A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Radiation fibrosis--current clinical and therapeutic perspectives.

Cancer survivors previously treated with curative radiotherapy are at risk of developing long-term toxicities due to radiation-induced normal tissue injury. Radiation fibrosis is an important component of the spectrum of radiation injury and at the present time treatment for this condition is limited. Data from both studies of clinical intervention and from preclinical models support the idea that fibrosis is a dynamic process and may in part be reversible. Clinical therapeutic interventions for radiation fibrosis have included empirical treatments, such as antioxidant therapies using superoxide dismutase, or vitamin E and pentoxifylline, and although evidence for therapeutic efficacy exists, further randomised studies are required. Potential therapeutic strategies that have shown promise in preclinical models include targeting pro-fibrotic cytokines such as: (1) transforming growth factor beta 1, (2) platelet-derived growth factor and its receptor tyrosine kinase and (3) connective tissue growth factor and the Rho/ROCK intracellular signalling pathway. Progress in the understanding of stem cell biology and the involvement of stem cells in radiation injury has led to the investigation of their role as a therapeutic strategy for ameliorating this disease process by promoting organ regeneration and repair. In this review we discuss the clinical and pathological features of radiation fibrosis and present the available clinical data and laboratory data relevant to these approaches to therapeutic intervention.

Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders.

The primary aim of this randomized, controlled trial was to assess the effectiveness of botulinum toxin A (BoNT-A) injections into the submandibular and parotid glands on drooling in children with cerebral palsy (CP) and other neurological disorders. Secondary aims were to ascertain the duration of any such effect and the timing of maximal response. Of the 48 participants (27 males, 21 females; mean age 11y 4mo [SD 3y 3mo], range 6-18y), 31 had a diagnosis of CP and 15 had a primary intellectual disability; 27 children were non-ambulant. Twenty-four children randomized to the treatment group received 25 units of BoNT-A into each parotid and submandibular gland. Those randomized to the control group received no treatment. The degree and impact of drooling was assessed by carers using the Drooling Impact Scale questionnaire at baseline and at monthly intervals up to 6 months postinjection/baseline, and again at 1 year. Maximal response was at 1 month at which time there was a highly significant difference in the mean scores between the groups. This difference remained statistically significant at 6 months. Four children failed to respond to the injections, four had mediocre results, and 16 had good results. While the use of BoNT-A can help to manage drooling in many children with neurological disorders, further research is needed to fully understand the range of responses.

Hypoxia can be detected in irradiated normal human tissue: a study using the hypoxic marker pimonidazole hydrochloride.

Chronic tissue hypoxia may play a role in the pathogenesis of late radiation fibrosis. In order to investigate this hypothesis, the immunohistochemical distribution of pimonidazole hydrochloride (n = 14 patients) and carbonic anhydrase IX (CAIX) (n = 38 patients) was studied in samples of previously irradiated normal human tissue. One sample of irradiated breast tissue, which also showed marked histological features of radiation injury, stained positive for pimonidazole hydrochloride. No CAIX staining was seen in irradiated tissue other than some evidence of physiological hypoxia in the epidermis of two samples of irradiated skin; both were positive for pimonidazole and one was focally positive for CAIX. Pimonidazole hydrochloride staining of tissue with morphological changes of radiation injury could support a role for hypoxia in the pathogenesis of late normal tissue fibrosis in humans.

The impact of expression profiling on prognostic and predictive testing in breast cancer.

Expression profiling has been extensively applied to the study of breast cancer and undoubtedly is changing the way breast cancer is perceived. Over the past few years, several groups have described prognostic "signatures" (gene lists) that are purported to be more accurate prognostic factors than well established clinical and pathological features. In addition, cDNA and oligonucleotide microarrays have also been used to devise predictive "signatures" in the setting of neoadjuvant chemotherapy setting. However, it seems that the enthusiasm with this new technology has led most of us to turn a blind eye to some serious methodological problems which are evident in landmark papers on breast cancer expression profiling. These issues include small and biased cohorts of patients, inappropriate statistical analysis and lack of thorough validation of the technology. In this review, we critically revisit the most relevant cDNA microarray studies on breast cancer prognosis and prediction published to date. Although the results are promising, further optimisation and standardisation of the technique and properly designed clinical trials are required before microarrays can reliably be used as tools for clinical decision making.

Distinct brain systems for processing concrete and abstract concepts.

Behavioral and neurophysiological effects of word imageability and concreteness remain a topic of central interest in cognitive neuroscience and could provide essential clues for understanding how the brain processes conceptual knowledge. We examined these effects using event-related functional magnetic resonance imaging while participants identified concrete and abstract words. Relative to nonwords, concrete and abstract words both activated a left-lateralized network of multimodal association areas previously linked with verbal semantic processing. Areas in the left lateral temporal lobe were equally activated by both word types, whereas bilateral regions including the angular gyrus and the dorsal prefrontal cortex were more strongly engaged by concrete words. Relative to concrete words, abstract words activated left inferior frontal regions previously linked with phonological and verbal working memory processes. The results show overlapping but partly distinct neural systems for processing concrete and abstract concepts, with greater involvement of bilateral association areas during concrete word processing, and processing of abstract concepts almost exclusively by the left hemisphere.

Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas.

BACKGROUND: The aim of this study was to assess the efficacy of temozolomide in patients with World Health Organisation (WHO) grade II gliomas treated with surgery alone using imaging and clinical criteria. PATIENTS AND METHODS: Thirty patients with histologically verified WHO grade II gliomas (17 astrocytoma, 11 oligodendroglioma, two mixed oligoastrocytoma) following surgery 2-104 months (median 23 months) after initial diagnosis received temozolomide 200 mg/m(2)/day for 5 days, on a 28-day cycle, for a maximum of 12 cycles or until tumour progression. Median age was 40 years (range 25-68 years). Median follow-up from entry into the study was 3 years [range 23-47 months (for patients alive)]. Objective response was assessed by 3-monthly magnetic resonance imaging and monthly health-related quality of life (HQoL) and clinical assessment. Tumour size was measured as the high signal intensity area on fluid attenuated inversion recovery sequences. Responses were assessed using change in the product of two perpendicular diameters as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). RESULTS: Twenty-nine of 30 patients entered into the study were evaluable for response. Three patients had a PR, 14 MR, 11 SD and one PD. Twenty-four patients received 12 cycles of chemotherapy. Of 29 evaluable patients, three discontinued after four, five and six cycles and two after 10 cycles. Nine patients progressed (three during chemotherapy-one PD and two initial SD-and six after completion of chemotherapy); five had evidence of transformation. The 3-year progression-free survival was 66%. Five patients died; the actuarial 3-year survival was 82%. Ninety-six per cent of patients with impaired HQoL had improvement in at least one HQoL domain. There was improvement in 115 of the 207 domains (56%). Fifteen of 28 patients (54%) with epilepsy had reduction in seizure frequency, of whom six became seizure free. Six patients had transient grade III/IV haematological toxicity (11 episodes; 3.5%). CONCLUSIONS: Temozolomide has single-agent activity in patients with WHO grade II cerebral glioma, with modest improvement in quality of life and improvement in epilepsy control. On present evidence, temozolomide cannot be considered as primary therapy without formal comparison with other treatment modalities.

Neural correlates of lexical access during visual word recognition.

People can discriminate real words from nonwords even when the latter are orthographically and phonologically word-like, presumably because words activate specific lexical and/or semantic information. We investigated the neural correlates of this identification process using event-related functional magnetic resonance imaging (fMRI). Participants performed a visual lexical decision task under conditions that encouraged specific word identification: Nonwords were matched to words on orthographic and phonologic characteristics, and accuracy was emphasized over speed. To identify neural responses associated with activation of nonsemantic lexical information, processing of words and nonwords with many lexical neighbors was contrasted with processing of items with no neighbors. The fMRI data showed robust differences in activation by words and word-like nonwords, with stronger word activation occurring in a distributed, left hemisphere network previously associated with semantic processing, and stronger nonword activation occurring in a posterior inferior frontal area previously associated with grapheme-to-phoneme mapping. Contrary to lexicon-based models of word recognition, there were no brain areas in which activation increased with neighborhood size. For words, activation in the left prefrontal, angular gyrus, and ventrolateral temporal areas was stronger for items without neighbors, probably because accurate responses to these items were more dependent on activation of semantic information. The results show neural correlates of access to specific word information. The absence of facilitatory lexical neighborhood effects on activation in these brain regions argues for an interpretation in terms of semantic access. Because subjects performed the same task throughout, the results are unlikely to be due to task-specific attentional, strategic, or expectancy effects.

Raynaud's phenomenon after radical radiotherapy for tumours of the head and neck.

Endothelial cell injury is implicated in the development of radiation induced tissue damage and may also be involved in the pathophysiology of secondary Raynaud's phenomenon. Two patients are presented in whom the typical symptoms and signs of Raynaud's phenomenon developed as a late complication of radical radiotherapy. One had Raynaud's of the tongue and one of the lip. Both patients had a prior history of primary Raynaud's phenomenon and in each case the symptoms were repeatedly precipitated by sudden cold exposure. The possible pathogenesis of radiation induced Raynaud's phenomenon in the head and neck region is discussed.

Characterizing semantic space: neighborhood effects in word recognition.

A specification of the structural characteristics of the mental lexicon is a central goal in word recognition research. Of various word-level characteristics, semantics remains the most resistant to this endeavor. Although there are several theoretically distinct models of lexical semantics with fairly clear operational definitions (e.g., in terms of feature sharing, category membership, associations, or cooccurrences), attempts to empirically adjudicate between these different models have been scarce. In this paper, we present several experiments in which we examined the effects of semantic neighborhood size as defined by two models of lexical semantics--one that defines semantics in terms of associations, and another that defines it in terms of global co-occurrences. We present data that address the question of whether these measures can be fruitfully applied to examinations of lexical activation during visual word recognition. The findings demonstrate that semantic neighborhood can predict perforrmance on both lexical decision and word naming.

Semantic information is used by a deep dyslexic to parse compounds.

We report a case study of a 48 year-old patient, J.O., who was tested 20 years after the removal of a tumor in the left temporal-parietal region. This surgery and subsequent radiation resulted in right side paralysis and numerous language problems. Tests of J.O.'s single word reading abilities indicate that she could be classified as a deep dyslexic with over 16% of her errors in word naming having a clear semantic relationship with the target word (Coltheart, 1980). We examined her ability to read compound words aloud and following Libben (1993) we provide evidence that J.O. is a second case in which there is obligatory access of morphological constituents of compound words. These data are discussed within the context of Libben's (1998) compound word processing model.

The cost effectiveness of a home hazard reduction program to reduce falls among older persons.

BACKGROUND: The effectiveness of individual components (other than exercise) of multifactorial intervention packages aimed to reduce the incidence of falls in older people is uncertain. There have been no randomised trials of home modifications alone for the prevention of falls. OBJECTIVES: To estimate the cost-effectiveness of just one component of a multifactorial approach to falls prevention, that is, a home hazard reduction program. The study estimates the size and direction of change in resource use within and between the hospital, home and community sectors. METHODS: A randomised trial was conducted to evaluate the effectiveness of home modifications for prevention of falls among older people. An occupational therapist (O/T) with experience in aged care assessed homes for environmental hazards and supervised the necessary home modifications. SUBJECTS: The subjects in this study were people aged 65 years and older and most were recruited during a hospital stay. The cost-effectiveness analysis was based on a randomised trial with a total of 530 subjects. RESULTS: The incremental cost per fall prevented was $4,986. A sensitivity analysis was conducted by removing 12 outlier subjects (6 control and 6 intervention). The incremental cost per fall prevented was $1,921 for all subjects and was cost saving for subjects who had fallen in the 12 months prior to randomisation. CONCLUSIONS & IMPLICATIONS: A single factor home hazard reduction program is more likely to be most cost-effective amongst older people who have a history of falls.

Recurrent differentiated thyroid cancer without elevation of serum thyroglobulin.

Thyroglobulin (Tg) is a reliable tumor marker in patients with well-differentiated thyroid cancer (WDTC). We identified 11 patients who had undetectable serum Tg and no thyroglobulin antibody (TgAb) in the presence of clinical disease. Three had residual disease after ablation of the thyroid by surgery plus radioiodine and 8 relapsed after a disease-free interval. Histologic review confirmed that 7 of the tumors were papillary carcinomas and 4 were follicular carcinomas. Immunohistochemical staining for Tg was positive in 6 of 7 papillary and in 3 of 4 follicular carcinomas. There were no identifiable histologic or clinical features that could be used to predict further patients who may relapse with absence of this serum marker. Negative serum Tg did not appear to be an adverse prognostic feature. During follow-up, measurement of Tg and TgAb should be supplemented by radioiodine scanning and radiological imaging in patients in whom recurrence is likely or suspected.

Advice on hair and scalp care during cranial radiotherapy: a prospective randomized trial.

BACKGROUND: The advice on hair washing during brain irradiation is aimed at minimizing radiation induced skin toxicity. We performed a prospective randomized trial to assess the effect of advice on scalp care on the local skin reaction in patients undergoing cranial radiotherapy. METHODS: One hundred and nine patients undergoing cranial radiotherapy were randomized into two groups. Patients in group 1 were advised not to wash hair during treatment and patients in group 2 to maintain normal pattern of hair washing. They were assessed weekly over a period of 10 weeks from the start of treatment. Symptoms of pain and itching were recorded using a modified RTOG/EORTC acute skin reaction scoring system and skin reaction was assessed clinically using erythema/desquamation score. The frequency of hair washing and the distress of changing the practice of normal hygiene were recorded on a diary card. Skin reaction scores were compared as a summary measure using area under the curve per week (AUC/week) and median scores, and the differences between groups were assessed by means of the t-test. RESULTS: One hundred and nine patients commencing cranial radiotherapy according to standard protocol were randomized into the trial (group 1, 55 patients; group 2, 54 patients). Patients asked to restrict hair washing, washed at a lower average frequency. There were no significant differences between scores of skin reaction in the two groups for each of the variables measured. CONCLUSIONS: The practice of normal hair washing is not associated with increased severity of adverse skin reaction. As a request to change the pattern of normal hygiene may cause distress, the current advice should be to maintain normal hair washing during cranial radiotherapy.

Home visits by an occupational therapist for assessment and modification of environmental hazards: a randomized trial of falls prevention.

OBJECTIVE: To determine whether occupational therapist home visits targeted at environmental hazards reduce the risk of falls. DESIGN: A randomized controlled trial. SETTING: Private dwellings in the community in Sydney, Australia. PARTICIPANTS: A total of 530 subjects (mean age 77 years), recruited primarily before discharge from selected hospital wards. INTERVENTION: A home visit by an experienced occupational therapist, who assessed the home for environmental hazards and facilitated any necessary home modifications. MEASUREMENTS: The primary study outcome was falls, ascertained over a 12-month follow-up period using a monthly falls calendar. RESULTS: Thirty six percent of subjects in the intervention group had at least one fall during follow-up, compared with 45% of controls (P = .050). The intervention was effective only among subjects (n = 206) who reported having had one or more falls during the year before recruitment into the study; in this group, the relative risk of at least one fall during follow-up was 0.64 (95% confidence interval, 0.50-0.83). Similar results were obtained when falls data were analyzed using survival analysis techniques (proportional and multiplicative hazards models) and fall rates (mean number of falls per person per year). About 50% of the recommended home modifications were in place at a 12-month follow-up visit. CONCLUSIONS: Home visits by occupational therapists can prevent falls among older people who are at increased risk of falling. However, the effect may not be caused by home modifications alone. Home visits by occupational therapists may also lead to changes in behavior that enable older people to live more safely in both the home and the external environment.

Quantifying variability in the planum temporale: a probability map.

The acquisition of definitive evidence for systematic hemispheric asymmetries in the size of the planum temporale (PT) has been restricted by difficulties in identifying, standardizing and measuring the region of interest. In this paper an operational definition for identifying the problematic posterior border of the PT on magnetic resonance imaging (MRI) scans is proposed. An interactive voxel-painting program was used to identify and label the PT simultaneously in horizontal, sagittal and coronal planes in MRI scans, transformed into the standardized Talairach-Tournoux stereo-taxic space, from 50 normal right-handed volunteers. Both grey matter volume and cortical surface area of the PT were measured, while controlling for individual variation in overall brain shape and volume. The labeled tissue was averaged together to produce a probability map in standardized space of the region of interest. The PT region is highly variable, with no single voxel being labeled with a probability of >65%. In this study there were no significant hemispheric differences in volume or area of the PT. An asymmetry in area and volume was introduced by using an alternative method - the 'knife-cut' method - for identifying the posterior border. Implications for functional neuroimaging of the PT are discussed.

Radiotherapy in the treatment of benign meningioma of the skull base.

OBJECT: This study was undertaken to assess the long-term efficacy and toxicity of conventional fractionated external-beam radiation in the treatment of benign skull base meningioma. METHODS: This is a retrospective study of 82 patients with histologically verified benign skull base meningioma treated by surgery followed by fractionated external-beam radiation at the Royal Marsden Hospital between 1962 and 1992. The 5- and 10-year progression-free survival (PFS) rates were 92% and 83%, respectively, with the site of disease being the only independent prognostic factor for tumor control according to multivariate analysis. The 10-year PFS rate for patients with sphenoid ridge meningiomas was 69% compared with 90% for those with tumors in the parasellar region. The overall 10-year survival rate was 71%, with performance status and patient age found to be significant independent prognostic factors. Six patients had worsening vision, which was due to cataract in five cases and retinopathy in one. There were no recorded cases of cranial nerve neuropathy. CONCLUSIONS: The excellent long-term tumor control and length of survival with minimal toxicity associated with conventional external-beam radiation should serve as a baseline for evaluation of new treatment strategies such as radiosurgery and skull base surgery.

Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies.

We reviewed 107 blood flow activation studies carried out with positron emission tomography and published between January 1993 and November 1996. These studies had reported their findings as peaks of significant difference in cerebral blood-flow (CBF) between two scans/tasks and had located the peaks in standardized stereotaxic space. We coded each task along several dimensions, including the type and rate of input and output, the types of cognitive processes, and the relative difficulty of tasks within a study. Based on this coding, a difference score (A-B) was calculated for each subtraction. Subsequently, the frequency distributions of the difference scores for subtractions yielding a peak in the anterior cingulate region (cingulate peak) were compared with those distributions obtained from subtractions without a cingulate peak (no cingulate-peak). The cingulate peak subtractions (n = 158) differed from the no cingulate peak subtractions (n = 229) in terms of difficulty level (p = 0.001) and the presence of a remote memory component (p = 0.01). Regional differences in the frequency distribution of certain task parameters, such as difficulty level, recent memory and the use of the hand for responding, were also observed when peaks found in the anterior cingulate cortex (ACC) were further classified as located in the rostral vs caudal ACC, supracallosal vs subcallosal ACC, and limbic vs paralimbic parts of the supracallosal ACC. We conclude that task difficulty plays a major role in modulating blood-flow response in the ACC, possibly interacting with other parameters such as the nature of the response and memory demands.

Functional anatomy of musical processing in listeners with absolute pitch and relative pitch.

We used both structural and functional brain imaging techniques to investigate the neural basis of absolute pitch (AP), a specialized skill present in some musicians. By using positron emission tomography, we measured cerebral blood flow during the presentation of musical tones to AP possessors and to control musicians without AP. Listening to musical tones resulted in similar patterns of increased cerebral blood flow in auditory cortical areas in both groups, as expected. The AP group also demonstrated activation of the left posterior dorsolateral frontal cortex, an area thought to be related to learning conditional associations. However, a similar pattern of left dorsolateral frontal activity was also observed in non-AP subjects when they made relative pitch judgments of intervals, such as minor or major. Conversely, activity within the right inferior frontal cortex was observed in control but not in AP subjects during the interval-judgment task, suggesting that AP possessors need not access working memory mechanisms in this task. MRI measures of cortical volume indicated a larger left planum temporale in the AP group, which correlated with performance on an pitch-naming task. Our findings suggest that AP may not be associated with a unique pattern of cerebral activity but rather may depend on the recruitment of a specialized network involved in the retrieval and manipulation of verbal-tonal associations.