Better long-term speech outcomes in stroke survivors who received early clinical speech and language therapy: What's driving recovery?

Establishing whether speech and language therapy after stroke has beneficial effects on speaking ability is challenging because of the need to control for multiple non-therapy factors known to influence recovery. We investigated how speaking ability at three time points post-stroke differed in patients who received varying amounts of clinical therapy in the first month post-stroke. In contrast to prior studies, we factored out variance from: initial severity of speaking impairment, amount of later therapy, and left and right hemisphere lesion size and site. We found that speaking ability at one month post-stroke was significantly better in patients who received early therapy (n = 79), versus those who did not (n = 64), and the number of hours of early therapy was positively related to recovery at one year post-stroke. We offer two non-mutually exclusive interpretations of these data: (1) patients may benefit from the early provision of self-management strategies; (2) therapy is more likely to be provided to patients who have a better chance of recovery (e.g., poor physical and/or mental health may impact suitability for therapy and chance of recovery). Both interpretations have implications for future studies aiming to predict individual patients' speech outcomes after stroke, and their response to therapy.

Right hemisphere structural adaptation and changing language skills years after left hemisphere stroke.

Stroke survivors with acquired language deficits are commonly thought to reach a 'plateau' within a year of stroke onset, after which their residual language skills will remain stable. Nevertheless, there have been reports of patients who appear to recover over years. Here, we analysed longitudinal change in 28 left-hemisphere stroke patients, each more than a year post-stroke when first assessed-testing each patient's spoken object naming skills and acquiring structural brain scans twice. Some of the patients appeared to improve over time while others declined; both directions of change were associated with, and predictable given, structural adaptation in the intact right hemisphere of the brain. Contrary to the prevailing view that these patients' language skills are stable, these results imply that real change continues over years. The strongest brain-behaviour associations (the 'peak clusters') were in the anterior temporal lobe and the precentral gyrus. Using functional magnetic resonance imaging, we confirmed that both regions are actively involved when neurologically normal control subjects name visually presented objects, but neither appeared to be involved when the same participants used a finger press to make semantic association decisions on the same stimuli. This suggests that these regions serve word-retrieval or articulatory functions in the undamaged brain. We teased these interpretations apart by reference to change in other tasks. Consistent with the claim that the real change is occurring here, change in spoken object naming was correlated with change in two other similar tasks, spoken action naming and written object naming, each of which was independently associated with structural adaptation in similar (overlapping) right hemisphere regions. Change in written object naming, which requires word-retrieval but not articulation, was also significantly more correlated with both (i) change in spoken object naming; and (ii) structural adaptation in the two peak clusters, than was change in another task-auditory word repetition-which requires articulation but not word retrieval. This suggests that the changes in spoken object naming reflected variation at the level of word-retrieval processes. Surprisingly, given their qualitatively similar activation profiles, hypertrophy in the anterior temporal region was associated with improving behaviour, while hypertrophy in the precentral gyrus was associated with declining behaviour. We predict that either or both of these regions might be fruitful targets for neural stimulation studies (suppressing the precentral region and/or enhancing the anterior temporal region), aiming to encourage recovery or arrest decline even years after stroke occurs.

The PLORAS Database: A data repository for Predicting Language Outcome and Recovery After Stroke.

The PLORAS Database is a relational repository of anatomical and functional imaging data that has primarily been acquired from stroke survivors, along with standardized scores on a wide range of sensory, motor and cognitive abilities, demographic details and medical history. As of January 2015, we have data from 750 patients with an expected accrual rate of 200 patients per year. Expansion will accelerate as we extend our collaborations. The main aim of the database is to Predict Language Outcome and Recovery After Stroke (PLORAS) on the basis of a single structural (anatomical) brain scan that indexes the stereotactic location and extent of brain damage. Predictions are made for individual patients by indicating how other patients with the most similar brain damage, cognitive abilities and demographic details recovered their language skills over time. Predictions are validated by longitudinal follow-ups of patients who initially presented with speech and language difficulties. The PLORAS Database can also be used to predict recovery of other cognitive abilities on the basis of anatomical brain scans. The functional imaging data can be used to understand the neural mechanisms that support recovery from brain damage; and all the data can be used to understand the main sources of inter-subject variability in structure-function mappings in the human brain. Data will be made available for sharing, subject to: funding, ethical approval and patient consent.

Gradual lesion expansion and brain shrinkage years after stroke.

BACKGROUND AND PURPOSE: Lesioned brains of patients with stroke may change through the course of recovery; however, little is known about their evolution in the chronic phase. Here, we aimed to quantify the extent of lesion volume change and brain atrophy in the chronic poststroke brain using magnetic resonance imaging. METHODS: Optimized T1-weighted scans were collected more than once (time between visits=2 months to 6 years) in 56 patients (age=36-90 years; time poststroke=3 months to 20 years). Volumetric changes attributable to lesion growth and atrophy were quantified with automated procedures. We looked at how volumetric changes related to time between visits, using nonparametric statistics, after controlling for age, time poststroke, and brain and lesion size at the earlier time. RESULTS: Lesions expanded more in patients who had longer time-intervals between their imaging sessions (partial rank correlation ρ=0.56; P<0.001). The median rate of lesion growth was 1.59 cm(3) per year. Across patients, the whole-brain atrophy rate was 0.95% per year, with accelerated atrophy in the ipsilesional hemisphere. CONCLUSIONS: We show gradual lesion expansion many years after stroke, beyond that expected by normal aging and after controlling for other variables. Future studies need to understand how structural reorganization enables long-term recovery even when the brain is shrinking.

Treatment of relapsed/refractory germ cell tumours: an equipoise between conventional and high dose therapy.

OPINION STATEMENT: Patients with relapsed germ cell tumors (GCT) are potentially curable despite the failure of initial cisplatin based therapy. The recent identification of robust prognostic markers has helped clarify this area of uncertainty. However, unlike the initial treatment of metastatic disease where cisplatin based combination therapy is standard of care, there is no consensus on treatment in the relapsed setting. Instead there is a genuine equipoise between high dose therapy (HDCT) and conventional dose therapy (CDCT) in this relapsed setting. The randomised data fails to support the use of HDCT although retrospective analysis consistently shows it may be superior, especially if tandem or triple high dose therapy is used. This has resulted in different approaches worldwide with some stating HDCT should not be used outside of a trial and others suggesting it is standard of care. Re-challenging relapsed patients with conventional dose cisplatin based therapy would seem to be counterintuitive, but the addition of drugs such as ifosamide and paclitaxel results in genuine activated in selected patients with relapsed disease. This appears particularly relevant as HDCT is associated with significant morbidity and mortality, which was highlighted in a randomised trial. However large single institution data suggests this treatment related toxicity may not be such as concern and treatment related mortality can be as low as only 3 % in selected centres. Overall there is a need to answer this question of CDCT v.s. HSCT definitively. For this reason a prospective global randomised trial (TIGER trial) comparing conventional dose therapy (paclitaxel, ifosamide and cisplatin [TIP]) and triple high dose therapy (paclitaxel and ifosamide followed by high dose carboplatin and etoposide [TI CE]) is planned for 2012 (TIGER trial). Due to the rarity of this disease and complexities associated with a global trial, this study faces many challenges. Nevertheless it is hoped that it will finally address this area major of uncertainty in GCTs.

The effect of sunitinib on immune subsets in metastatic clear cell renal cancer.

BACKGROUND: Sunitinib is standard first-line therapy for metastatic clear cell renal cancer (MCRC). It is associated with leucopenia; however, its effects on specific immune cell subsets are unclear. Alterations in immune cell subsets may contribute to tumour progression. METHODS: Lymphocyte subsets (CD3, 4, 8, 19 and 56) were measured in 43 untreated MCRC patients who received sunitinib. The protocol included a structured treatment interruption of 5 weeks. Cell populations were measured at specific time points during sunitinib treatment and the treatment break. RESULTS: Sunitinib was associated with significant declines in total leucocyte (-48%), neutrophil (-62%), CD3 total T cell (-31%) and CD4 counts (32%; p < 0.05). There was no significant change in CD19 B lymphocyte, CD8 or CD56 natural killer cells. During the sunitinib-free interval, all parameters recovered to baseline. No patients developed opportunistic infections or neutropenic sepsis. The level of specific immune subsets at presentation or occurrence of a fall in specific counts had an effect on progression-free survival (p > 0.05). CONCLUSIONS: Sunitinib is associated with reversible inhibition of specific lymphocyte subsets which has implications for the immunological control of MCRC and its use in combination with other agents. Despite suppressive effects, there was no evidence of predisposition to immune suppressive-related infection.

Phase 1, pharmacogenomic, dose-expansion study of pegargiminase plus pemetrexed and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer.

INTRODUCTION: We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis. METHODS: Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2 ) with Pem (500 mg/m2 ) and Cis (75 mg/m2 ), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry. RESULTS: ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%-97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%-70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9-4.8) and 7.2 (95% CI 5.1-18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3). CONCLUSIONS: ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.

Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer.

PURPOSE: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. PATIENTS AND METHODS: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. RESULTS: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. CONCLUSION: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.

On-line monitoring of continuous flow chemical synthesis using a portable, small footprint mass spectrometer.

For on-line monitoring of chemical reactions (batch or continuous flow), mass spectrometry (MS) can provide data to (1) determine the fate of starting materials and reagents, (2) confirm the presence of the desired product, (3) identify intermediates and impurities, (4) determine steady state conditions and point of completion, and (5) speed up process optimization. Recent developments in small footprint atmospheric pressure ionization portable mass spectrometers further enable this coupling, as the mass spectrometer can be easily positioned with the reaction system to be studied. A major issue for this combination is the transfer of a sample that is representative of the reaction and also compatible with the mass spectrometer. This is particularly challenging as high concentrations of reagents and products can be encountered in organic synthesis. The application of a portable mass spectrometer for on-line characterization of flow chemical synthesis has been evaluated by coupling a Microsaic 4000 MiD to the Future Chemistry Flow Start EVO chemistry system. Specifically, the Hofmann rearrangement has been studied using the on-line mass spectrometry approach. Sample transfer from the flow reactor is achieved using a mass rate attenuator (MRA) and a sampling make-up flow from a high pressure pump. This enables the appropriate sample dilution, transfer, and preparation for electrospray ionization. The capability of this approach to provide process understanding is described using an industrial pharmaceutical process that is currently under development. The effect of a number of key experimental parameters, such as the composition of the sampling make-up flow and the dilution factor on the mass spectrometry data, is also discussed.

A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer.

BACKGROUND: Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study. METHODS: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n=15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response. RESULTS: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5mg orally (PO) once daily (OD) and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1-4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2-11 months). Pharmacokinetic data at the MTD showed stable kinetics with time. CONCLUSION: Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

The management of low-stage non-seminomatous germ cell tumors.

The prognosis of patients with stage I non-seminomatous germ cell tumors is in general very good. However, a large number of patients relapse with metastatic disease after orchidectomy Therefore, adjuvant treatment, in the form of either chemotherapy or retroperitoneal dissection is recommended, although active surveillance has been found to be as good a way of treating these patients with overall excellent results.

Sequential FDG-PET/CT as a biomarker of response to Sunitinib in metastatic clear cell renal cancer.

PURPOSE: To test the hypothesis that sequential (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant. EXPERIMENTAL DESIGN: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. (18)F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUV(max)) at 4 and 16 weeks with overall survival (OS). RESULTS: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUV(max) = 6.8, range: <2.5-18.4). In multivariate analysis, a high SUV(max) and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36-8.45) and 3.67 (95% CI: 1.43-9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40-1.99) or OS (HR for responders = 0.80; 95% CI: 0.34-1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43-19.02) and HR = 12.13 (95% CI: 3.72-46.45), respectively]. CONCLUSIONS: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant.