Effect of retirement on cognitive function: the Whitehall II cohort study

Abstract

According to the 'use it or lose it' hypothesis, a lack of mentally challenging activities might exacerbate the loss of cognitive function. On this basis, retirement has been suggested to increase the risk of cognitive decline, but evidence from studies with long follow-up is lacking. We tested this hypothesis in a cohort of 3433 civil servants who participated in the Whitehall II Study, including repeated measurements of cognitive functioning up to 14 years before and 14 years after retirement. Piecewise models, centred at the year of retirement, were used to compare trajectories of verbal memory, abstract reasoning, phonemic verbal fluency, and semantic verbal fluency before and after retirement. We found that all domains of cognition declined over time. Declines in verbal memory were 38% faster after retirement compared to before, after taking account of age-related decline. In analyses stratified by employment grade, higher employment grade was protective against verbal memory decline while people were still working, but this 'protective effect' was lost when individuals retired, resulting in a similar rate of decline post-retirement across employment grades. We did not find a significant impact of retirement on the other cognitive domains. In conclusion, these findings are consistent with the hypothesis that retirement accelerates the decline in verbal memory function. This study points to the benefits of cognitively stimulating activities associated with employment that could benefit older people's memory.

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Modified anterior-only reduction and fixation for traumatic cervical facet dislocation (AO type C injuries)

Abstract

Purpose

Surgical reduction of uni and bi-facetal dislocations of the cervical spine (AO type C injuries) can be performed by posterior, anterior or combined approaches. Ease of access, low infection rates and less risks of neurological worsening has popularized anterior approach. However, the reduction of locked cervical facets can be intricate through anterior approach. We analyzed the safety, efficacy and outcomes at a minimum 1 year, of a novel anterior reduction technique for consecutively treated cervical facet dislocations.

Materials and methods

Patients with single level traumatic sub-axial cervical dislocation (n = 39) treated by this modified anterior technique were studied. The technique involved standard Smith–Robinson approach, discectomy beyond PLL, use of inter-laminar distracter to distract while Caspar pins were used as "joysticks" (either flexion–extension or lateral rotation moments are provided), to reduce the sub-luxed facets. Among 51 patients with cervical type C injury treated during the study period, 4 patients who had spontaneous reduction and 8 treated by planned global fusion were excluded.

Results

39 patients of mean age 49.9 years were studied. The levels of injury included (C3–4 = 2, C4–5 = 5, C5–6 = 20, C6–7 = 12). 18 were bi-facetal and 21 were uni-facetal dislocation. One facet was fractured in 17 and both in 5 patients. 30% (n = 13) had a concomitant disc prolapse. The neurological status was as follows: 9 ASIA A, 9 ASIA C, 13 ASIA D and 8 ASIA E. All the patients were successfully reduced by this technique and fixed with anterior locking cervical locking plates. No supplemental posterior surgery was performed. 22 patients with incomplete deficit showed recovery. The mean follow-up was 14.3 months and there was no implant failure except one patient who had partial loss of the reduction.

Conclusion

Patients with traumatic sub-axial cervical dislocation (AO type C injuries) can be safely and effectively reduced by this technique. Other advantages include minimal blood loss, less risks of infection, shorted fusion zone, good fusion rate and neurological recovery.

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Predicting Persistent Post-surgery Pain

Might parameters derived from a preoperative cold pain test predict the development of persistent postoperative pain after breast cancer surgery?
British Journal of Anaesthesia

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Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the standard therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-soluble antimalarial drug artemisinin derivative, SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degradation of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Additionally, SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2–AMPK–ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic molecule for the treatment of DLBCL, along with R-CHOP regimen.

Our research reported an artemisinin derivative, SM1044, induces autophagy-dependent apoptosis which is triggered by an increased acetylation of Survivin, a modification which induces its interaction with LC3-II and its degradation. We also unraveled that the activation of CaMKK2–AMPK–ULK1 axis was molecular basis of SM1044-dependent stimulation of autophagy. These investigations not only point to SM1044 as a promising molecule in fighting diffuse large B-cell lymphoma (DLBCL), but also unravel important information of the molecular pathways involved in the oncogenesis of DLBCL.

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Effects of Th17 cells and IL-17 in the progression of cervical carcinogenesis with high-risk human papillomavirus infection

Abstract

The existence of Th17 cells and IL-17 was recently shown in several types of infectious diseases, but their distribution and functions in cervical lesions with high-risk human papillomavirus (HPV) infection have not been fully elucidated. In this study, the frequency of Th17 cells in peripheral blood samples obtained from 28 cervical squamous cell carcinoma patients, 26 CIN1 patients, 30 CIN2 patients, 29 CIN3 patients, 25 high-risk HPV-infected women with normal cervical cytology, and 30 healthy controls was determined by flow cytometry. Besides, the levels of IL-17 in peripheral blood samples as well as in supernatant of cervical tissue homogenate were assessed by enzyme-linked immunosorbent assay (ELISA) simultaneously. We found that during the disease progression of cervical lesions, the proportion of Th17 cells in the total CD4⁺ cells showed a gradually increased tendency compared with the controls (P < 0.05). Moreover, levels of IL-17 in serum and supernatant of cervical tissue homogenate showed the same tendency as the proportion of Th17 cells (P < 0.05). When compared in pairs, the levels of IL-17 in supernatant differed significantly among the study groups and the control group (P < 0.05), but no significant difference was observed in serum (P > 0.05). In conclusions, the results indicate that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV especially in the cervical microenvironment, which contribute to the disease progression of its associated cervical lesions.

In this work, we evaluated the frequency of Th17 cells in peripheral blood samples obtained from cervical squamous cell carcinoma patients, CIN1 patients, CIN2 patients, CIN3 patients, high-risk HPV-infected women with normal cervical cytology, and healthy controls,as well as the levels of IL-17 in peripheral blood samples and in supernatant of cervical tissue homogenate. So we had come to the conclusion that Th17 cells and IL-17 may play a role of immune enhancement in the infection of high-risk HPV, which contribute to the disease progression of its associated cervical lesions.

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Personality and breast cancer screening in women of the GAZEL cohort study

Abstract

The potential benefit of breast cancer screening is mitigated by the risk of false positives and overdiagnosis, thus advocating for a more personalized approach, based on the individual benefit-harm balance. Since personality might influence the women's appraisal of this balance, this prospective observational cohort study examined whether it could influence mammography use. A total of 2691 postmenopausal women of the GAZEL Cohort Study completed the Bortner Type A Rating Scale and the Buss and Durkee Hostility Inventory in 1993. Associations between personality scores and subsequent mammography use, self-reported through up to five triennial follow-up questionnaires, were estimated with Odds Ratio (OR) and 95% confidence interval (CI) with logistic mixed model regressions, adjusting for age, occupational grade, marital status, family history of breast cancer, age at menarche, age at first delivery, gynecological follow-up, hormone therapy use, and depressive symptoms. Individual propensity scores were used to weight the analyses to control for potential selection biases. More than 90% of the participants completed at least two follow-up questionnaires. Type A personality, but not hostility, was associated with mammography use in both univariate (crude OR [95% CI]: 1.62 [1.24–2.11], P < 0.001) and multivariate analyses (OR [95% CI]: 1.46 [1.13–1.90], P < 0.01). Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among postmenopausal women. While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

Type A personality traits (i.e., sense of time urgency, high job involvement, competitiveness) independently predicted mammography use among 2691 postmenopausal women of the GAZEL Cohort Study (adjusted Odds Ratio [95% confidence interval]: 1.46: [1.13–1.90], P < 0.01). While paying more attention to the adherence of women with low levels of these traits, clinicians may help those with higher levels to better consider the risks of false positives and overdiagnosis.

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Three-dimensional morphological analysis of the human sacroiliac joint: influences on the degenerative changes of the auricular surfaces

Abstract

The sacroiliac joint (SIJ) is responsible for weight transmission between the spine and lower extremity. However, details of the structure and function of the SIJ remain unclear. In a previous study, we devised a method of quantitatively evaluating the level of degeneration of the SIJ using an age estimation procedure for the auricular surface of the ilium. Our results in that study suggested that the degree of degeneration of the joint surface may be associated with the morphology of the auricular surface of the ilium. In that study, however, the morphology of the auricular surface of the ilium was simplified for analysis, meaning that more detailed investigations were required in future. In the present study, we focused on individual differences in the shape of SIJ and carried out three-dimensional quantitative evaluation of the morphology of the auricular surface of the ilium to ascertain its association with joint degeneration. We produced three-dimensional images of the right auricular surfaces of the ilium of 100 modern Japanese men (age 19–83), and obtained the three-dimensional rectangular coordinates of 11 defined measurement points. We then calculated 16 parameters indicating the morphological characteristics of the auricular surfaces of the ilium from the three-dimensional rectangular coordinates of these measurement points, and used these to perform principal component analysis to investigate trends in the morphology of the auricular surface of the ilium. We found that the morphology of the auricular surface of the ilium could be characterized in terms of (i) size, (ii) concavity of the posterior border and (iii) amount of undulation. An investigation of the correlation between these parameters and age suggested that the amount of undulation of the auricular surface of the ilium tends to diminish with advancing age. In an investigation of the association between morphology of the auricular surface of the ilium and degeneration of the articular surface when the subjects were divided into a high-degeneration group (n = 55) and a low-degeneration group (n = 45) and the 16 parameters were compared, there was a significant difference in the amount of undulation of the auricular surface of the ilium. In an investigation limited to older subjects aged ≥ 60 (n = 47) at the time of death, there were significant differences between the high-degeneration group (n = 27) and low-degeneration group (n = 20) in terms not only of the parameters indicating the amount of undulation of the auricular surface of the ilium but also of those indicating the amount of the concavity of the posterior border. These results suggested that the amount of undulation of the auricular surface of the ilium may affect the degree of degeneration of the articular surface. In addition, in older subjects, the degree of concavity of the posterior border of the SIJ may also affect the degree of degeneration of the articular surface. It is thus likely that differences in the morphology of the auricular surface of the ilium may affect degenerative changes in the SIJ.

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Delayed Metallic Embolization of a Cor-Knot Fastener

THORAC CARDIOV SURG Reports 2017; 06: e40-e41
DOI: 10.1055/s-0037-1612613

Background The Cor-Knot device is a titanium fastener which is widely used in cardiac valve procedures. Adverse events associated with use of the device have been rare. Case Description A patient underwent robotic mitral valve repair using the Cor-Knot fastener. Five years later, he suffered a cerebral vascular accident secondary to embolization of a metallic foreign body. He had had no other medical procedures which could account for a source of metallic embolization. Conclusion Long-term surveillance after use of the Cor-Knot fastener is limited. Metallic embolization may be possible with this device and warrants awareness within the medical community.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Perturbation of theta-gamma coupling at the temporal lobe hinders verbal declarative memory

Publication date: Available online 25 December 2017
Source:Brain Stimulation
Author(s): Gabriel Amador de Lara, Ivan Alekseichuk, Zsolt Turi, Albert Lehr, Andrea Antal, Walter Paulus
BackgroundPhase-amplitude cross-frequency coupling (PAC) is characterized by the modulation of the power of a fast brain oscillation (e.g., gamma) by the phase of a slow rhythm (e.g., theta). PAC in different sub- and neocortical regions is known to underlie effective neural communications and correlates with successful long-term memory formation.Objective/Hypothesis: The present work aims to extend earlier observational data, by probing the functional role of theta-gamma PAC in the left temporal cortex in humans during verbal long-term memory encoding.MethodsIn three double-blinded, placebo-controlled experiments (n = 72), we employed cross-frequency transcranial alternating current stimulation (tACS) to externally modulate ongoing PAC during a verbal-associative learning task. Three types of cross-frequency tACS protocols were used: bursts of high gamma tACS were coupled to the peak or trough of the theta tACS cycle, and a control condition where gamma tACS was continuously superimposed at theta tACS cycles.ResultsGamma bursts coupled to the trough of theta tACS induced robust behavioral impairment in memory performance (p < .01), whereas gamma burst coupled to the peak or continuously superimposed with theta tACS had no significant behavioral effects.ConclusionsOur results demonstrate direct evidence regarding the importance of theta-gamma coupling in verbal long-term memory formation.



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Validation of the Mandarin Chinese Version of the Pediatric Voice-Related Quality of Life (pVRQOL)

The purposes of this study were to adapt and validate the English version of the pediatric Voice-Related Quality of Life questionnaire into Mandarin Chinese, and to determine the cutoff point for screening children with and without voice disorders.

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The Vocal Cord Dysfunction Questionnaire: Validity and Reliability of the Persian Version

The aim of this study was to develop, validate, and assess the reliability of the Persian version of Vocal Cord Dysfunction Questionnaire (VCDQP).

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Editor-in-Chief’s Note – Thank you to Reviewers

The Editors would like to thank those listed below who have given their valuable help over the last year, between 1st October 2016 and 30th September 2017, in the review of manuscripts submitted to Chemical Senses.

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Articles highlighted

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Differences in Taste Perception and Spicy Preference: A Thai–Japanese Cross-cultural Study

Abstract

Taste perception is influenced by several factors. However, the relation between taste perception and food culture is unclear. This study compared taste thresholds between populations with different food culture, i.e. Thai and Japanese. A matched case–control study was conducted in 168 adults (84 for each; aged between 50 and 90 years). The age, sex, systemic disease, medication, smoking, xerostomia, and oral hygiene of both groups were not different. Recognition thresholds (RTs) of sweet, salty, sour, bitter, and umami were measured using filter paper disc (FPD). Detection taste thresholds were measured using electrogustometry. Spicy preference was measured by calibrated questionnaires. Higher RTs of all tastes and higher detection taste thresholds were found in Thai as compared to those of Japanese (P < 0.0001). Separate analyses of healthy and unhealthy persons confirmed the significant differences between 2 countries. The average thresholds for sweet, salty, sour, and bitter in Thai and Japanese were 4 and 2, respectively. The average threshold for umami in Thai and Japanese was 5 and 3, respectively. Moreover, Thai population had stronger preference for spicy food (P < 0.0001) with 70% mild- or moderate and 10% strong lovers, compared to over 90% non- or mild-spicy lovers in Japanese. In addition, 70% of Thai consumed spicy food weekly, whilst 80% of Japanese consumed it monthly. Our findings suggested that population with stronger spicy preference such as Thai had much poorer taste sensitivity and perception than that with milder preference like Japanese. Extensive international survey is needed to conclude the influence of food culture on taste perception.

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The Association Between Diabetes and Olfactory Function in Adults

Abstract

Diabetes is a significant chronic disease that in limited studies has been linked with olfactory dysfunction. We investigated the cross-sectional association between diabetes and olfactory dysfunction in 3151 adults aged ≥40 years who participated in US National Health and Nutrition Examination Survey 2013–2014 with information on olfactory dysfunction and diabetes. Diabetes was defined from fasting serum glucose ≥126 mg/dL, oral glucose tolerance test ≥200 mg/dL, HbA1c levels ≥6.5%, physician-diagnosed diabetes, or current use of oral hypoglycemic agents and/or insulin. Self-reported olfactory dysfunction was defined as a positive answer to any of the following questions: 1) "Have you had problem with smell in the past 12 months?"; 2) "Have you had a change in the ability to smell since age 25?", or 3) "Do you have phantom smells?". Participants were considered to have severe hyposmia or anosmia if they had <5 correct answers in the 8-item pocket smell test. Analyses were adjusted for the main confounders, including olfactory dysfunction risk factors. Compared to non-diabetics, diabetics under insulin treatment showed a higher prevalence of phantom odors [OR(95% CI): 2.42 (1.16; 5.06)] and a non-significant higher prevalence of severe hyposmia/anosmia [OR(95% CI): 1.57 (0.89; 2.78)]. Amongst diabetics, there was a significant trend to severe hyposmia/anosmia for those on more aggressive treatments [OR (95% CI) including oral and insulin treatment compared to those who reported no use of drug treatment, respectively: 1.33 (0.60; 2.96) and 2.86 (1.28; 6.40); P trend 0.01]. No association was observed between diabetes duration and prevalence of olfactory dysfunction.

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Effect of Radiation on Sucrose Detection Thresholds of Mice

Abstract

Radiotherapy is one of the most common treatments for head and neck cancers, with an almost obligate side effect of altered taste (Conger AD. 1973. Loss and recovery of taste acuity in patients irradiated to the oral cavity. Radiat Res. 53:338–347.). In mice, targeted irradiation of the head and neck causes transient repression of proliferation of basal epithelial cells responsible for taste cell replacement, leading to a temporary depletion of taste sensory cells within taste buds, including Type II taste cells involved in detection of sweet stimuli (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474–3484.). These findings suggest that irradiation may elevate sucrose detection thresholds, peaking at 7 days postirradiation when loss of Type II cells is greatest. To test this hypothesis, sucrose detection thresholds (concentration detected in 50% of presentations) were measured in mice for 15 days after treatment of: 1) irradiation while anesthetized, 2) anesthetic alone, or 3) saline. Mice were trained to distinguish water from several concentrations of sucrose. Mice were irradiated with one 8 Gy dose (RADSOURCE-2000 X-ray Irradiator) to the nose and mouth while under 2,2,2-tribromethanol anesthesia (Avertin). Unexpectedly, mice given anesthesia showed a small elevation in sucrose thresholds compared to saline-injected mice, but irradiated mice show significantly elevated sucrose thresholds compared to either control group, an effect that peaked at 6–8 days postirradiation. The timing of loss and recovery of sucrose sensitivity generally coincides with the reported maximal reduction and recovery of Type II taste cells (Nguyen HM, Reyland ME, Barlow LA. 2012. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci. 32:3474–3484.). Thus, even a single dose of irradiation can significantly alter detection of carbohydrates, an important consideration for patients undergoing radiotherapy.

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The Influence of Circadian Timing on Olfactory Sensitivity

Abstract

Olfactory sensitivity has traditionally been viewed as a trait that varies according to individual differences but is not expected to change with one's momentary state. Recent research has begun to challenge this position and time of day has been shown to alter detection levels. Links between obesity and the timing of food intake further raise the issue of whether odor detection may vary as a function of circadian processes. To investigate this question, 37 (21 male) adolescents (M age = 13.7 years) took part in a 28-h forced desynchrony (FD) protocol with 17.5 h awake and 10.5 h of sleep, for 7 FD cycles. Odor threshold was measured using Sniffin' Sticks 6 times for each FD cycle (total threshold tests = 42). Circadian phase was determined by intrinsic period derived from dim light melatonin onsets. Odor threshold showed a significant effect of circadian phase, with lowest threshold occurring on average slightly after the onset of melatonin production, or about 1.5^○ (approximately 21:08 h). Considerable individual variability was observed, however, peak olfactory acuity never occurred between 80.5^○ and 197.5^○ (~02:22–10:10 h). These data are the first to show that odor threshold is differentially and consistently influenced by circadian timing, and is not a stable trait. Potential biological relevance for connections between circadian phase and olfactory sensitivity are discussed.

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Superadditive and Subadditive Neural Processing of Dynamic Auditory-Visual Objects in the Presence of Congruent Odors

Abstract

Our sensory experiences comprise a variety of different inputs at any given time. Some of these experiences are unmistakable, others are ambiguous and profit from additional sensory information. Here, we explored whether the presence of a congruent odor influences the neural processing and sensory interaction of audio-visual objects using degraded videos (V) and sounds (A) of dynamic objects in unimodal and bimodal (AV) combinations without or with a congruent odor (VO, AO, AVO). Analyses of EEG data revealed superadditive and subadditive interaction effects. The topography and timing of these effects suggest evaluative rather than sensory processes as the underlying cause. Together, the results suggest that the mere presence of an odor affects the processing of A, V, and AV objects differently while multisensory interactions of AV and AVO objects have common neuronal mechanisms pointing to a robust, modality-independent network for the processing of redundant sensory information.

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From Nose to Memory: The Involuntary Nature of Odor-evoked Autobiographical Memories in Alzheimer’s Disease

Abstract

Research suggests that odors may serve as a potent cue for autobiographical retrieval. We tested this hypothesis in Alzheimer's disease (AD) and investigated whether odor-evoked autobiographical memory is an involuntary process that shares similarities with music-evoked autobiographical memory. Participants with mild AD and controls were asked to retrieve 2 personal memories after odor exposure, after music exposure, and in an odor-and music-free condition. AD participants showed better specificity, emotional experience, mental time travel, and retrieval time after odor and music exposure than in the control condition. Similar beneficial effects of odor and music exposure were observed for autobiographical characteristics (i.e., specificity, emotional experience, and mental time travel), except for retrieval time which was more improved after odor than after music exposure. Interestingly, regression analyses suggested executive involvement in memories evoked in the control condition but not in those evoked after music or odor exposure. These findings suggest the involuntary nature of odor-evoked autobiographical memory in AD. They also suggest that olfactory cuing could serve as a useful and ecologically valid tool to stimulate autobiographical memory, at least in the mild stage of the disease.

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Interactions of Lemon, Sucrose and Citric Acid in Enhancing Citrus, Sweet and Sour Flavors

Abstract

Flavorants such as lemon extract that activate olfactory receptors may also evoke or enhance flavor qualities such as sour and sweet that are typically considered gustatory. Similarly, flavorants such as sucrose and citric acid that activate gustatory receptors may enhance flavors such as citrus that are typically considered olfactory. Here, we ask how lemon extract, sucrose, and citric acid, presented separately and together, affect sweet, sour, and citrus flavors. We accomplished this by testing, in the same 12 subjects, lemon extract and sucrose (Experiment 1), lemon extract and citric acid (Experiment 2), and lemon extract, sucrose, and citric acid (Experiment 3). Results showed that both lemon extract and citric acid increased the ratings of citrus and sour intensity. Lemon extract did not affect sweet, but citric acid did, mainly in Experiment 3. Sucrose systematically increased only sweet intensity and modulated the effect of lemon extract on sour. The most robust multiquality effect was the enhancement of sour by lemon extract. These outcomes suggest, first, a role played by experience with the statistical associations of gustatory and olfactory flavorants and, second, that lemon flavor is complex, having citrus and sour qualities that may not be fully separable in perception.

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Role of Endocannabinoids on Sweet Taste Perception, Food Preference, and Obesity-related Disorders

Abstract

The prevalence of obesity and obesity-related disorders such as type 2 diabetes (T2D) and metabolic syndrome has increased significantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide. Chronic overeating of highly palatable foods is one of the main responsible aspects behind overweight. Food choice is driven by food preference, which is influenced by environmental and internal factors, from availability to rewarding properties of food. Consequently, the acquisition of a dietary habit that may lead to metabolic alterations is the result of a learning process in which many variables take place. From genetics to socioeconomic status, the response to food and how this food affects energy metabolism is heavily influenced, even before birth. In this work, we review how food preference is acquired and established, particularly as regards sweet taste; towards which flavors and tastes we are positively predisposed by our genetic background, our early experience, further lifestyle, and our surroundings; and, especially, the role that the endocannabinoid system (ECS) plays in all of this. Ultimately, we try to summarize why this system is relevant for health purposes and how this is linked to important aspects of eating behavior, as its function as a modulator of energy homeostasis affects, and is affected by, physiological responses directly associated with obesity.

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EMCrit Podcast 215 – A Disagreement of Toxicologists with Dantastic Mr. Tox/&Howard

Dantastic Mr. Tox/&Howard discuss some Tox stuff and Santa Beards

EMCrit Project by Scott Weingart.

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Fatigue, quality of life and walking ability in adults with cerebral palsy

Publication date: March 2018
Source:Gait & Posture, Volume 61
Author(s): Sofia Lundh, Salmir Nasic, Jacques Riad
IntroductionFew studies on fatigue, quality of life and walking ability in adults with cerebral palsy (CP) are available.It is unclear whether these variables are associated.AimThe aim was to study the influence of CP on fatigue, quality of life, and gait of adult patients.Material and methodsThree-dimensional gait analysis was performed on 24 women and 26 men, mean age 32.1 (range 21.7–67.2), 23 with unilateral and 27 with bilateral CP. The Gait Profile Score was calculated; Fatigue Severity and EQ Visual Analogue scales were used.ResultsFatigue severity was higher than in controls, mean 3.8 (SD 1.8) vs 3.0 (p = 0.012). Fatigue in the unilateral group was 3.3 (SD 1.8) and in the bilateral 4.2 (SD 1.7), (p = 0.07). EQ Visual Analogue scale in the unilateral group was mean 79.5 (21.9) and in the bilateral 64.0 (20.8), p = 0.007.The group with bilateral CP tended toward crouch gait, decreased balance and low walking speed. Muscle work was shifted from the ankle to hip muscles.Fatigue correlated with the Gait Profile Score, CC = 0.31 (p = 0.038), and with knee flexion deviation, CC = 0.31 (p = 0.037).DiscussionCrouch gait, increased knee flexion in stance, contributes to increased deviation in the lower extremity associated with high fatigue and low quality of life in adults with CP, effects more pronounced in those with bilateral CP. Compensation mechanisms in gait were noted.ConclusionRational follow-up programs for CP, ideally identifying risk factors early, should be established to prevent development of fatigue and deterioration of gait in adulthood.



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Dynamic joint stiffness of the ankle in healthy and rheumatoid arthritis post-menopausal women

Publication date: February 2018
Source:Gait & Posture, Volume 60
Author(s): Pedro Aleixo, José Vaz-Patto, Helena Moreira, João Abrantes
The purpose of this study was to compare rheumatoid arthritis post-menopausal women (RAPW) with pathological involvement of the lower limb joints and age-matched healthy post-menopausal women (AHPW) in regard to the dynamic joint stiffness of the ankle (DJSankle) during the stance phase of gait. Data were collected from 18 RAPW and 18 AHPW. Gait was assessed by a three-dimensional motion analysis system synchronised with a force plate. Subjects walked barefoot at natural and self-selected speed, performing 14 valid trials (comprising 7 left and 7 right foot-steps on a force plate). The stance phase was split into three sub-phases that corresponded to the three angular displacements of the ankle that occurred during this phase, namely, controlled plantar flexion (CPF), controlled dorsiflexion (CDF), and powered plantar flexion (PPF). A linear model represented each sub-phase and computed DJSankle. Model fitting was assessed by the coefficient of determination (R²). The coefficient of variation (CV) was used to assess intra-individual variability. In all sub-phases, R² values for both groups were higher than 0.85. There were no differences in the R² values among groups. RAPW showed a higher DJSankle during the CPF (p < 0.05). CDF and PPF yielded no differences among groups. During CPF, RAPW yielded a higher CV for DJSankle (p < 0.01). RAPW also yielded lower ankle angular displacements during CPF and PPF (p < 0.05). Findings suggested that the stance phase of RAPW and AHPW can be studied by a linear ankle 'moment of force −– angle' relationship. During CPF, RAPW exhibited excessive ankle stiffness and presented a higher intra-individual DJSankle variability.



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PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS)

Background/Aim: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs. Materials and Methods: In our study we evaluated PTCH1 gene-carrier probands affected by NBCCS to detect the incidence of BFHs and their correlation with this rare syndrome. Results: Among probands we recognized 4 patients with BFHs. We found 15 germline PTCH1 mutations, uniformly distributed across the PTCH1 gene. Six of them had familial history of NBCCS, two of them were novel and have not been described previously. Conclusion: NBCCS and BFHS may be the same genetic entity and not two distinctive syndromes. The inclusion of BFH in the NBCCS cutaneous tumor spectrum might be useful for the recognition of misdiagnosed NBCCS cases that could benefit from tailored surveillance strategies.

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Cancer Progenitor Cells: The Result of an Epigenetic Event?

The concept of cancer stem cells was proposed in the late 1990s. Although initially the idea seemed controversial, the existence of cancer stem cells is now well established. However, the process leading to the formation of cancer stem cells is still not clear and thus requires further research. This article discusses epigenetic events that possibly produce cancer progenitor cells from predisposed cells by the influence of their environment. Every somatic cell possesses an epigenetic signature in terms of histone modifications and DNA methylation, which are obtained during lineage-specific differentiation of pluripotent stem cells, which is specific to that particular tissue. We call this signature an epigenetic switch. The epigenetic switch is not fixed. Our epigenome alters with aging. However, depending on the predisposition of the cells of a particular tissue and their microenvironment, the balance of the switch (histone modifications and the DNA methylation) may be tilted to immortality in a few cells, which generates cancer progenitor cells.

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The Role of Prophylactic Cranial Irradiation for Non-small Cell Lung Cancer

Background: The use of prophylactic cranial irradiation (PCI) to treat brain metastases (BM) in non-small cell lung cancer (NSCLC) is restricted due to the potential associated toxicity and lack of survival benefit. BM can have a negative impact on neurocognitive function (NF) and quality of life (QOL). The aim of this review was to assess the impact of PCI on disease-specific and NF and QOL outcomes. Materials and Methods: An electronic database literature search was completed to identify relevant studies. Results: Fourteen published articles were included. PCI significantly reduced the incidence of BM, but no significant survival advantage was found. NF decline was reported in one trial. No significant difference in QOL with PCI was reported. PCI was well tolerated by the majority of patients with NSCLC and associated with a relatively low toxicity. Conclusion: PCI reduces the incidence of BM without any significant survival advantage. PCI has the potential to be beneficial in practice for certain patients with locally advanced NSCLC, based on disease factors and patient preference.

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The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma

Background/Aim: This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue. Patients and Methods: Thirty patients who underwent surgery for bone or soft tissue metastatic lesions of RCC were retrospectively evaluated. The surgical procedures were wide resection in 14 patients (group 1) and intralesional resection in 16 (group 2). Results: The 3-, 5-, 10-, and 15-year overall survival (OS) was 76%, 48%, 35%, and 23%, respectively, and OS was significantly favorable in group 1. In addition, recurrence-free survival rate was significantly higher in group 1. In the multivariate analysis, intralesional resection was an independent risk factor for poor prognosis. There was no significant difference in surgical time, though intraoperative hemorrhage was significantly larger in group 2. Conclusion: The wide resection of bone and soft tissue metastatic lesions of RCC is a favorable option for controlling local metastasis and improving prognosis.

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Regimens of Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis from Colorectal Cancer

Although systemic chemotherapy has been improved, peritoneal carcinomatosis remains a factor of poor prognosis in patients with colorectal cancer. In order to achieve a higher drug concentration in the peritoneal cavity, intraperitoneal chemotherapy has been performed. However, the optimal regimen for intraperitoneal chemotherapy has not been determined. In this review of intraperitoneal chemotherapy for colorectal cancer, we summarize regimens of hyperthermic intraperitoneal chemotherapy (HIPEC) and other intraperitoneal chemotherapy modalities, such as early postoperative intraperitoneal chemotherapy (EPIC) and sequential postoperative intraperitoneal chemotherapy (SPIC). Mitomycin C and oxaliplatin are the most common chemotherapeutic agents used for HIPEC. Some combination therapies such as those involving bevacizumab, H₂O₂, and amifostine have potential to increase HIPEC efficacy. 5-Fluorouracil is used mainly for EPIC and SPIC. Some new agents such as paclitaxel, melphalan, and various nanoparticles have been developed. These novel chemotherapeutic agents may achieve clinical implementation in the future.

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Computed Tomography Density Change in the Thyroid Gland Before and After Radiation Therapy

Background/Aim: Hypothyroidism is an established adverse effect of radiation therapy for head and neck cancer, and computed tomography (CT) density of the thyroid gland is lower in hypothyroid than euthyroid individuals. No previous studies have evaluated changes in CT densities of the thyroid gland caused by radiation therapy. The aim was to investigate the relationship between the change in CT density of the thyroid gland before and after radiation therapy for head and neck cancer and hypothyroidism. Materials and Methods: This retrospective study analyzed data of 24 patients treated by radiation therapy for head and neck cancers. After dosimetric analysis of received radiation therapy, a Picture Archiving and Communication System was used to manually contour the thyroid on pre-treatment CT images to enable determination of mean thyroid gland CT densities and received radiation doses. Pre- and post-treatment thyroid function was assessed on the basis of serum TSH concentrations. Multivariate and univariate analyses were used to determine what clinical factors are associated with post-radiation therapy decrease in CT density of the thyroid and Pearson's ² test was used to assess correlations between these densities and TSH concentrations. Results: Mean CT densities of the thyroid gland decreased from before to after radiation therapy in 73.9% of our patients (median decrease 16.8 HU). Serum TSH concentrations were significantly higher in patients with greater then median decreases in CT density than in those with lesser or no decreases. Conclusion: Post-radiation therapy hypothyroidism may be predicted by significant decreases in CT density of the thyroid gland.

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Should Adjuvant Radiation Therapy Be Systematically Proposed for Male Breast Cancer? A Systematic Review

Background: Guidelines for radiotherapy in male breast cancer (MBC) are lacking. Some extrapolate the results from female breast cancer trials, while others advocate systematic adjuvant irradiation. We evaluated clinical practices and outcomes with respect to radiation therapy in MBC treated with locoregional irradiation in the adjuvant setting using a systematic literature review. Material and Methods: We included studies with data about adjuvant radiotherapy published between 1984 and 2017 and including at least 40 patients. Results: We found 29 retrospective series, 10,065 men were diagnosed with breast cancer; 3-100% (mean=54%) received adjuvant radiotherapy. Tumor size and nodal involvement were the strongest prognostic factors. Approximatively half of all cases had nodal metastases. Radiation therapy improved locoregional control in six series, overall survival in three and distant metastasis-free survival in one. Conclusion: MBC is diagnosed at a highly advanced stage and may be linked with poorer outcomes. Adjuvant radiation therapy must, at least, be proposed to men with positive nodes. Despite the large number of cases gathered here, arguments for radiotherapy in other prognostic subgroups (especially in pN0) may exist but are not well supported.

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Hepatic Resection Followed by Hepatic Arterial Infusion Chemotherapy for Hepatocellular Carcinoma with Intrahepatic Dissemination

Background/Aim: To investigate the utility of adjuvant hepatic arterial infusion chemotherapy (HAIC) following hepatectomy for patients with hepatocellular carcinoma (HCC) with intrahepatic dissemination (IHD) after local ablation therapy. Patients and Methods: Twelve patients with HCC with IHD were divided into two groups: HAIC group (n=6) underwent hepatectomy followed by HAIC; and the non-HAIC group (n=6) underwent hepatectomy alone. HAIC with cisplatin and 5-fluorouracil was started within a month and was continued for a month: Results: At the first local ablation, tumors close to the major portal vein and insufficient ablation were recognized in eight (67.7%) and six (58.3%) of the patients, respectively. In the HAIC group, the 1-, 3-, and 5-year disease-free and overall survival rates were 50.0%, 16.7%, and 16.7%, and 83.3%, 83.3% and 62.5%, respectively. Three patients in the HAIC group remain alive after 10 years of follow-up. Conclusion: Hepatic resection with short-term postoperative HAIC may provide excellent outcomes in patients with HCC and IHD.

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Managing Focal Nodular Hyperplasia of the Liver: Surgery or Minimally-invasive Approaches? A Review of the Preferable Treatment Options

Background/Aim: Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver. As of 2017, many clinical, radiological and surgical features have been largely documented. On the other hand, little is still known about the correlation of FNH with hepatocellular carcinoma, nor the preferable modality of treatment. Our aim was to elucidate the latter topic. Materials and Methods: We investigated the pertinent literature available as of 2017 through four popular search engines (PubMed, Science Direct, Scopus and Google Scholar). Four main approaches were selected: conservative treatment, surgery, radiofrequency ablation (RFA) and transarterial embolization (TAE). Results: We found most works to be on conservative and surgical approaches. On the contrary, only one article has been published for RFA to date. Seventeen articles dealt with TAE. Conclusion: TAE currently represents the most cogent and successful alternative to surgery.

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Molecular Basis for Mitochondrial Signaling

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Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect?

Non-small cell lung cancer constitutes the most common type of lung cancer, accounting for 85-90% of lung cancer, and is a leading cause of cancer-related death. Despite the progress during the past years, poor prognosis remains a challenge and requires further research and development of novel antitumor treatment. Recently, the role of histone deacetylases in gene expression has emerged showing their regulation of the acetylation of histone proteins and other non-histone protein targets and their role in chromatin organization, while their inhibitors, the histone deacetylase inhibitors, have been proposed to have a potential therapeutic role in diverse malignancies, including non-small cell lung cancer. This review article focuses on the role of histone deacetylase inhibitors in the treatment of non-small cell lung cancer and the major molecular mechanisms underlying their antitumor activity recognized so far.

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Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy

Background/Aim: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. Patients and Methods: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). Results: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade ≤2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2≤ urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. Conclusion: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT.

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Our ACE in the HOLE: Justifying the Use of Angiotensin-converting Enzyme Inhibitors as Adjuvants to Standard Chemotherapy

Angiotensin-I-converting enzyme (ACE) inhibitors have been very effective in treating cardiac hypertension since their clinical inception over four decades ago. Since then, it has been established that angiotensin II, the product of ACE, has oncogenic and pro-proliferative qualities, which begs the question as to whether ACE inhibitors may have oncolytic characteristics. In fact, scattered reports suggest that ACE inhibitors are oncolytic and oncopreventive, but the available literature has yet to be thoroughly examined. In the present review, we examine the available literature and determine that ACE inhibitors would have great utility in the prevention and treatment of cancer. At the same time, they would augment the efficacy of chemo- and radiotherapy as well as mitigating damage to healthy tissue by standard chemotherapeutic regimens. We review some of the mounting clinical evidence and show that ACE inhibitors have oncolytic activity in multiple types of cancer and discuss the ability of ACE inhibitors to prevent cardiotoxicity of multiple chemotherapies. Our analysis demonstrates that the actions of ACE inhibitors converge on vascular endolthelial growth factor to reduce its levels in tumors and prevent construction of blood vessels to masses, leaving them nutrient-depleted and subsequently hindering their growth. Given that ACE inhibitors are approved by the Federal Drug Administration and the therapeutic dose for hypertension treatment also slows the growth of multiple cancers types, ACE inhibitors are in a perfect position to be repurposed as oncolytic agents, that would widely increase their utility in the clinic.

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Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Elderly Patients: Complete Cytoreduction Is Feasible and Crucial for Improved Survival Despite High Carcinomatosis Index

Background: We aimed to study the surgical outcomes of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in elderly patients, and investigate whether the pursuit of complete cytoreduction implies a survival benefit despite a high peritoneal carcinomatosis index (PCI). Patients and Methods: All CRS and HIPEC procedures performed for patients with peritoneal surface malignancy (PSM) ≥65 years old between 2005-2017 were included. A control group comprising patients 60-64 years old who underwent CRS and HIPEC over the same period was also selected for comparison of characteristics and outcomes. Results: A total of 54 elderly patients and 27 control patients were included. Increasing age did not result in any difference in demographics, perioperative characteristics, or surgical outcomes. Elderly patients who achieved completeness of cytoreduction (CC) 0/1 were compared to those with CC2/3, and were found to have a higher body mass index, lower peritoneal cancer index, higher rate of inpatient mortality, and a significantly longer median survival (43 vs. 15 months; p=0.020). Cox multivariate regression identified Charlson score ≥2, the occurrence of major morbidities, colorectal and sarcoma primary tumor, and CC2/3 as significant predictors of poor survival. Conclusion: CRS and HIPEC are feasible in elderly patients without a significant effect of increasing age on the surgical outcomes. CC0/1 carries higher postoperative mortality rate, but yields a longer overall survival. Baseline comorbidities, postoperative complications, certain histologies, and CC2/3 are predictors of poor prognosis in this population. PCI is a predictor of CC, but not of survival when CC0/1 is achieved.

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Pacifastin-derived Peptides Target Tumors for Use in In Vivo Imaging

Background/Aim: Developments in imaging have improved cancer diagnosis, but identification of malignant cells during surgical resection remains a challenge. The aim of this study was to investigate the pacifastin family of peptides for novel activity targeting tumor cells and the delivery of either imaging or therapeutic agents. Materials and Methods: Variants of pacifastin family peptides were generated, chemically modified and tested in human tumor xenografts. Results: A tumor-homing peptide-dye conjugate (THP1) accumulated in tumors in vivo and was internalized into cells. Examination of related peptides revealed residues critical for accumulation and allowed the engineering of improved tumor-targeting variants. A THP1-drug conjugate carrying the microtubule inhibitor, MMAE, showed limited activity in vitro and no difference compared to vehicle control in vivo. Conclusion: Although there are some obstacles to developing pacifastin-derived peptides for therapeutic activity, these optimized peptides have great promise for cancer imaging.

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The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy

Background/Aim: We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. Patients and Methods: Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. Results: The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. Conclusion: Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.

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In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

Background: We generated humanized/de-immunized immunotoxins targeting the prostate-specific membrane antigen (PSMA) and tested their cytotoxic activity against prostate cancer cells in vitro. Materials and Methods: The humanized/de-immunized version of our murine anti-PSMA single-chain antibody fragment (scFv) D7, termed hD7-1(VL-VH), was ligated to the 40-kDa toxin domain of Pseudomonas aeruginosa exotoxin A (PE40), and to the deimmunized 24-kDa toxin domains PE24 or PE24mut. The immunotoxins designated as hD7-1(VL-VH)-PE40, hD7-1(VL-VH)-PE24 and hD7-1(VL-VH)-PE24mut were bacterially expressed and purified by affinity chromatography. Binding and cytotoxicity were examined by flow cytometry and viability assay, respectively. Results: All immunotoxins revealed strong binding to prostate cancer cells expressing PSMA and specific cytotoxicity, with half-maximal inhibitory concentration values in the picomolar range. Conclusion: We successfully created powerful anti-PSMA immunotoxins with reduced immunogenicity for further clinical development and application against advanced prostate cancer.

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Clinical Significance of PD-L1 Expression in Brain Metastases from Non-small Cell Lung Cancer

Aim: To investigate the association between positivity for programmed cell death-ligand 1 (PD-L1) in brain metastases (BM) and the prognosis or clinical factors in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Thirty-two patients with surgically resected brain-metastatic NSCLC were enrolled. The PD-L1 expression in BM was analyzed using the antibody against human PD-L1 (clone SP142). The PD-L1 positivity was defined as PD-L1 expression on brain-metastatic tumor cells of ≥5%. Results: Seven (21.9%) out of 32 patients showed PD-L1 positivity in BM. The PD-L1-positive BM group had a significantly shorter brain-specific disease-free survival than the PD-L1-negative BM group (p<0.05). PD-L1 positivity in BM was significantly associated with a heavy smoking history and the administration of radiotherapy for BM before surgery (p<0.05 and p<0.05, respectively). Conclusion: The PD-L1 expression in BM from NSCLC may be associated with local recurrence following surgery, and the smoking- or radiotherapy-derived effects.

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Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation

Background/Aim: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3–FOXO1) fusion oncoprotein has the worst prognosis. The goal of this study was to investigate the chemotherapeutic effects of sphingosine on PAX3–FOXO1-positive ARMS cells [tumor protein p53 (TP53)-mutated RH30 and TP53 wild-type RH18 cells]. Materials and Methods: The proliferation, cell death, apoptosis, cell cycle, and MYCN proto-oncogene (MYCN) expression of RH30 and RH18 cells were determined. Results: Sphingosine inhibited the growth and caused cell death in a dose-dependent manner in both cell lines. Sphingosine triggered cell death by inducing apoptosis without affecting the cell cycle. MYCN expression was down-regulated within 2 and 4 h of sphingosine treatment in both RH30 and RH18 cells. Conclusion: Sphingosine exerts antiproliferative and pro-apoptotic effects via MYCN down-regulation independently of TP53 mutation status in PAX3–FOXO1-positive ARMS cells.

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Chordomas and Chondrosarcomas of the Skull Base and Spine. 2nd Edition

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