Publication date: Available online 4 October 2016
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Brenda Marquina-Sánchez, Jesús González-Jorge, Valeria Hansberg-Pastor, Talia Wegman-Ostrosky, Noemi Baranda-Ávila, Sonia Mejía-Pérez, Ignacio Camacho-Arroyo, Aliesha González-Arenas
Intracellular progesterone receptors (PRs) and protein kinases C (PKCs) are known regulators of cancer cell proliferation and metastasis. Both PRs and PKCs are found overexpressed in grade IV human astrocytomas, also known as glioblastomas, which are the most frequent and aggressive brain tumors. In the present study, we investigated whether PR activation by PKC induces the migration and invasion of glioblastoma derived cell lines and if PKCα and δ isoforms are involved in PR activation. We observed that PKC activation with tetradecanoylphorbol acetate (TPA) increases the migration and invasion capacity of two glioblastoma derived human cell lines (U251 MG and U87) and that the treatment with the PR receptor antagonist RU486 blocks these processes. Interestingly, the pharmacological inhibition of the isoenzymes PKCα and PKCδ also resulted in a blocked PR transcriptional activity. Also, TPA-dependent PR activation increases the expression of progesterone-induced blocking factor (PIBF), a known PR target gene. These results hint to an existing cross-talk between PKCs and PRs in regulating the infiltration process of human glioblastomas.
http://ift.tt/2d0o97s
Τρίτη 4 Οκτωβρίου 2016
The interplay between intracellular progesterone receptor and PKC plays a key role in migration and invasion of human glioblastoma cells
Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells
Publication date: Available online 4 October 2016
Source:Trends in Cell Biology
Author(s): Darcie L. Moore, Sebastian Jessberger
Accumulating evidence suggests that mammalian cells asymmetrically segregate cellular components ranging from genomic DNA to organelles and damaged proteins during cell division. Asymmetric inheritance upon mammalian cell division may be specifically important to ensure cellular fitness and propagate cellular potency to individual progeny, for example in the context of somatic stem cell division. We review here recent advances in the field and discuss potential effects and underlying mechanisms that mediate asymmetric segregation of cellular components during mammalian cell division.
http://ift.tt/2cQixJI
Ambient Pressure Evaluation Through Sub-harmonic Response of Chirp-Sonicated Microbubbles
Source:Ultrasound in Medicine & Biology
Author(s): Siyu Liu, Jun Wu, Yuyang Gu, Xiasheng Guo, Juan Tu, Di Xu, Dong Zhang
The sub-harmonic response generated by oscillating ultrasound contrast microbubbles has been proven to be a potentially efficient and effective measure for non-invasive blood pressure evaluation. In this work, an improved approach to ambient pressure measurement is proposed, and the general principle underlying this approach is the combination of sub-harmonic responses of microbubbles with a chirp excitation technique. Agreement between theoretical and experimental studies indicates that compared with sinusoidal excitation, the chirp technique is beneficial in that it produces bubble sub-harmonics with higher amplitudes and lower generation thresholds and thus offers better sensitivity for ambient pressure evaluations. Studies that took the chirp parameters (e.g., central frequency, bandwidth and pulse length) into account were also carried out to determine an optimized routine for the proposed method.
http://ift.tt/2cQho4P
Echo Decorrelation Imaging of Rabbit Liver and VX2 Tumor during In Vivo Ultrasound Ablation
Source:Ultrasound in Medicine & Biology
Author(s): Tyler R. Fosnight, Fong Ming Hooi, Ryan D. Keil, Alexander P. Ross, Swetha Subramanian, Teckla G. Akinyi, Jakob K. Killin, Peter G. Barthe, Steven M. Rudich, Syed A. Ahmad, Marepalli B. Rao, T. Douglas Mast
In open surgical procedures, image-ablate ultrasound arrays performed thermal ablation and imaging on rabbit liver lobes with implanted VX2 tumor. Treatments included unfocused (bulk ultrasound ablation, N = 10) and focused (high-intensity focused ultrasound ablation, N = 13) exposure conditions. Echo decorrelation and integrated backscatter images were formed from pulse-echo data recorded during rest periods after each therapy pulse. Echo decorrelation images were corrected for artifacts using decorrelation measured prior to ablation. Ablation prediction performance was assessed using receiver operating characteristic curves. Results revealed significantly increased echo decorrelation and integrated backscatter in both ablated liver and ablated tumor relative to unablated tissue, with larger differences observed in liver than in tumor. For receiver operating characteristic curves computed from all ablation exposures, both echo decorrelation and integrated backscatter predicted liver and tumor ablation with statistically significant success, and echo decorrelation was significantly better as a predictor of liver ablation. These results indicate echo decorrelation imaging is a successful predictor of local thermal ablation in both normal liver and tumor tissue, with potential for real-time therapy monitoring.
http://ift.tt/2dGXpvh
Modelling of the optimal bupivacaine dose for spinal anaesthesia in ambulatory surgery based on data from systematic review
BACKGROUND: Spinal bupivacaine is used for day-case surgery but the appropriate dose that guarantees hospital discharge is unknown. OBJECTIVE: We sought to determine the spinal bupivacaine dose that prevents delayed hospital discharge in ambulatory surgery. DESIGN: Systematic review of clinical trials. DATA SOURCES: Comprehensive search in electronic databases of studies published between 1996 and 2014 reporting the use of spinal bupivacaine in ambulatory patients. Additional articles were retrieved through hyperlinks and by manually searching reference lists in original articles, review articles and correspondence published in English and French. MAIN OUTCOME MEASURES: Data were used to calculate, motor block duration and discharge time, an estimated maximal effect (Emax: maximum theoretical time of motor block) and the effective dose to obtain half of Emax (D50) with 95% confidence intervals (CIs). A simulation was performed to determine the dose corresponding to a time to recovery of 300 min for motor function, and 360 min for discharge, in 95% of the patients. RESULTS: In total, 23 studies (1062 patients) were included for analysis of the time to recovery of motor function, and 12 studies (618 patients) for the time to hospital discharge. The Emax for recovery of motor function was 268 min [95% CI (189 to 433 min)] and the D50 was 3.9 mg [95% CI (2.3 to 6.2 mg)]. A 7.5-mg dose of bupivacaine enables resolution of motor block and ambulation within 300 min in 95% of the patients. A 5-mg dose or less was associated with an unacceptable failure rate. CONCLUSION: Ambulatory surgery is possible under spinal anaesthesia with bupivacaine although the dose range that ensures reliable anaesthesia with duration short enough to guarantee ambulatory management is narrow.http://ift.tt/2dGTWgf
Anaesthesia and orphan disease: Hutchinson–Gilford progeria syndrome, a case report and summary of previous cases
No abstract availablehttp://ift.tt/2cQef4Y
Work stress and satisfaction in relation to personality profiles in a sample of Dutch anaesthesiologists: A questionnaire survey
BACKGROUND: Working in anaesthesia is stressful, but also satisfying. Work-related stress can have a negative impact on mental health, whereas work-related satisfaction protects against these harmful effects. OBJECTIVE(S): How work stress and satisfaction are experienced may be related to personality. Our aim was to study the relationship between personality and perception of work in a sample of Dutch anaesthesiologists. DESIGN: Questionnaire survey. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic questionnaires to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of those, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: The questionnaires assessed general work-related stress and satisfaction and anaesthesia-specific stress. A factor analysis was performed on the stress and satisfaction questionnaires. Personality traits were assessed using the Big Five Inventory. To identify personality profiles, a cluster analysis was performed on the Big Five Inventory. Scores of the extracted factors contributing to job stress and satisfaction were compared between the profiles we identified. RESULTS: Our analysis extracted six factors concerning general job stress. Of those, the emotionally difficult caseload contributed the most to job stress. The analysis also extracted four factors concerning general job satisfaction. Good relationships with patients and their families and being appreciated by colleagues contributed the most to satisfaction. The cluster analysis resulted in two distinct personality profiles: a distressed profile (n = 215) and a resilient profile (n = 440). General and anaesthesia-specific job stress was significantly higher and job satisfaction was significantly lower in the distressed profile, compared with the resilient profile. Experience of the emotionally difficult caseload did not differ between the two profiles CONCLUSION: Personality profiles were found to be related to anaesthesiologists' experience of work-related stress and satisfaction. One-third of the anaesthesiologists in our sample were categorised as distressed and are at risk of developing work-related mental health problems.http://ift.tt/2cQf0uR
Epidural abscess after epidural analgesia in children: report of two cases
No abstract availablehttp://ift.tt/2cQeVHk
Stressors in anaesthesiology: development and validation of a new questionnaire: A cross-sectional study of Portuguese anaesthesiologists
BACKGROUND: Stress in anaesthesiologists is a common and multifactorial problem related to patients, colleagues and organisations. The consequences of stress include depression, work–home conflicts and burnout. Reduction in stress can be achieved by reducing the number and magnitude of stressors or by increasing resilience strategies. OBJECTIVES: We have created the self-reporting 'Stress Questionnaire in Anaesthesiologists' (SQA), to qualify the sources of stress in anaesthesiologists' professional lives, and measure the level of associated stress. Our study aimed to develop and validate the SQA using exploratory and confirmatory factor analyses. Construct validity was assessed through correlations between SQA and negative psychological outcomes as well as by comparing perception of stress among different known groups. DESIGN: A questionnaire-based cross-sectional, correlational, observational study. SETTINGS: The study was conducted between January 2014 and December 2014, throughout different anaesthesia departments in Portuguese hospitals. Data collection was from a representative subset at one specific time point. PARTICIPANTS: A sample of 710 anaesthesia specialists and residents from Portugal. MAIN OUTCOME MEASURES: The primary outcome measure was to identify specific stressors in anaesthesiologists. Secondary outcome was the association between stressors and burnout, depression symptoms, anxiety, stress, rumination, satisfaction with life and functional impairment. RESULTS: The exploratory analysis showed the SQA is a tri-dimensional instrument and confirmatory analysis showed the tri-dimensional structure presented good model fit. The three dimensions of SQA correlated positively with other stress measures and burnout, but negatively with satisfaction with life. CONCLUSION: SQA is a well adjusted measure for assessing stressors in anaesthesia physicians and includes clinical, organisational and team stress factors. Results showed that the SQA is a robust and reliable instrument.http://ift.tt/2cQeSLP
Impact of age on anaesthesiologists’ competence: A narrative review
The international anaesthesia community is getting older, in line with trends worldwide, and as men and women age there is the risk that psychophysiological decline could have an impact on clinical practice. Impairment of technical and nontechnical skills could have a negative impact on patients' safety and outcomes. The ageing process may not necessarily go hand-in-hand with a predictable pattern of decreased competence as not all aspects of functional decline are affected at the same rate and to the same extent. The development of simulation has provided a means of detecting and perhaps reversing the decline in ability associated with age. The introduction of recertification based on an assessment of competence at simulation sessions could play a crucial role in maintaining a high standard of patient care and an appropriate level of patient safety.http://ift.tt/2cQeBsj
The efficacy of local infiltration analgesia in the early postoperative period after total knee arthroplasty: A systematic review and meta-analysis
BACKGROUND: Local infiltration analgesia (LIA) has emerged as an alternative treatment for postoperative pain after total knee arthroplasty (TKA). Its efficacy remains inconclusive with inconsistent results from previous studies and meta-analyses. There is no agreement on which local anaesthetic agent and infiltration technique is most effective and well tolerated. OBJECTIVE: The objective was to compare LIA after primary TKA with placebo or no infiltration in terms of early postoperative pain relief, mobilisation, length of hospital stay (LOS) and complications when used as a primary treatment or as an adjunct to regional anaesthesia. The role of injection sites, postoperative injection or infusion and multimodal drug injection with ketorolac were also explored. DESIGN: A systematic review and meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: A literature search was performed using PubMed and SCOPUS up to September 2015. ELIGIBILITY CRITERIA: RCTs comparing LIA with placebo or no infiltration after primary TKA in terms of pain score and opioid consumption at 24 and 48 h, mobilisation, LOS and complications were included. RESULTS: In total 38 RCTs were included. LIA groups had lower pain scores, opioid consumption and postoperative nausea and vomiting, higher range of motion at 24 h and shorter LOS than no injection or placebo. After subgroup analysis, intraoperative peri-articular but not intra-articular injection had lower pain score at 24 h than no injection or placebo with the pooled mean difference of pain score at rest of −0.89 [95% CI (−1.40 to −0.38); I2 = 92.0%]. Continuing with postoperative injection or infusion reduced 24-h pain score with the pooled mean difference at rest of −1.50 [95% CI (−1.92 to −1.08); I2 = 60.5%]. There was no additional benefit in terms of pain relief during activity, opioid consumption, range of movement or LOS when LIA was used as an adjunct to regional anaesthesia. Four out of 735 patients receiving LIA reported deep knee infection, three of whom had had postoperative catheter placement. CONCLUSION: LIA is effective for acute pain management after TKA. Intraoperative peri-articular but not intra-articular injection may be helpful in pain control up to 24 h. The use of postoperative intra-articular catheter placement is still inconclusive. The benefit of LIA as an adjunctive treatment to regional anaesthesia was not demonstrated.http://ift.tt/2cQdUiw
Incidence and severity of chronic pain after caesarean section: A systematic review with meta-analysis
BACKGROUND: The frequency of caesarean section has increased dramatically in recent decades. Despite this, robust data regarding the consequences of caesarean section in terms of developing chronic postsurgical pain (CPSP) are still lacking. OBJECTIVE: This systematic review analysed the incidence and severity of CPSP in women 3 to less than 6, 6 to less than 12, and at least 12 months after caesarean section. DESIGN: Systematic review of prospective and retrospective observational studies and randomised controlled trials with meta-analysis. DATA SOURCE: We searched MEDLINE to May 2015. ELIGIBILITY CRITERIA: We included all studies investigating the incidence and/or severity of CPSP at least 3 months after caesarean section. The primary outcome was chronic postsurgical wound pain (CPSP 'wound'). Secondary outcomes were persistent pain in the back area, pelvic region or reported as residual pain, and severity of 'birth-related' chronic pain. RESULTS: Meta-analysis using the random-effects model based on 15 studies (n = 4475) reporting CPSP 'wound' at 3 to less than 6 months after caesarean section revealed an incidence of 15.4% [95% confidence interval (CI): 9.9 to 20.9%]. For 6 to less than 12 and at least 12 months after caesarean section, the incidence of CPSP 'wound' was estimated at 11.5% (95% CI: 8.1 to 15.0%, n = 3345) and 11.2% (95% CI: 7.4 to 15.0%, n = 3451), respectively. Meta-regression analysis using the publication year as predictor revealed stable CPSP 'wound' incidences at each postoperative time slot from 2002 to the present. Of those patients who reported chronic pain, 9.6% (95% CI: 0.0 to 21.0%) had severe pain, 23.5% (95% CI: 10.0 to 37.0%) had moderate pain and 49.2% (95% CI: 18.9 to 79.4%) had mild pain at 6 months. LIMITATIONS: Major limitations are high statistical heterogeneity of the meta-analyses and inconsistencies in reporting severity of chronic 'birth-related' pain. CONCLUSION: This meta-analysis finds a clinically relevant incidence of CPSP 'wound' after caesarean section ranging from 15% at 3 months to 11% at 12 months or longer that has been largely stable in recent years.http://ift.tt/2cQfZLt
Clinical concentrations of morphine are cytotoxic on proliferating human fibroblasts in vitro
BACKGROUND: Morphine and other opioids are routinely used systemically and as wound infusions in the postoperative period. Their effect on wound and fracture healing remains unclear. OBJECTIVE: The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of morphine on human fibroblasts. DESIGN: Laboratory in-vitro study. SETTING: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich. MATERIALS: Monolayers of human fibroblasts. INTERVENTION(S): Exposure of human fibroblast monolayers to several concentrations of morphine, for different periods of time, with and without an artificially induced inflammatory process. MAIN OUTCOME MEASURES: Cell count, cell viability, cell proliferation and apoptosis. RESULTS: A concentration, time and exposure-dependent cytotoxic effect of morphine-mediated apoptosis was observed. Simulated inflammatory conditions seemed to lessen toxic effects. CONCLUSION: Cytotoxic effects of morphine are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to morphine cytotoxicity especially in the presence of higher concentration and longer exposure times.http://ift.tt/2cQf11U
Is there any analgesic benefit from preoperative vs. postoperative administration of etoricoxib in total knee arthroplasty under spinal anaesthesia?: A randomised double-blind placebo-controlled trial
BACKGROUND: Optimal postoperative analgesia is a challenge for the anaesthesiologist, with the ideal combination of methods, drugs, doses and timing of administration still the subject of research. The COX-2 inhibitors are a class of NSAIDs that may provide useful perioperative analgesia but the optimal timing of administration has not been elucidated. OBJECTIVE: We hypothesised that etoricoxib given 1 h before total knee arthroplasty under spinal anaesthesia will decrease the cumulative dose of intravenous and subcutaneous morphine required to maintain pain intensity of 3 or less on a 10-point numerical rating scale (NRS) during the first postoperative 48 h compared with the same dose of etoricoxib given after surgery. DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: University hospital, between January and September, 2014. PATIENTS: Overall, 165 patients scheduled for total knee arthroplasty under spinal anaesthesia. INTERVENTIONS: The patients were randomised into one of three groups: the ETORICOX-PREOP group received etoricoxib 120 mg orally 1 h before surgery, one placebo pill at the end of surgery and a further 120 mg etoricoxib after 24 h; the ETORICOX-POSTOP group received one placebo pill 1 h before surgery and etoricoxib 120 mg at the end of surgery and after 24 h. The PLACEBO group received one placebo pill 1 h before surgery, one at end of surgery and a third after 24 h. MAIN OUTCOME MEASURES: The primary outcome measure was the cumulative dose of intravenous and subcutaneous morphine required during the first postoperative 48 h to maintain a 10-point numerical pain rating scale value of 3 or less. Secondary outcomes measures were duration of analgesia from initiation of spinal anaesthesia until the first analgesic requirement and the side-effects of the treatment. RESULTS: The quantity of morphine over the first postoperative 48 h required by the ETORICOX-PREOP group (44 ± 16 mg) and the ETORICOX-POSTOP group (52 ± 23 mg) were both significantly less than the PLACEBO group (71 ± 20 mg) (P = 0.001), demonstrating a morphine-sparing effect of etoricoxib of the order of 30%; the difference between the PRE vs. POST groups was statistically significant (P = 0.02), favouring a preemptive analgesic effect. Also, there was evidence of a longer time to first analgesia compared with PLACEBO in the PREOP group (P = 0.02) but no significant difference between PREOP and POSTOP groups (P = 0.30). There was no difference in side-effects among the three study groups and there were no serious adverse effects of etoricoxib. CONCLUSION: Preemptive administration of etoricoxib 120 mg orally in patients undergoing total knee arthroplasty under spinal anaesthesia is superior to postoperative administration of the same dose in terms of its morphine-sparing effect during the first postoperative 48 h, but not in prolonging the time to first analgesia, and is associated with a similar incidence of side-effects. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT 02534610.http://ift.tt/2dGTDlX
The laryngeal mask airway in elective paediatric day case ENT surgery: a prospective audit
No abstract availablehttp://ift.tt/2dGSfQ0
Scholar : These new articles for Chemistry and Ecology are available online
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Agammaglobulinemia associated to nasal polyposis due to a hypomorphic RAG1 mutation in a 12 years old boy
Publication date: Available online 3 October 2016
Source:Clinical Immunology
Author(s): Cristina Cifaldi, Alessia Scarselli, Davide Petricone, Silvia Di Cesare, Maria Chiriaco, Alessia Claps, Paolo Rossi, Enrica Calzoni, Yasuhiro Yamazaki, Luigi Daniele Notarangelo, Gigliola Di Matteo, Caterina Cancrini, Andrea Finocchi
Recombination-activating gene (RAG) 1 and 2 mutations in humans cause T− B− NK+ SCID and Omenn Syndrome, but milder phenotypes associated with residual protein activity have been recently described.We report a male patient with a diagnosis of common variable immunodeficiency (CVID) born from non-consanguineous parents, whose immunological phenotype was characterized by severe reduction of B cells and agammaglobulinemia for which several candidate genes were excluded by targeted Sanger sequencing. Next Generation Sequencing revealed two compound heterozygous mutations in the RAG1 gene: the previously described p.R624H, and the novel p.Y728H mutation, as well as the known polymorphism p.H249R. This case reinforces the notion of large phenotypic spectrum in RAG deficiency and opens questions on the management and follow-up of these patients.
http://ift.tt/2dpCbA7
B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses
Publication date: Available online 4 October 2016
Source:Clinical Immunology
Author(s): Judith Fraussen, Nele Claes, Bart Van Wijmeersch, Jack van Horssen, Piet Stinissen, Raymond Hupperts, Veerle Somers
Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of costimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86+ and CD80+ B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced proinflammatory T cells in response to myelin basic protein (MBP), in contrast to B cells of HC. Immunomodulatory treatment restored B cell costimulatory molecule expression and caused significantly reduced B cell induced T cell responses. Together, these results demonstrate the potential of B cells from MS patients to induce autoreactive proinflammatory T cell responses. Immunomodulatory therapy abrogated this effect, emphasizing the importance of B cell antigen presentation and costimulation in MS pathology.
http://ift.tt/2dPiaBe
Differential activation behavior of dermal dendritic cells underlies the strain-specific Th1 responses to single epicutaneous immunization
Publication date: Available online 3 October 2016
Source:Journal of Dermatological Science
Author(s): Chih-Hung Lee, Jau-Shiuh Chen, Hsien-Ching Chiu, Chien-Hui Hong, Ching-Yi Liu, Yng-Cun Ta, Li-Fang Wang
BackgroundEpicutaneous immunization with allergens is an important sensitization route for atopic dermatitis. We recently showed in addition to the Th2 response following single epicutaneous immunization, a remarkable Th1 response is induced in B6 mice, but not in BALB/c mice, mimicking the immune response to allergens in human non-atopics and atopics.ObjectiveWe investigated the underlying mechanisms driving this differential Th1 response between BALB/c and B6 mice.MethodsWe characterized dermal dendritic cells by flow cytometric analysis. We measured the induced Th1/Th2 responses by measuring the IFN-γ/IL-13 contents of supernatants of antigen reactivation cultures of lymph node cells.ResultsWe demonstrate that more dermal dendritic cells with higher activation status migrate into draining lymph nodes of B6 mice compared to BALB/c mice. Dermal dendritic cells of B6 mice have a greater ability to capture protein antigen than those of BALB/c mice. Moreover, increasing the activation status or amount of captured antigen in dermal dendritic cells induced a Th1 response in BALB/c mice. Further, differential activation behavior, but not antigen-capturing ability of dermal dendritic cells between BALB/c and B6 mice is dendritic cell-intrinsic.ConclusionThese results show that the differential activation behavior of dermal dendritic cells underlies the strain-specific Th1 responses following single epicutaneous immunization. Furthermore, our findings highlight the potential differences between human atopics and non-atopics and provide useful information for the prediction and prevention of atopic diseases.
http://ift.tt/2cPMkH2
Differential diagnosis of herpetiform vesicles by a non-invasive, molecular method using crusts or blister roofs: Sensitivity, specificity and likelihood ratio
Publication date: Available online 3 October 2016
Source:Journal of Dermatological Science
Author(s): Tomoko Miyake, Takenobu Yamamoto, Yoji Hirai, Keiji Iwatsuki
http://ift.tt/2dsxR1C
Estrogens and selective estrogen receptor modulators in acromegaly
Abstract
Despite recent advances in acromegaly treatment by surgery, drugs, and radiotherapy, hormonal control is still not achieved by some patients. The impairment of IGF-1 generation by estrogens in growth hormone deficient patients is well known. Patients on oral estrogens need higher growth hormone doses in order to achieve normal IGF-1 values. In the past, estrogens were one of the first drugs used to treat acromegaly. Nevertheless, due to the high doses used and the obvious side effects in male patients, this strategy was sidelined with the development of more specific drugs, as somatostatin receptor ligands and dopamine agonists. In the last 15 years, the antagonist of growth hormone receptor became available, making possible IGF-1 control of the majority of patients on this particular drug. However, due to its high cost, pegvisomant is still not available in many centers around the world. In this setting, the effect of estrogens and also of selective estrogen receptor modulators on IGF-1 control was reviewed, and proved to be an ancillary tool in the management of acromegaly. This review describes data concerning their efficacy and place in the treatment algorithm of acromegaly.
http://ift.tt/2dFy1AO
Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases
Abstract
Pregnancy in Cushing's syndrome (CS) is extremely rare due to the influence of hypercortisolism on the reproductive axis. Purpose of this study is to investigate whether the etiology of CS in pregnancy determines a different impact on the fetal/newborn and maternal outcomes. We performed a systematic review of cases published in the literature from January 1952 to April 2015 including the words "Cushing AND pregnancy". We included 168 manuscripts containing 220 patients and 263 pregnancies with active CS during pregnancy and with a history of CS but treated and cured hypercortisolism at the time of gestation. Adrenal adenoma was the main cause of active CS during pregnancy (44.1 %). Women with active CS had more gestational diabetes mellitus (36.9 vs. 2.3 %, p = 0.003), gestational hypertension (40.5 vs. 2.3 %, p < 0.001) and preeclampsia (26.3 vs. 2.3 %, p = 0.001) than those with cured disease. The proportion of fetal loss in active CS was higher than in cured CS (23.6 vs. 8.5 %, p = 0.021), as well as global fetal morbidity (33.3 vs. 4.9 %, p < 0.001). The predictors of fetal loss in active CS were etiology of hypercortisolism [Odds Ratio –OR—for pregnancy-induced CS 4.7 (95 % Confidence Interval–CI 1.16–18.96), p = 0.03], publication period [OR for "1975–1994" 0.10 (95 % CI 0.03–0.40), p = 0.001] and treatment during gestation (p = 0.037, [OR medical treatment 0.25 (95 % CI 0.06–1.02), p = 0.052], [OR surgical treatment 0.34 (95 % CI 0.11–1.06), p = 0.063]). The period of diagnosis of CS (before, during or after pregnancy) was the only predictor of overall fetal morbimortality [OR for diagnosis during pregnancy 4.66 (95 % CI 1.37–15.83), p = 0.014]. Patients with active CS, especially in pregnancy-induced CS, experienced more problems in pregnancy and had the worst fetal prognosis in comparison to other causes. Diagnosis of CS during pregnancy was also associated with worse overall fetal morbimortality. Both medical treatment and surgery during pregnancy appeared to be protective in avoiding fetal loss.
http://ift.tt/2d0cwx5
Postoperative Concurrent Chemoradiotherapy With Docetaxel for High-Risk Head and Neck Cancers
Interventions: Drug: Docetaxel; Drug: Cisplatinum; Radiation: IMRT
Sponsors: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University; Fudan University
Not yet recruiting - verified October 2016
http://ift.tt/2cQ0K5a
Study of Proton Versus Photon Beam Radiotherapy in the Treatment of Head and Neck Cancer
Interventions: Radiation: Photon intensity modulated radiation therapy (IMRT); Radiation: Proton beam radiotherapy (PBRT)
Sponsor: Memorial Sloan Kettering Cancer Center
Recruiting - verified October 2016
http://ift.tt/2dGEUaw
Tisotumab Vedotin (HuMax®-TF-ADC) Safety Study in Patients With Solid Tumors
Intervention: Drug: Tisotumab vedotin (HuMax-TF-ADC)
Sponsor: Genmab
Recruiting - verified October 2016
http://ift.tt/2cQ1iIn
Reducing lack of fusion during selective laser melting of CoCrMo alloy: Effect of laser power on geometrical features of tracks
Publication date: 15 December 2016
Source:Materials & Design, Volume 112
Author(s): K. Darvish, Z.W. Chen, T. Pasang
There is a need to understand how selective laser melting (SLM) parameters affect the size and shape of tracks which are the predominant factor relating to the amount of lack of fusion (LOF) formed during SLM. This study is needed as severe LOF impacts quality. In this work on CoCrMo alloy SLM, experiments and analysis have been conducted to reveal how laser power (P) and thus energy, as other parameters are kept unchanged, affect the geometrical features of SLM tracks and the formation of LOF. It has been found that the track was insufficient to overlap and prevent LOF when the recommended condition (P=180W) was used. Increasing P increases the size and improves the shape stability of the tracks. It will be shown that there is a rapid decay in the amount of LOF as P increases from 180W to 220W, as the result of the geometrical effect of the track size on overlapping coverage. However, residual LOF has remained even when P has increased to >300W. Evidence of large size spatters causing this and of the high laser beam penetrating capability to reduce the spatter effect is presented and discussed.
Graphical abstract
http://ift.tt/2dpMq6P
Grain orientation statistics of grain-clusters and the propensity of multiple-twinning during grain boundary engineering
Publication date: 15 December 2016
Source:Materials & Design, Volume 112
Author(s): Tingguang Liu, Shuang Xia, Baoshun Wang, Qin Bai, Bangxin Zhou, Cheng Su
Large grain-cluster or so-called twin-related domain is a typical characteristic of the grain boundary (GB) engineered microstructure. Grain-cluster is formed via numerous twinning operations starting from single nucleus, and the process is referred to as multiple-twinning. This work investigated the orientation diversity within grain-clusters and the twinning ordering of multiple-twinning based on the statistics of grain-orientations in 30 large-sized grain-clusters from GB-engineered Ni-based alloy 690. The statistics show that the grain-cluster apparently has several dominant orientations. A few dominant orientations occupy most area and most grains in a grain-cluster. Moreover most misorientations between these dominant orientations are of low-order ∑3n-type (n=1, 2), and the 4 sub-dominant orientations are twinning variants of the first-dominant orientation in most cases. These statistical characteristics of grain-clusters reflect the general behavior of multiple-twinning: back-and-forth pattern and preferential orientations. The twinning operations produce not only higher (forward) but also lower (backward) generation orientations, and the backward probability is higher than the forward. The multiple-twinning shows a propensity to form or access to a few preferential orientations, and results in the formation of dominant orientations of the formed grain-cluster.
Graphical abstract
http://ift.tt/2dpMnaQ
The decisive role played by graphene nanoplatelets on improving the tribological performance of Y2O3-Al2O3-SiO2 glass coatings
Publication date: 15 December 2016
Source:Materials & Design, Volume 112
Author(s): Alberto Gómez-Gómez, Andrés Nistal, Eugenio García, M. Isabel Osendi, Manuel Belmonte, Pilar Miranzo
Graphene nanoplatelets (GNPs) have proved to be effective fillers for enhancing the mechanical and tribological properties of bulk ceramics and glasses, also with the added benefit of developing electrical and thermal functionalities. Similarly, enhanced transport performance has recently been shown for glass-ceramics coatings of the Y2O3-Al2O3-SiO2 (YAS) system containing a small amount of GNP fillers, intended for applications in the aerospace industry. In the present work, the wear and friction behaviour of GNP/YAS coatings –containing 0, 1.2 and 2.3wt.% GNPs- on silicon carbide substrates is evaluated. The flame spraying process used for coating fabrication induces a structure of splats oriented parallel to the substrate with GNPs located at the inter-splat boundaries forming a connected network of platelets mainly oriented parallel to the surface as well. Unlubricated ball–on-plate reciprocating wear tests show that both the friction coefficient and the wear rate decreased by 35% and 65%, respectively, for 2.3wt.% of GNPs. A wear mechanism for GNP/YAS coatings based on both the progressive exfoliation of the graphene sheets and the effect of the GNPs on preventing crack propagation within the coating is proposed.
Graphical abstract
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Feasibility and acceptance of simultaneous amyloid PET/MRI
Abstract
Purpose
Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time.
Methods
100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [18F]florbetaben or [11C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach.
Results
In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as "MCI-unlikely due to AD", "MCI due to AD-intermediate likelihood", and "MCI due to AD-high likelihood", respectively. 50 % of the probable AD dementia patients were categorized as "High level of evidence of AD pathophysiological process", and 56 % of the possible AD dementia patients as "Possible AD dementia - with evidence of AD pathophysiological process". With regard to the International Working Group 2 classification, 36 subjects had both positive diagnostic and progression biomarkers. The patient/caregiver survey revealed a gain of convenience in 88 % of responders as compared to a theoretically separate PET and MR imaging. In the referrer survey, an influence of the combined amyloid-beta PET/MRI on the final diagnosis was reported by 82 % of responders, with a referrer acceptance score of 3.7 ± 1.0 on a 5-point scale.
Conclusion
Simultaneous amyloid PET/MRI is feasible and provides imaging biomarkers of all categories which are able to supplement the clinical diagnosis of MCI due to AD and that of AD dementia. Further, patient and referrer convenience is improved by this one-stop-shop imaging approach.
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Paraneoplastic syndrome demonstrated on 99m Tc-HMDP bone scan
Abstract
A 23-year-old man, with no relevant medical history, presented with inflammatory peripheral and axial polyarthritis, wrist pain, and persistent low-grade fever for the past 4 months. A bone scintigraphy showed intense periosteal early and delayed uptake in long bones, with normal uptake in the spine, pelvis, and rib cage, and no clear focus of hypermetabolism. CT scan revealed a mediastinal mass. A biopsy of the mass demonstrated Hodgkin lymphoma with bulky disease. This paraneoplastic syndrome as the first sign of intrathoracic Hodgkin's disease is rare.
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Evaluation of tumour hypoxia during radiotherapy using [ 18 F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer
Abstract
Background and purpose
Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.
Material and methods
[18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.
Results
At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.
Conclusions
[18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.
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Characterization of the radiolabeled metabolite of tau PET tracer 18 F-THK5351
Abstract
Purpose
18F-THK5351 is a novel radiotracer developed for in vivo imaging of tau pathology in the brain. For the quantitative assessment of tau deposits in the brain, it is important that the radioactive metabolite does not enter the brain and that it does not bind to tau fibrils. The purpose of the study was to identify a radiolabeled metabolite of 18F-THK5351 in blood samples from human subjects and to characterize its pharmacological properties.
Methods
Venous blood samples were collected from three human subjects after injection of 18F-THK5351 and the plasma metabolite was measured by high performance thin layer chromatography. In addition, mass spectrometry analysis and enzymatic assays were used to identify this metabolite. Mice were used to investigate the blood–brain barrier permeability of the radioactive metabolite. Furthermore, the binding ability of the metabolite to tau aggregates was evaluated using autoradiography and binding assays using human brain samples.
Results
About 13 % of the unmetabolized radiotracer was detectable in human plasma at 60 min following the injection of 18F-THK5351. The isolated radiometabolite of 18F-THK5351 was the sulphoconjugate of THK5351. This metabolite could be produced in vitro by incubating THK5351 with liver but not brain homogenates. The metabolite did not penetrate the blood–brain barrier in mice, and exhibited little binding to tau protein aggregates in post-mortem human brain samples.
Conclusions
These results suggest that the sole metabolite detectable in plasma seems to be generated outside the brain and does not cross into the brain, which does not affect quantitative analysis of PET images.
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18 F-FDG PET/CT imaging factors that predict ischaemic stroke in cancer patients
Abstract
Purpose
18F-FDG PET/CT can acquire both anatomical and functional images in a single session. We investigated which factors of 18F-FDG PET/CT imaging have potential as biomarkers for an increased risk of ischaemic stroke in cancer patients.
Methods
From among cancer patients presenting with various neurological symptoms and hemiparesis, 134 were selected as eligible for this retrospective analysis. A new infarct lesion on brain MRI within 1 year of FDG PET/CT defined future ischaemic stroke. The target-to-background ratio (TBR) of each arterial segment was used to define arterial inflammation on PET imaging. Abdominal obesity was defined in terms of the area and proportion of visceral adipose tissue (VAT), subcutaneous adipose tissue and total adipose tissue (TAT) on a single CT slice at the umbilical level.
Results
Ischaemic stroke confirmed by MRI occurred in 30 patients. Patients with stroke had higher TBRs in the carotid arteries and abdominal aorta (P < 0.001) and a higher VAT proportion (P = 0.021) and TAT proportion (P = 0.041) than patients without stroke. Multiple logistic regression analysis showed that TBRs of the carotid arteries and abdominal aorta, VAT and TAT proportions, and the presence of a metabolically active tumour were significantly associated with future ischaemic stroke. Combining PET and CT variables improved the power for predicting future ischaemic stroke.
Conclusion
Our findings suggest that arterial FDG uptake and hypermetabolic malignancy on PET and the VAT proportion on CT could be independent predictors of future ischaemic stroke in patients with cancer and could identify those patients who would benefit from medical treatment.
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Synthesis and preclinical evaluation of an Al 18 F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand
Abstract
Purpose
The aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.
Methods
Several conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.
Results
Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv.
Conclusion
18F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.
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Prospective evaluation of [ 11 C]Choline PET/CT in therapy response assessment of standardized docetaxel first-line chemotherapy in patients with advanced castration refractory prostate cancer
Abstract
Purpose
The aim of this study was to prospectively evaluate the value of [11C] Choline PET/CT in monitoring early and late response to a standardized first-line docetaxel chemotherapy in castration refractory prostate cancer (mCRPC) patients.
Methods
Thirty-two patients were referred for [11C] Choline PET/CT before the start of docetaxel chemotherapy, after one and ten chemotherapy cycles (or - in case of discontinuation - after the last administered cycle) for therapy response assessment. [11C] Choline uptake (SUVmax, SUVmean), CT derived Houndsfield units (HUmax, HUmean), and volume of bone, lung, and nodal metastases and local recurrence were measured semi-automatically at these timepoints. Change in SUVmax, SUVmean, HUmax, HUmean, and volume was assessed between PET 2 and 1 (early response assessment, ERA) and PET 3 and 1 (late response assessment, LRA) on a patient and lesion basis. Results of PET/CT were compared to clinically used RECIST 1.1 and clinical criteria based therapy response assessment including PSA for defining progressive disease (PD) and non-progressive disease (nPD), respectively. Relationships between changes of SUVmax and SUVmean (early and late) and changes of PSAearly and PSAlate were evaluated. Prognostic value of initial SUVmax and SUVmean was assessed. Statistical analyses were performed using SPSS.
Results
In the patient-based ERA and LRA there were no statistically significant differences in change of choline uptake, HU, and volume between PD and nPD applying RECIST or clinical response criteria. In the lesion-based ERA, decrease in choline uptake of bone metastases was even higher in PD (applying RECIST criteria), whereas in LRA the decrease was higher in nPD (applying clinical criteria). There were only significant correlations between change in choline uptake and PSA in ERA in PD, in LRA no significant correlations were discovered. Initial SUVmax and SUVmean were statistically significantly higher in nPD (applying clinical criteria).
Conclusion
There is no significant correlation between change in choline uptake in [11C] Choline PET/CT and clinically routinely used objective response assessment during the early and late course of docetaxel chemotherapy. Therefore, [11C] Choline PET/CT seems to be of limited use in therapy response assessment in standardized first-line chemotherapy in mCRPC patients.
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Guidelines to PET measurements of the target occupancy in the brain for drug development
Abstract
This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.
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Striatal hypometabolism in premanifest and manifest Huntington’s disease patients
Abstract
Purpose
To assess metabolic changes in cerebral 18F-FDG PET/CT in premanifest and manifest Huntington's disease (HD) subjects compared to a control group and to correlate 18F-FDG uptake patterns with different disease stages.
Materials and methods
Thirty-three gene-expanded carriers (Eight males; mean age: 43 y/o; CAG > 39) were prospectively included. Based on the Unified Huntington's Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain 18F-FDG PET/CT and MRI. 18F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox.
Results
Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of 18F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50 voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50 voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50 voxels).
Conclusion
18F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. 18F-FDG PET/CT appears as a promising method to monitor the response to disease-modifying therapies even if applied in premanifest subjects.
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Comparison of bone scintigraphy and 68 Ga-PSMA PET for skeletal staging in prostate cancer
Abstract
Purpose
The aim of our study was to compare the diagnostic performance of 68Ga-PSMA PET and 99mTc bone scintigraphy (BS) for the detection of bone metastases in prostate cancer (PC) patients.
Methods
One hundred twenty-six patients who received planar BS and PSMA PET within three months and without change of therapy were extracted from our database. Bone lesions were categorized into benign, metastatic, or equivocal by two experienced observers. A best valuable comparator (BVC) was defined based on BS, PET, additional imaging, and follow-up data. The cohort was further divided into clinical subgroups (primary staging, biochemical recurrence, and metastatic castration-resistant prostate cancer [mCRPC]). Additionally, subgroups of patients with less than 30 days delay between the two imaging procedures and with additional single-photon emission computed tomography (SPECT) were analyzed.
Results
A total of 75 of 126 patients were diagnosed with bone metastases. Sensitivities and specificities regarding overall bone involvement were 98.7–100 % and 88.2–100 % for PET, and 86.7–89.3 % and 60.8–96.1 % (p < 0.001) for BS, with ranges representing results for 'optimistic' or 'pessimistic' classification of equivocal lesions. Out of 1115 examined bone regions, 410 showed metastases. Region-based analysis revealed a sensitivity and specificity of 98.8–99.0 % and 98.9–100 % for PET, and 82.4–86.6 % and 91.6–97.9 % (p < 0.001) for BS, respectively. PSMA PET also performed better in all subgroups, except patient-based analysis in mCRPC.
Conclusion
Ga-PSMA PET outperforms planar BS for the detection of affected bone regions as well as determination of overall bone involvement in PC patients. Our results indicate that BS in patients who have received PSMA PET for staging only rarely offers additional information; however, prospective studies, including a standardized integrated x-ray computed tomography (SPECT/CT) protocol, should be performed in order to confirm the presented results.
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The reoxygenation of hypoxia and the reduction of glucose metabolism in head and neck cancer by fractionated radiotherapy with intensity-modulated radiation therapy
Abstract
Purpose
The purpose of this study was to prospectively investigate reoxygenation in the early phase of fractionated radiotherapy and serial changes of tumoricidal effects associated with intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer (HNC) using F-18 fluoromisonidazole (FMISO) PET and F-18 fluorodeoxyglucose (FDG) PET.
Methods
Patients with untreated HNC underwent FMISO-PET and FDG-PET studies prospectively. A PET evaluation was conducted before each IMRT (Pre-IMRT), during IMRT (at 30 Gy/15 fr) (Inter-IMRT), and after completion of IMRT (70 Gy/35 fr) (Post-IMRT). FMISO-PET images were scanned by a PET/CT scanner at 4 h after the FMISO injection. We quantitatively analyzed the FMISO-PET images of the primary lesion using the maximum standardized uptake (SUVmax) and tumor-to-muscle ratio (TMR). The hypoxic volume (HV) was calculated as an index of tumor hypoxia, and was defined as the volume when the TMR was ≥ 1.25. Each FDG-PET scan was started 1 h after injection. The SUVmax and metabolic tumor volume (MTV) values obtained by FDG-PET were analyzed.
Results
Twenty patients finished the complete PET study protocol. At Pre-IMRT, 19 patients had tumor hypoxia in the primary tumor. In ten patients, the tumor hypoxia disappeared at Inter-IMRT. Another seven patients showed the disappearance of tumor hypoxia at Post-IMRT. Two patients showed tumor hypoxia at Post-IMRT. The FMISO-PET results showed that the reduction rates of both SUVmax and TMR from Pre-IMRT to Inter-IMRT were significantly higher than the corresponding reductions from Inter-IMRT to Post-IMRT (SUVmax: 27 % vs. 10 %, p = 0.025; TMR: 26 % vs. 12 %, p = 0.048). The reduction rate of SUVmax in FDG-PET from Pre-IMRT to Inter-IMRT was similar to that from Inter-IMRT to Post-IMRT (47 % vs. 48 %, p = 0.778). The reduction rate of the HV in FMISO-PET from Pre-IMRT to Inter-IMRT tended to be larger than that from Inter-IMRT to Post-IMRT (63 % vs. 40 %, p = 0.490). Conversely, the reduction rate of the MTV in FDG-PET from Pre-IMRT to Inter-IMRT was lower than that from Inter-IMRT to Post-IMRT (47 % vs. 74 %, p = 0.003).
Conclusions
Both the intensity and the volume of tumor hypoxia rapidly decreased in the early phase of radiotherapy, indicating reoxygenation of the tumor hypoxia. In contrast, the FDG uptake declined gradually with the course of radiotherapy, indicating that the tumoricidal effect continues over the entire course of radiation treatment.
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Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease
Abstract
Purpose
The cannabinoid type 2 receptor (CB2R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB2R is primarily found on microglia. CB2R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB2R tracer [11C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB2R availability regionally colocalized to Aβ deposits is present in vivo.
Methods
Dynamic 90-min [11C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [11C]PIB scan 40 min after injection. In four HC, a retest scan with [11C]NE40 PET was performed within 9 weeks to investigate test–retest characteristics.
Results
[11C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time–activity curves best; both binding potential (BPND) and distribution volume (V T) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BPND were in the range of 0.7 – 1.8 and 0.6 – 1.6, respectively. Test values in HC were about 30 % for V T and BPND. AD patients showed overall significantly lower CB2R binding. No relationship was found between regional or global amyloid load and CB2R availability.
Conclusion
Kinetic modelling of [11C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [11C]NE40 PET shows lower CB2R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [11C]NE40 binds to CB2R with lower affinity and/or selectivity than to CB1R.
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