Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Mismatch Negativity and Theta Oscillations Evoked by Auditory Deviance in Early Schizophrenia.

BACKGROUND: Amplitude reduction of mismatch negativity (MMN), an event-related potential component indexing NMDA receptor-dependent auditory echoic memory and predictive coding, is widely replicated in schizophrenia. Time-frequency analyses of single-trial electroencephalography epochs suggest that theta oscillation abnormalities underlie MMN deficits in schizophrenia. However, this has received less attention in early schizophrenia (ESZ). METHODS: Patients with ESZ (n = 89), within 5 years of illness onset, and healthy control subjects (n = 105) completed an electroencephalography MMN paradigm (duration-deviant, pitch-deviant, duration + pitch double-deviant). Repeated measures analyses of variance assessed group differences in MMN, theta intertrial phase coherence (ITC), and theta total power from frontocentral electrodes, after normal age adjustment. Group differences were retested after covarying MMN and theta measures. RESULTS: Relative to healthy control subjects, patients with ESZ showed auditory deviance deficits. Patients with ESZ had MMN deficits for duration-deviants (p = .041), pitch-deviants (ps = .007), and double-deviants (ps < .047). Patients with ESZ had reduced theta ITC for standards (ps < .040) and duration-deviants (ps < .030). Furthermore, patients with ESZ had reduced theta power across deviants at central electrodes (p = .013). MMN group deficits were not fully accounted for by theta ITC and power, and neither were theta ITC group deficits fully accounted for by MMN. Group differences in theta total power were no longer significant after covarying for MMN. CONCLUSIONS: Patients with ESZ showed reduced MMN and theta total power for all deviant types. Theta ITC showed a relatively specific reduction for duration-deviants. Although MMN and theta ITC were correlated in ESZ, covarying for one did not fully account for deficits in the other, raising the possibility of their sensitivity to dissociable pathophysiological processes.

Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n = 41) and ESZ (n = 70) relative to healthy controls (HC; n = 74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps < .024) relative to HC and CHR-P, with this reduction specific to the rich-club even after accounting for other connections in ESZ relative to HC (ps < .048). There was also cortical thinning of rich-club regions in ESZ (ps < .013). In contrast, there was no strong evidence of global network organization differences among the three groups. Although connectome abnormalities were not present in CHR-P overall, CHR-P converters to psychosis (n = 9) had fewer connections among rich-club regions (ps < .037) and greater modularity (ps < .037) compared to CHR-P non-converters (n = 19). Lastly, symptom severity and antipsychotic dosage were not significantly associated with connectome metrics (ps < .012). Findings suggest that rich-club and connectome organization abnormalities are present early in schizophrenia and in CHR-P individuals who subsequently transition to psychosis.

Health-related toxicity of emerging per- and polyfluoroalkyl substances: Comparison to legacy PFOS and PFOA.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent, manufactured chemicals used in various manufacturing processes and found in numerous commercial products. With over 9000 compounds belonging to this chemical class, there is increasing concern regarding human exposure to these compounds due to their persistent, bioaccumulative, and toxic nature. Human exposure to PFAS may occur from a variety of exposure sources, including, air, food, indoor dust, soil, water, from the transfer of PFAS from non-stick wrappers to food, use of cosmetics, and other personal care products. This critical review presents recent research on the health-related impacts of PFAS exposure, highlighting compounds other than Perfluorooctanoic acid (PFOA) and Perfluoroctane sulfonate (PFOS) that cause adverse health effects, updates the current state of knowledge on PFAS toxicity, and, where possible, elucidates cause-and-effect relationships. Recent reviews identified that exposure to PFAS was associated with adverse health impacts on female and male fertility, metabolism in pregnancy, endocrine function including pancreatic dysfunction and risk of developing Type 2 diabetes, lipid metabolism and risk of childhood adiposity, hepatic and renal function, immune function, cardiovascular health (atherosclerosis), bone health including risk for dental cavities, osteoporosis, and vitamin D deficiency, neurological function, and risk of developing breast cancer. However, while cause-and-effect relationships for many of these outcomes were not able to be clearly elucidated, it was identified that 1) the evidence derived from both animal models and humans suggested that PFAS may exert harmful impacts on both animals and humans, however extrapolating data from animal to human studies was complicated due to differences in exposure/elimination kinetics, 2) PFAS precursor kinetics and toxicity mechanism data are still limited despite ongoing exposures, and 3) studies in humans, which provide contrasting results require further investigation of the long-term-exposed population to better evaluate the biological toxicity of chronic exposure to PFAS.

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

BACKGROUND: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues. METHODS: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels. RESULTS: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%. CONCLUSIONS: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

Human papillomavirus infection and intrauterine growth restriction: a data-linkage study.

OBJECTIVE: Using unbiased population data, to examine whether having a positive Pap smear, and thus a high probability of Human Papilloma Virus (HPV) infection, is a significant risk factor for intrauterine growth restriction (IUGR) in a subsequent pregnancy. STUDY DESIGN AND METHODS: Two independent population-based databases, namely the South Australian Perinatal Statistics Collection and the South Australian Cervical Screening Database, were deidentified and linked by the SANT Datalinkage Service. Analyses were performed on cases where Pap smear screening data was available for up to 2 years prior to a singleton live birth. Population characteristics and pregnancy related data were compared statistically by normal birth weight versus IUGR (10th percentile - known as small for gestational age (SGA), small for gestational age) and (3rd percentile birth weight - known as VLBW, very low birth weight). The association between cervical screening results and IUGR was assessed using generalized linear log binomial regression models. RESULTS: A total of 31,827 women met the criteria. Of these, 1311 women (4.1%) had a positive Pap smear within 2 years of the current pregnancy. Those having a positive Pap smear were more likely to have a baby with IUGR than those with negative smear results. For SGA, 5.8% babies were from mothers with positive Pap smears compared to 4.0% with negative smears indicating a 40% higher risk of having an SGA baby (95%CI 20-70%) among women with positive Pap smears. For VLBW, 7.6% mothers had positive Pap smears compared with 4.0% with negative smears (p < .001), which reflects a 90% increased risk (95%CI 40-150%). These associations reduced to 20% (95%CI 1-40%) and 50% (95%CI 10-100%) for SGA and VLBW, respectively, after adjusting for all other significant covariates including maternal age, ethnicity, marital status, occupation, smoking, pregnancy history, and maternal health during pregnancy. CONCLUSIONS: Mothers with a positive Pap smear have an increased risk of IUGR, especially for VLBW, which is independent of other risk factors. The results confirm previous findings in a small study and emphasise the need to consider the risks of both cancer and IUGR in all HPV vaccination programs.

Multimodal neuromarkers in schizophrenia via cognition-guided MRI fusion.

Cognitive impairment is a feature of many psychiatric diseases, including schizophrenia. Here we aim to identify multimodal biomarkers for quantifying and predicting cognitive performance in individuals with schizophrenia and healthy controls. A supervised learning strategy is used to guide three-way multimodal magnetic resonance imaging (MRI) fusion in two independent cohorts including both healthy individuals and individuals with schizophrenia using multiple cognitive domain scores. Results highlight the salience network (gray matter, GM), corpus callosum (fractional anisotropy, FA), central executive and default-mode networks (fractional amplitude of low-frequency fluctuation, fALFF) as modality-specific biomarkers of generalized cognition. FALFF features are found to be more sensitive to cognitive domain differences, while the salience network in GM and corpus callosum in FA are highly consistent and predictive of multiple cognitive domains. These modality-specific brain regions define-in three separate cohorts-promising co-varying multimodal signatures that can be used as predictors of multi-domain cognition.

Multimodal Fusion With Reference: Searching for Joint Neuromarkers of Working Memory Deficits in Schizophrenia.

By exploiting cross-information among multiple imaging data, multimodal fusion has often been used to better understand brain diseases. However, most current fusion approaches are blind, without adopting any prior information. There is increasing interest to uncover the neurocognitive mapping of specific clinical measurements on enriched brain imaging data; hence, a supervised, goal-directed model that employs prior information as a reference to guide multimodal data fusion is much needed and becomes a natural option. Here, we proposed a fusion with reference model called "multi-site canonical correlation analysis with reference + joint-independent component analysis" (MCCAR+jICA), which can precisely identify co-varying multimodal imaging patterns closely related to the reference, such as cognitive scores. In a three-way fusion simulation, the proposed method was compared with its alternatives on multiple facets; MCCAR+jICA outperforms others with higher estimation precision and high accuracy on identifying a target component with the right correspondence. In human imaging data, working memory performance was utilized as a reference to investigate the co-varying working memory-associated brain patterns among three modalities and how they are impaired in schizophrenia. Two independent cohorts (294 and 83 subjects respectively) were used. Similar brain maps were identified between the two cohorts along with substantial overlaps in the central executive network in fMRI, salience network in sMRI, and major white matter tracts in dMRI. These regions have been linked with working memory deficits in schizophrenia in multiple reports and MCCAR+jICA further verified them in a repeatable, joint manner, demonstrating the ability of the proposed method to identify potential neuromarkers for mental disorders.

Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia.

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine×nicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia.

Supervised multimodal fusion and its application in searching joint neuromarkers of working memory deficits in schizophrenia.

Multimodal fusion is an effective approach to better understand brain disease. To date, most current fusion approaches are unsupervised; there is need for a multivariate method that can adopt prior information to guide multimodal fusion. Here we proposed a novel supervised fusion model, called "MCCAR+jICA", which enables both identification of multimodal co-alterations and linking the covarying brain regions with a specific reference signal, e.g., cognitive scores. The proposed method has been validated on both simulated and real human brain data. Features from 3 modalities (fMRI, sMRI, dMRI) obtained from 147 schizophrenia patients and 147 age-matched healthy controls were included as fusion input, who participated in the Function Biomedical Informatics Research Network (FBIRN) Phase III study. Our aim was to investigate the group co-alterations seen in three types of MRI data that are also correlated with working memory performance. One joint IC was found both significantly group-discriminating (p=7.4E-06, 0.001, 7.0E-09) and highly correlated with working memory scores(r=0.296, 0.241, 0.301) and PANSS negative scores (r=-0.229, -0.276, -0.240) for fMRI, dMRI and sMRI, respectively. Given the simulation and FBIRN results, MCCAR+jICA is shown to be an effective multivariate approach to extract accurate and stable multimodal components associated with a particular measure of interest, and promises a wide application in identifying potential neuromarkers for mental disorders.

Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans.

BACKGROUND: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers. METHODS: From an initial sample of 17 subjects (age range 18-55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session. RESULTS: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. CONCLUSION: Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.

Protraction of anaphase B in lymphocyte mitosis with ageing: possible contribution to age-related cancer risk.

Ageing is associated with a reduction in the fidelity of cell division as shown by increases in trisomic and polyploid cells; however, to date, the underlying age-specific changes in cell division have not been identified. Understanding these specific changes in cell division could give insight into the aetiology some age-related illnesses, especially cancer. Using blood collected from 72 women aged 18-53 years, this study recorded the frequencies of cells in each of the stages of mitosis in synchronised lymphocyte cultures harvested at controlled temperature without microtubule inhibitors. Factor analysis identified four components that accounted for >67.5% of the variance in the data. The component we named 'Spindle elongation efficiency', which was primarily influenced by the time taken to complete anaphase B, showed a major change with age: women aged ≥36 showed a highly statistically significant protraction of anaphase B compared with those aged ≤35 (t = -2.74, df = 70, P = 0.006) and linear regression showed a logarithmic change in this component with age (R = 0.297, P = 0.011). This phosphorylation-dependent phase of the cycle is responsible for increasing the distance between the two sets of daughter chromosomes and in older subjects the daughter nuclei at telophase were often poorly separated. Inefficient spindle elongation with ageing probably results from decreased cellular energy. Insufficient force at anaphase B might fail to resolve merotelic kinetochore attachments such that lagging at anaphase would be uncorrected and lead to trisomy and polyploidy in daughter cells.

Glutamatergic modulation of auditory information processing in the human brain.

BACKGROUND: Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans. METHODS: This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day. RESULTS: Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive. CONCLUSIONS: NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

Preconception risk factors and SGA babies: Papilloma virus, omega 3 and fat soluble vitamin deficiencies.

BACKGROUND: Small for gestational date (SGA) babies have a poor 'whole of life' prognosis and major factors affecting SGA may be present prior to conception. AIMS: To discover whether lifestyle risk factors can be identified in women planning a pregnancy. STUDY DESIGN: Prospective study of women who were planning a pregnancy, who agreed to answer a detailed 250 question questionnaire prior to commencing to try to conceive, to being monitored, and within 7days of a positive pregnancy test having a vaginal ultrasound scan and answering further questions about the events since the last menstrual period. Details of all outcomes were recorded. SUBJECTS: 585 couples completed the study. OUTCOME MEASURES: The relationships between birth weights and questionnaire data was analysed using SPSS and parametric statistical analysis. RESULTS AND CONCLUSIONS: 401 women (67.9% of all participants) had live births. Eleven babies (2.7%) were less than the 3rd percentile in weight and a further 22 babies (5.4%) were between the 3rd and 10th weight percentiles. Mothers of SGA babies had a lower than average education, diets that were low in meat, fish, dairy foods and nuts or seeds and were more likely to conceive in the winter. Mothers of SGA babies were significantly more likely to have had a recent abnormal Pap smear test. Air travel in the month of conception was a risk factor in having a baby less than 10th percentile. CONCLUSION: The quality of lifestyle prior to conception is critical: prenatal counselling needs to be undertaken prior to conception.

Saturated fatty acid metabolism is key link between cell division, cancer, and senescence in cellular and whole organism aging.

Cellular senescence is an in vivo and in vitro phenomenon, accompanied by physiological changes including cessation of division and disturbances of organelle structure and function. Review of the literature was undertaken to determine whether there is evidence that whole organism aging and cell senescence share a common initiation pathway. In vivo aged cells of different lineages, including aged T lymphocytes, show high expression of the INK4A-p16 gene. In cell culture when telomeres are shortened past a key length or state, the Arf/Ink gene system (p16/p14 humans, p16/p19 mice) switches on and activates p53, which suppresses further cell division. The p53 gene is a key tumor suppressor and its deletion or mutation allows cancerous growth. The switching on of p53 also causes changes in fatty acid metabolism, especially down-regulation of both fatty acid synthase and stearoyl-CoA (delta-9) desaturase. The co-suppression of these genes together with enhanced uptake of extracellular fatty acids, leads to raised levels of cellular palmitate and induction of either apoptosis or senescence. In senescent cells, the fatty acid composition of the cellular membranes alters and leads to changes in both structure and function of organelles, especially mitochondria. Animal models of accelerated aging exhibit repression of stearoyl-CoA desaturase activity while anti-aging calorie restriction stimulates the same enzyme system. It is concluded that aging in cells and whole organisms share a common initiation pathway and that cellular senescence is protective against cancer. Healthy longevity is likely to be most enhanced by factors that actively suppress excessive cell division.

Stereotactic radiation treatment for recurrent nonbenign meningiomas.

OBJECT: The authors analyzed the results of stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) for the treatment of recurrent meningiomas that were described at initial resection as showing aggressive, atypical, or malignant features (nonbenign). METHODS: Twenty-five patients who underwent SRS and/or SRT for nonbenign meningiomas between December 1992 and August 2004 were included. Thirteen of these patients underwent treatment for multiple primary or recurrent lesions. In all, 52 tumors were treated. All histological sections were reviewed and reclassified according to World Health Organization (WHO) 2000 guidelines as benign (Grade I), atypical (Grade II), or anaplastic (Grade III) meningiomas. The median follow-up period was 42 months. Seventeen (68%) of the cases were reclassified as follows: WHO Grade I (five cases), Grade II (11 cases), and Grade III (one case). Malignant progression occurred in eight cases (32%) during the follow-up period; these cases were considered as a separate group. The 3-year progression-free survival (PFS) rates for the Grades I, II, and III, and malignant progression groups were 100, 83, 0, and 11%, respectively (p < 0.001). In the Grade II group, the 3-year PFS rates for patients treated with SRS and SRT were 100 and 33%, respectively (p = 0.1). After initial treatment, 22 new tumors required treatment using SRS or SRT; 17 (77%) of them occurred inside the original resection cavity. Symptomatic edema developed in one patient (4%). CONCLUSIONS: Stereotactic radiation treatment provided effective local control of "aggressive" Grade I and Grade II meningiomas, whereas Grade III lesions were associated with poor outcome. The outcome of cases in the malignant progression group was intermediate between that of the Grade II and Grade III groups, with the lesions showing a tendency toward malignancy.

Results of the phase I dose-escalating study of motexafin gadolinium with standard radiotherapy in patients with glioblastoma multiforme.

PURPOSE: Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme. METHODS AND MATERIALS: A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied. RESULTS: The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94). CONCLUSION: The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.

Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial.

PURPOSE: This single centre, open labelled, randomised non-inferiority trial compared concurrent chemoradiotherapy with carboplatin versus standard concurrent chemoradiotherapy with cisplatin in patients with locoregionally advanced nasopharyngeal cancer (NPC). PATIENTS AND METHODS: From August 1999 to December 2004, 206 patients with locally advanced NPC were randomised with 101 to cisplatin arm and 105 to carboplatin arm. Planned radiotherapy was the same in both groups. All the patients were evaluated for toxicity and survival according to the as-treated principle. RESULTS: With a median follow-up of 26.3 months (range 3-74.6 months), 59% of patients in the cisplatin arm completed the planned concurrent chemoradiation treatment, compared to 73% in the carboplatin arm. Forty-two percent of cisplatin patients completed the 3 cycles of adjuvant therapy compared to 70% in the carboplatin group. There were more renal toxicity, leucopenia, and anaemia in the cisplatin group, and more thrombocytopenia in the carboplatin arm. The 3 year disease free survival rates were 63.4% for the cisplatin group and 60.9% for the carboplatin group (p=0.9613) (HR 0.70, 95% confidence interval (CI): 0.50-0.98). The 3 year overall survival rates were 77.7% and 79.2% for cisplatin and carboplatin groups, respectively (p=0.9884) (HR 0.83, 95% CI: 0.63-1.010). CONCLUSION: We concluded that the tolerability of carboplatin based regimen is better than that of the cisplatin regimen. Moreover, the treatment efficacy of carboplatin arm is not different from the standard regimen in the treatment of locoregional advanced stage NPC.

Brainstem and trigeminal nerve changes after radiosurgery for trigeminal pain.

PURPOSE: To evaluate the significance of radiological changes on follow-up MRIs after SRS for TN. MATERIALS AND METHODS: Thirty-seven patients with follow-up MRI because of paresthesias, bilateral treatment, or failure were analyzed regarding pain outcome and complications. Mean age was 64.4 years; 14 underwent previous treatment. Twenty-nine had ETN, 5 secondary TN due to tumor or multiple sclerosis, and 3 had atypical TN. Ninety gray was prescribed for 20 patients, 70 Gy for 5, and 80/85 Gy for 2. A 5-mm collimator was used in 32 (88.9%) cases. Mean follow-up was 15 months (range, 4-52 months). RESULTS: Excellent/good pain relief was sustained in 67% of cases at 13 months' follow-up. Enhancement on MRIs was observed in 21 cases (56.75%) with nerve enhancement in 9, pons enhancement in 4, pons-nerve enhancement in 4, and tumor enhancement in 4. Magnetic resonance images were unremarkable in 16 cases. Pain recurred in 4 cases (5.5-10 months). Pons enhancement correlated with pain relief (P = .0087) but not with nerve enhancement (P = .22). Incidence of slight paresthesias was 66.6%. No anesthesia dolorosa or ophthalmologic problems were observed. Paresthesias correlated with enhancement (P = .02), but not with brainstem volume encompassed by the 20%, 30%, and 50% isodoseline (P = .689, .525, .908). Enhancement free probability at 12 months was 48.5% (Kaplan-Meier). CONCLUSIONS: Pons enhancement seems to be prognostic for pain relief without higher incidence of complications. Pons volume irradiated did not predict enhancement occurrence. Radiation delivery to the brainstem-REZ interface seems to improve pain outcome, although more paresthesias should be expected.