeared less concerned about the discolouration and child's gender did not appear to influence parents' decision-making, nor the child's preferences regarding the use of SDF. Parents considered SDF to be particularly useful for anxious or uncooperative children but raised concerns about potential bullying at schools due to the unacceptable dental aesthetics when SDF is applied to anterior teeth. They believed they may be judged by others as neglecting their child's oral health due to the black staining. Both parents and children were more accepting of the SDF when applied to less-visible posterior teeth. Parents accepted the use of SDF if such treatment avoided extractions under GA. CONCLUSION: Despite the unfavourable aesthetics of SDF (black staining), parents appreciated SDF treatment, especially for uncooperative or younger children. However, both parents and children shared concerns about bullying at schools as a consequence of the black staining. Raising awareness about SDF was identified as one approach to encourage the uptake of SDF.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Metrics of progress in the understanding and management of threats to Australian birds.

Although evidence-based approaches have become commonplace for determining the success of conservation measures for the management of threatened taxa, there are no standard metrics for assessing progress in research or management. We developed 5 metrics to meet this need for threatened taxa and to quantify the need for further action and effective alleviation of threats. These metrics (research need, research achievement, management need, management achievement, and percent threat reduction) can be aggregated to examine trends for an individual taxon or for threats across multiple taxa. We tested the utility of these metrics by applying them to Australian threatened birds, which appears to be the first time that progress in research and management of threats has been assessed for all threatened taxa in a faunal group at a continental scale. Some research has been conducted on nearly three-quarters of known threats to taxa, and there is a clear understanding of how to alleviate nearly half of the threats with the highest impact. Some management has been attempted on nearly half the threats. Management outcomes ranged from successful trials to complete mitigation of the threat, including for one-third of high-impact threats. Progress in both research and management tended to be greater for taxa that were monitored or occurred on oceanic islands. Predation by cats had the highest potential threat score. However, there has been some success reducing the impact of cat predation, so climate change (particularly drought), now poses the greatest threat to Australian threatened birds. Our results demonstrate the potential for the proposed metrics to encapsulate the major trends in research and management of both threats and threatened taxa and provide a basis for international comparisons of evidence-based conservation science.

Medidas de Progreso en el Entendimiento y el Manejo de las Amenazas que Enfrentan las Aves Australianas Resumen Aunque los métodos basados en evidencias se han vuelto muy comunes para la determinación del éxito de las medidas de conservación del manejo de los taxones amenazados, hoy en día no existen medidas estandarizadas para la evaluación del progreso de la investigación o el manejo. Desarrollamos cinco medidas para cumplir con esta necesidad que tienen los taxones amenazados y para cuantificar la necesidad de una mayor acción y un alivio efectivo de las amenazas. Estas medidas (falta de investigación, éxito de la investigación, falta de manejo, éxito del manejo y porcentaje de reducción de amenazas) pueden agregarse para examinar las tendencias de un taxón individual o las tendencias de las amenazas para múltiples taxones. Probamos la utilidad de estas medidas por medio de su aplicación en aves australianas amenazadas, que parece ser la primera vez que se evalúa el progreso en la investigación y en el manejo de amenazas para el caso de varios taxones amenazados dentro de un grupo faunístico a escala continental. Se ha realizado algún tipo de investigación sobre casi tres cuartas partes de las amenazas conocidas para los taxones, y hay un claro entendimiento de cómo aliviar casi la mitad de las amenazas con el impacto más alto. Se ha intentado algún tipo de manejo con casi la mitad de las amenazas. Los resultados del manejo variaron desde ensayos exitosos hasta la mitigación completa de la amenaza, incluso para un tercio de las amenazas de alto impacto. Tanto el progreso en la investigación como en el manejo tendió a ser mayor para los taxones que estaban siendo monitoreados, o que ocurrían en islas oceánicas. La depredación por gatos tuvo el puntaje más como amenaza potencial. Sin embargo, ha habido poco de éxito en la reducción del impacto de la depredación por gatos, así que ahora el cambio climático (particularmente la sequía) es la mayor amenaza para las aves amenazadas en Australia. Nuestros resultados demuestran el potencial que tienen las medidas propuestas de encapsular las tendencias más importantes en la investigación y en el manejo tanto de las amenazas como de los taxones amenazados y de proporcionar una base para comparaciones internacionales de la ciencia de la conservación basada en evidencias.

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

BACKGROUND: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. PATIENTS AND METHODS: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. RESULTS: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. CONCLUSION: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. CLINICALTRIALS.GOV: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.

BACKGROUND: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients ≥60 years treated on the R-CHOP14v21 trial with extended follow-up. PATIENTS AND METHODS: Six hundred and four R-CHOP14v21 patients ≥60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. RESULTS: Elderly DLBCL patients received high dose intensities with median total doses of ≥98% for all agents. Toxicities were similar in both arms with the exception of more grade ≥3 neutropenia (P < 0.0001) and fewer grade ≥3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. CONCLUSIONS: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. TRIAL NUMBERS: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study.

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma: An updated review of published data from the named patient program.

Brentuximab vedotin was available via named patient program (NPP) to patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma in ∼60 non-US/Canadian countries, before local approval. Published results were examined recently; through systematic literature review, we identified 12 new NPP publications. Most (10/12) publications included new NPP data describing 8 unique cohorts (N=480; all R/R HL) and new participating countries. Overall response rates were 58-80%, and complete remission rates were 10-40%. With median follow-up of 9.5-26 months, median progression-free survival was 5-10.5 months and median overall survival (OS) had not been reached in most cohorts; 1- and 2-year OS was 67-76% and 58-67%, respectively. Tolerability was as expected from previous reports. Despite intrinsic bias and heterogeneous cohorts, this update supports previous findings showing comparable efficacy and tolerability of brentuximab vedotin between real-world practice and phase 2 trial results in R/R HL.

Distinguishing clinical and radiological features of non-traumatic convexal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The full spectrum of causes of convexal subarachnoid hemorrhage (cSAH) requires further investigation. Therefore, our objective was to describe the spectrum of clinical and imaging features of patients with non-traumatic cSAH. METHODS: A retrospective observational study of consecutive patients with non-traumatic cSAH was performed at a tertiary referral center. The underlying cause of cSAH was characterized and clinical and imaging features that predict a specific etiology were identified. The frequency of future cSAH or intracerebral hemorrhage (ICH) was determined. RESULTS: In all, 88 patients [median age 64 years (range 25-85)] with non-traumatic cSAH were identified. The most common causes were reversible cerebral vasoconstriction syndrome (RCVS) (26, 29.5%), cerebral amyloid angiopathy (CAA) (23, 26.1%), indeterminate (14, 15.9%) and endocarditis (9, 10.2%). CAA patients commonly presented at an older age than RCVS patients (75 years versus 51 years, P < 0.0001). Thirteen patients (14.7%) had recurrent cSAH, and 12 patients (13.6%) had a subsequent ICH. However, the risk was high amongst those with CAA compared to those caused by RCVS, with recurrent cSAH in 39.1% and subsequent lobar ICH in 43.5% of CAA cases. CONCLUSIONS: Our study demonstrates the clinical diversity of cSAH. Older age, sensorimotor dysfunction and stereotyped spells suggest CAA as the underlying cause. Younger age and thunderclap headache predict RCVS. Yet, various other causes also need to be considered in the differential diagnosis.

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study.

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Experience of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma and relapsed/refractory systemic anaplastic large-cell lymphoma in the Named Patient Program: Review of the literature.

Brentuximab vedotin was made available via a Named Patient Program (NPP) to non-US/Canadian patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL) until approval in their respective countries. We re-evaluated the efficacy and safety NPP data in a pooled analysis. Through a systematic literature review, 21 NPP publications were identified describing 14 cohorts (N=245). Among patients with a specified diagnosis, 207 had HL, 28 had ALCL, and one had CD30+ T-cell lymphoma (not specified). In cohorts reporting response, overall response and complete remission rates were 67% and 26%, respectively, in R/R HL, and 75% and 74%, respectively, in R/R ALCL. Incidences of grade 3/4 neurologic and hematologic toxicities were 6% and 12%, respectively; 5% of patients discontinued because of toxicity. In real-world practice, response rates and tolerability to brentuximab vedotin are similar to those reported in the two pivotal phase 2 trials in these settings.

The clinical features, management and prognostic effects of pathological fractures in a multicenter series of 373 patients with diffuse large B-cell lymphoma of the bone.

BACKGROUND: Pathological fractures (PFs) occur in 10%-20% of patients with diffuse large B-cell lymphoma (DLBCL) of the bone. The clinical features and the effects of this severe complication on management and prognosis have not been previously analyzed in a large series. PATIENTS AND METHODS: The effects of PF on management and prognosis were reviewed in an international retrospective series of 373 patients with newly diagnosed bone DLBCL, comparing 78 patients with PF at presentation (group 'PF-BL') and 295 patients without PF ('controls'). RESULTS: At a median follow-up of 53 months (range 3-246), PF-BL patients exhibited lower rates of overall response (ORR, 78% versus 85%; P = 0.17), 5-year progression-free survival (PFS, 53 ± 6% versus 61 ± 3%; P = 0.02) and 5-year overall survival (OS, 54 ± 6% versus 68 ± 3%, P = 0.008) than controls. Initial surgical stabilization of the PF did not change therapeutic outcome (5-year OS: 45 ± 9% versus 54 ± 10%; P = 0.20). PF-BL patients referred to irradiation of the fractured bone before chemotherapy exhibited a significantly poorer outcome than patients managed with the inverse sequence (ORR: 52% versus 92%, P = 0.0005; 5-year OS: 22 ± 14% versus 64 ± 9%, P = 0.007). Multivariate analysis confirmed the independent association between PF and worse survival and the negative effect of radiotherapy as initial therapy. CONCLUSION: Fracture is an independent, adverse prognostic event in patients with bone DLBCL. Anthracycline-based chemotherapy followed by radiotherapy seems to be the better treatment sequence. Initial fracture stabilization does not seem to improve outcome; it should be used to improve patient's quality of life only if chemotherapy delays can be avoided.

A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity.

BACKGROUND: Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1-3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured. METHODS: Dose escalation of doxorubicin in cycles 1-3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m(-2)) with doxorubicin reduced to 25 mg m(-2) or omitted in cycles 4-6 to maintain cumulative exposure of 103-130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD. RESULTS: Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m(-2), so 45 mg m(-2) was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD. CONCLUSION: Escalated ABVD incorporating doxorubicin at 45 mg m(-2) in cycles 1-3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.