Eribulin for the treatment of advanced breast cancer: A prospective observational registry study.

OBJECTIVE: Eribulin treatment improved overall survival with predictable toxicities in phase 3 trials of patients with previously treated, locally advanced/metastatic breast cancer. This study (NCT02443428) prospectively observed eribulin-treated patients in real-world clinical practice. METHODS: This observational multicentre registry study enrolled 76 patients with locally advanced/metastatic breast cancer who had ≤2 prior chemotherapeutic regimens for advanced disease. Eribulin was administered at a 1.23 mg/m2 dose (days 1 and 8 of every 21-day cycle). Adverse events (AEs) were monitored and effectiveness was assessed per local practice. RESULTS: AEs occurred in 98.7% of patients; 88.2% had eribulin-related AEs. The most common AEs were fatigue (64.5%), alopecia (36.8%), nausea (35.5%) and constipation (30.3%). Serious AEs occurred in 42.1% of patients. The most common grade 3/4 AEs were neutropenia (9.2%), febrile neutropenia (9.2%), dyspnoea (5.3%) and pleural effusion (5.3%). No fatal AEs occurred. Dose reductions occurred in 31.6% of patients, 42.1% experienced dose delays and 9.2% discontinued due to worsening condition. There were complete responses in 2.6% and partial responses in 15.8% of patients. Median time to progression and overall survival were 4.0 and 8.3 months, respectively. CONCLUSION: Eribulin was well tolerated in real-world clinical practice, comparable to safety and effectiveness reported in other clinical trials.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.

INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

A randomised, pragmatic clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (ACUFOCIN).

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity posing a major clinical challenge for managing patients receiving specific chemotherapy regimens (e.g., Taxanes). There is a growing body of literature suggesting acupuncture can improve CIPN symptoms. The purpose of the ACUFOCIN trial was to collect preliminary data on the safety, feasibility, acceptability and initial effectiveness of acupuncture as a treatment for CIPN, comparing use of acupuncture plus standard care (Acupuncture) against standard care alone (Control). METHOD: At a tertiary cancer centre, a pragmatic, randomised, parallel group design study was used to investigate the effectiveness of a 10-week course of acupuncture. Participants experiencing CIPN of ≥ Grade II, recording a 'Most Troublesome' CIPN symptom score of ≥3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised to 'Acupuncture' or 'Control' arms. Clinicians were blinded to allocated groups, however as it was not possible to blind participants, it cannot be guaranteed they did not disclose study allocation within their clinic assessments. The primary outcome measure was the number of patients reporting a ≥ 2-point improvement (success) in their MYMOP2 score at week 10. 100 participants (120 to allow for attrition) were required for a hypothesised improvement in success proportions from 30% to 55% using a primary analysis model with logistic regression adjusted for stratification factors and baseline MYMOP2 scores. Feasibility and acceptability of study design was addressed through percentage return of primary outcome, retention rate and a nested qualitative study. RESULTS: Primary MYMOP2 outcome data at week 10 was available for 108/120 randomised participants; this is greater than the 100 participants required to adequately power the study. There were 36/53 (68%) successes in 'Acupuncture' compared to 18/55 (33%) in 'Control'. Beneficial effects were seen in the secondary outcome data, including clinicians' grading of neuropathy, EORTC, QLQ-CIPN20, QLQ-C30 summary scores and patient reported pain scores. There were no serious adverse events reported within the study and only 16 acupuncture associated events, none of which required intervention. CONCLUSION: A 10-week course of acupuncture resulted in measurable improvement in participants symptoms of CIPN. The results warrant further investigation.

Prognostic factors for survival and ambulatory status at 8 weeks with metastatic spinal cord compression in the SCORAD randomised trial.

BACKGROUND: Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival. PATIENTS AND METHOD: SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348). RESULTS: The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p < 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p < 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set. CONCLUSIONS: Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.

Average duration of prior treatment lines predicts clinical benefit to eribulin chemotherapy in patients with metastatic breast cancer.

PURPOSE: The aim of this study was to identify factors associated with progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC) treated with eribulin in a real-world setting, to improve information provision in those considering treatment. METHODS: Patients treated with eribulin for MBC at The Christie NHS Foundation Trust, Manchester, UK, between August 2011 and December 2018 were included (n = 439). Data were collected by retrospective review of medical records and electronic prescribing systems. Factors such as biological subtype, distant recurrence-free interval, previous lines of chemotherapy and the 'average duration of previous treatment lines' (ADPT) (calculated as: (date of initiation of eribulin-date of MBC) / the number of previous treatment lines in the metastatic setting) were evaluated for prognostic impact using Cox proportional hazards regression. RESULTS: In the full cohort, the median PFS and OS were 4.1 months (95% CI 3.7-4.4) and 8.6 months (95% CI 7.4-9.8), respectively. Outcomes were significantly inferior for those with triple-negative breast cancer (TNBC) (n = 92); PFSTNBC: 2.4 months (95% CI 2.1-3.0), p = < 0.001 and OSTNBC: 5.4 months (95% CI 4.6-6.6), p = < 0.001. ADPT was the only factor other than subtype significantly associated with PFS and OS. Longer ADPT was also significantly associated with PFS and OS in those with TNBC. For example, women in the lowest ADPT tertile (< 5.0 months) achieved a median OS of only 4.3 months, whereas those in the upper ADPT tertile (> 8.7 months) had a median OS of 12.1 months (p = 0.004). CONCLUSION: Our results indicate that the ADPT lines is an important factor when predicting the outcome with eribulin chemotherapy in a palliative setting and that quantitative guidance on the likely PFS and OS with treatment can be provided using ADPT. Validation in additional cohorts is warranted.

A contemporary review of therapeutic and regenerative management of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) remains a common and debilitating form of stroke. This neurological emergency must be diagnosed and treated rapidly yet effectively. In this article, we review the medical, surgical, repair, and regenerative treatment options for managing ICH. Topics of focus include the management of blood pressure, intracranial pressure, coagulopathy, and intraventricular hemorrhage, as well as the role of surgery, regeneration, rehabilitation, and secondary prevention. Results of various phase II and III trials are incorporated. In summary, ICH patients should undergo rapid evaluation with neuroimaging, and early interventions should include systolic blood pressure control in the range of 140 mmHg, correction of coagulopathy if indicated, and assessment for surgical intervention. ICH patients should be managed in dedicated neurosurgical intensive care or stroke units where continuous monitoring of neurological status and evaluation for neurological deterioration is rapidly possible. Extravasation of hematoma may be helpful in patients with intraventricular extension of ICH. The goal of care is to reduce mortality and enable multimodal rehabilitative therapy.

Breast Cancer Management Guidelines During COVID-19 Pandemic.

The coronavirus disease (COVID-19) pandemic in 2020 has brought about complex challenges in healthcare delivery. With the new rules of lockdown and social distancing and with resources diverted to the management of COVID-19, there are difficulties in continuing usual cancer care. Patients are at risk of contracting COVID-19 with a high chance of patient to healthcare transmission and vice versa. Hospital visits, investigations and all modalities of treatment have potential complications that put patients at risk, some more than others. In this situation, there is a need to change our approach in the management of breast cancer to deliver it safely. We present modified guidelines based on the available consensus statements and evidence.

Systemic anti-cancer therapy delivery in the home: a service model.

The Christie NHS Foundation Trust is a leader in adapting patient care in response to treatment advances and new patient-centred care/efficiency initiatives. Due to extended waiting times in cancer clinics, The Christie developed an at-home treatment service to help reduce the pressure on clinics and improve patient experience. This article provides a detailed examination of the requirements necessary to successfully develop a home service for the delivery of systemic anticancer treatment. The authors discuss the criteria used to identify suitable at-home treatments, as well as necessary resources and equipment. The success of the Christie at Home service was examined using a patient survey to assess the standard of this care. Details are given regarding the challenges of implementing a homecare service and potential future challenges. As an example, systemic treatment with eribulin as a 'Christie at Home' therapy demonstrates the practicalities of introduction of new therapies in a homecare service.

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function.

BACKGROUND: Human umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI). METHODS: HUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals. RESULTS: We found that CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control. Cerebrovascular reactivity within the stroke-affected area, measured by CBF fMRI, was also increased (35.2 ± 3.5% versus 12.8 ± 4.3%), as well as the corresponding cerebrovascular density. Some engrafted cells appeared with microvascular-like morphology and stained positive for von Willebrand Factor (an endothelial cell marker), suggesting they differentiated into endothelial cells. Some engrafted cells also connected to host endothelial cells, suggesting they interacted with the host vasculature. Compared to the vehicle group, infarct volume at 28 days in the stem cell treated group was significantly smaller (160.9 ± 15.7 versus 231.2 ± 16.0 mm3); behavioral deficits were also markedly reduced by stem cell treatment at day 28 (19.5 ± 1.0% versus 30.7 ± 4.7% on the foot fault test; 68.2 ± 4.6% versus 86.6 ± 5.8% on the cylinder test). More tissue within initial perfusion-diffusion mismatch was rescued in the treatment group. CONCLUSIONS: Intraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume.

A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.

BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Multicenter experience of nonpegylated liposomal doxorubicin use in the management of metastatic breast cancer.

BACKGROUND: This study aimed to investigate the use of nonpegylated liposomal doxorubicin (NPLD) in the management of metastatic breast cancer (MBC) within routine UK clinical practice and to assess its efficacy and tolerability. PATIENTS AND METHODS: All patients that received NPLD for MBC at 5 institutions were identified. Clinicopathologic details, echocardiographic data, and toxicities were documented. Response to treatment, outcome, cardiotoxicity, and safety were assessed. RESULTS: 63 patients (median age at NPLD therapy, 53.5 years) who had received NPLD were identified; 18 (29%) were anthracycline-naïve, and 42 (67%) were anthracycline-pretreated (median cumulative dose of epirubicin, 450 mg/m(2)). In 3 cases, prior treatment history was not available. NPLD was most frequently (16 [25%] of 63 patients) administered as first-line chemotherapy (median, third-line; range, 1-9), although it was given later in anthracycline-pretreated patients (median, fourth-line; range, 1-9). Overall, 14 (29%) of 49 evaluable patients achieved an objective response, which increased to 10 (71%) of 14 when NPLD was given first-line (anthracycline-naïve, 8 [100%] of 8; anthracycline-pretreated, 2 [50%] of 4; adjuvant treatment unknown, 2). Median progression-free survival was 7 months (first-line, 18 months, vs. ≥ second-line, 6 months; P = .0066), and median overall survival was 10 months (first-line, 18 months, vs. ≥ second-line, 10 months; P = .0971). Toxicities tended to be grade 1 or 2. Three patients had cardiotoxicity (left ventricular ejection fraction < 50% or a fall of ≥ 10% from baseline), which resolved during treatment. CONCLUSION: NPLD was used in both anthracycline-naïve patients and those with prior exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines, with a low incidence of cardiotoxicity.

Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy.

OBJECTIVE: Cell-based therapies are being investigated as an adjunct to IV thrombolysis or mechanical thrombectomy in ischemic stroke. This review summarizes the potential applications as well as challenges of intravascular cell delivery in ischemic stroke. METHOD: We conducted a search of Medline as well as the clinicaltrials.gov Web site for all ongoing human clinical studies using stem cells in ischemic stroke patients. RESULT: The pros and cons of the various donor cell types and routes of cell delivery, including intravascular delivery, in ischemic stroke are discussed. In addition, the potential challenges in translation from bench to bedside, the optimal techniques for intravascular cell delivery, and an updated comprehensive list of ongoing clinical trials in ischemic stroke are highlighted. CONCLUSIONS: Stem cells have shown a promising role in ischemic stroke, in preclinical studies as well as initial pilot studies. Further studies are needed to assess intravascular cell therapy as a potential adjunct to thrombolysis or mechanical thrombectomy in ischemic stroke.

Nitric oxide facilitates delivery and mediates improved outcome of autologous bone marrow mononuclear cells in a rodent stroke model.

BACKGROUND: Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke. METHODS: Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed. RESULTS: CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits. CONCLUSIONS: NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.

Intra-arterial delivery of cell therapies for stroke.

Cell therapy is a novel investigational approach to enhance stroke recovery. Intra-arterial (IA) delivery has the potential advantage of selectively targeting cell therapies to the ischemic brain tissue. Over the past 10 years, IA cell delivery has been under investigation in patients with cardiac and peripheral vascular disease, and these studies have reported promising results. This article reviews the trial methodology and procedural details of these studies and discusses the rationale and challenges in designing IA cell therapy trials for ischemic stroke.

Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study.

BACKGROUND: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. METHODS: 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. FINDINGS: None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. INTERPRETATION: We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. FUNDING: Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.

Intravenous autologous bone marrow mononuclear cells for ischemic stroke.

OBJECTIVE: Cellular therapy is an investigational approach for stroke. Mononuclear cells (MNCs) from the bone marrow reduce neurological deficits in animal stroke models. We determined if autologous MNC infusion was feasible and safe in patients with ischemic stroke. METHODS: We conducted an open-label prospective study of a bone marrow harvest followed by readministration of autologous MNCs in 10 patients, 18 to 80 years old, with acute middle cerebral artery ischemic stroke. Bone marrow was aspirated from the iliac crest, and MNCs were separated at a Good Manufacturing Practices facility and administered intravenously up to a maximum of 10 million cells/kg. The harvest and infusion had to occur between 24 and 72 hours after stroke. Patients were monitored for 6 months. RESULTS: Bone marrow aspiration was successfully completed in all patients. Eight received 10 million cells/kg, and 2 received ≥7 million cells/kg. There were no significant adverse events related to harvest or infusion. Two patients had infarct expansion between enrollment and harvest and underwent hemicraniectomy after cell infusion. One patient died at 40 days due to a pulmonary embolism related to the stroke. There were no study-related severe adverse events. Median National Institutes of Health Stroke Scale score was 13 before harvest, 8 at 7 days, and 3 at 6 months. At 6 months, all surviving patients had shifted down by at least 1 point on the modified Rankin Scale compared to day 7. Seven of 10 patients achieved a Barthel Index ≥90. INTERPRETATION: This study suggests that a bone marrow harvest and reinfusion of autologous MNCs were safe and feasible in acute stroke patients.

Rechallenging with anthracyclines and taxanes in metastatic breast cancer.

Adjuvant use of anthracycline-taxane combination therapy is an accepted strategy in the management of high-risk early-stage breast cancer. However, the introduction of this regimen raises the question of how best to manage those patients who relapse following adjuvant therapy, and whether there is a role for rechallenging in the metastatic setting with the same agent, or class of agent, that has been utilized in the adjuvant setting. This Review examines the evidence for rechallenging with both anthracyclines and taxanes, and highlights the issues that need to be examined in the context of future clinical trials.

Evolving therapies for multiple sclerosis.

The introduction of immunomodulatory and immunosuppressive agents for treatment of multiple sclerosis (MS) has forever altered the natural course of this incurable and disabling neurodegenerative disorder. Despite early diagnosis of relapsing-remitting MS and early initiation of therapy, patients still experience breakthrough relapses and progression of their underlying MS pathology. The imperfect effectiveness, side effects, and toxicity of these agents, emphasize the necessity for development of more effective medications with less adverse events. This chapter presents readers with the most current information on the nature, mechanism(s) of action, and side effects of the most promising experimental agents currently under clinical trials. Some of the agents now at different stages of clinical trial have emerged as both safe and promising. The understanding of MS etiology will lead to the development of increasingly specific, safer, and effective treatments for MS by neuroscientists and neurologists.