The intrafollicular concentrations of biologically active cortisol in women rise abruptly shortly before ovulation and follicular rupture.

STUDY QUESTION: What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans? SUMMARY ANSWER: Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes. WHAT IS KNOWN ALREADY: Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T = 0 h, T = 12 h, T = 17 h, T = 32 h. A second sample was collected at oocyte pick up at T = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1, CYP21A2, HSD11B1, HSD11B2, and NR3C1 in GCs at the same time points. MAIN RESULTS AND THE ROLE OF CHANCE: The concentration of cortisol was significantly increased from a few nM at 0 h to around 100-140 nM (P ≤ 0.0001) at 32-36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25-40 nM (P ≤ 0.0001) at 32-36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs. LIMITATIONS, REASONS FOR CAUTION: The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Progesterone and 17-hydroxy-progesterone concentrations in follicular fluid and serum reflect their production in granulosa and theca cells.

RESEARCH QUESTION: How is the production of progesterone (P4) and 17-hydroxy-P4 (17-OH-P4) regulated between theca cells and granulosa cells during the follicular phase, during ovulation and after transformation into a corpus luteum? DESIGN: Three cohorts were examined: (i) 31 women undergoing natural and stimulated cycles, with serum hormone measurements taken every 3 days; (ii) 50 women undergoing ovarian stimulation, with hormone concentrations in serum and follicular fluid assessed at five time points during final follicle maturation; and (iii) 12 women undergoing fertility preservation, with hormone concentrations evaluated via the follicular fluid of small antral follicles. RESULTS: In the early follicular phase, theca cells primarily synthesized 17-OH-P4 while granulosa cells produced limited P4, maintaining the P4:17-OH-P4 ratio <1. As follicles reached follicle selection at a diameter of approximately 10 mm, P4 synthesis in granulosa cells was up-regulated, but P4 was mainly accumulated in follicular fluid. During final maturation, enhanced activity of the enzyme HSD3B2 in granulosa cells enhanced P4 production, with the P4:17-OH-P4 ratio increasing to >1. The concentration of 17-OH-P4 in the luteal phase was similar to that in the follicular phase, but P4 production increased in the luteal phase, yielding a P4:17-OH-P4 ratio significantly >1. CONCLUSIONS: The P4:17-OH-P4 ratio reflects the activity of granulosa cells and theca cells during the follicular phase and following luteinization in the corpus luteum. Managing the function of granulosa cells is key for reducing the concentration of P4 during ovarian stimulation, but the concerted action of FSH and LH on granulosa cells during the second half of the follicular phase makes this complex.

An exploration of gender and prolonged grief symptoms using network analysis.

BACKGROUND: Gender has been proposed as a potentially important predictor of bereavement outcomes. The majority of research in the field has explored this issue by examining gender differences in global grief severity. Findings have been mixed. In this study, we explore potential gender differences in grief using network analysis. This approach examines how individual symptoms relate to and reinforce each other, and so offers potential to shed light on novel aspects of grief expression across genders. METHOD: Graphical lasso networks were constructed using self-report data from 839 spousally bereaved older participants (584 female, 255 male) collected at 2- and 11- months post-bereavement. Edge strength, node strength and global network strength were compared to identify similarities and differences between gender networks across time. RESULTS: At both time points, the strongest connection for both genders was from yearning to pangs of grief. Yearning, pangs of grief, acceptance, bitterness and shock were prominent nodes at time 1. Numbness and meaninglessness emerged as prominent nodes at time 2. Males and females differed in the relative importance of shock at time 1, and the female network had greater overall strength than the male network at time 2. CONCLUSIONS: This study identified many similarities and few differences in the relationships between prolonged grief symptoms for males and females. Findings suggest that future studies should examine alternate sources of variation in grief outcomes. Limitations are discussed.

Supportive therapy and complementary medicine in renal cell carcinoma.

PURPOSE: As part of the German interdisciplinary S3-guideline "Diagnosis, Treatment and Followup of Renal Cell Carcinoma", this article aimes to provide guidance regarding the use of supportive therapy and complementary medicine in patients with advanced or metastatic renal cell carcinoma. METHODS: The German interdisciplinary S3-guidelines are national clinical practice guidelines that implement the highest methodological quality of evidence-based medicine. Recommendations and evidence-based statements are provided according to available evidence. RESULTS: Supportive and palliative care are important areas of tumor treatment and require knowledge on the management of a variety of issues. This article outlines the management of tumor-related symptoms such as pain, undesired treatment-related effects, palliative care and end-of-life care in patients with renal cell carcinoma. CONCLUSION: Patients with advanced or metastatic renal cell carcinoma should have access to supportive and palliative care according to their individual needs. There is very limited evidence regarding the impact of complementary medicine for the treatment of patients with renal cell carcinoma.

Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

Mindfulness-based cognitive therapy (MBCT) is cost-effective compared to a wait-list control for persistent pain in women treated for primary breast cancer-Results from a randomized controlled trial.

OBJECTIVE: To investigate the cost-effectiveness of mindfulness-based cognitive therapy (MBCT) compared to a wait-list control group for pain in women treated for breast cancer. METHODS: A total of 129 women were randomly allocated to MBCT or a wait-list control group. The primary outcome was the minimal clinically important difference (MCID) on pain intensity (≥2 point reduction on an 11-point Numeric Rating Scale). Analyses were conducted from the health care system perspective and included data on health care utilization and pain medication retrieved from national registries for the period from baseline (T1) to 6 months postintervention (T4). Bootstrap simulations were used to estimate confidence intervals for the incremental cost and effect measures, and cost-effectiveness acceptability curves. In sensitivity analyses, we replaced dropouts with last-observation-carried-forward and tested consequences of higher costs of the intervention. RESULTS: The intervention cost was 240€ per participant. The average total cost from T1 to T4 in the MBCT group was 1706€ compared with 2436€ in the control group (mean difference: 729€, P = .07). More women in the MBCT group (N:19/36; 52.8%) than in the control group (N:14/48; 29.2%) achieved an MCID in pain intensity (OR=2.71, P = .03). The MBCT was cost-effective with a probability of 85% with a value of an additional women achieving MCID set to zero remained cost-effective with a probability of 70% to 82% when smaller effect and higher MBCT costs were assumed. CONCLUSIONS: Our results suggest that MBCT is a cost-effective pain intervention for women treated for breast cancer. Future studies could include utility measures, indirect costs, and active control groups to increase the generalizability and pragmatic value of the results.

Clinical and psychological moderators of the effect of mindfulness-based cognitive therapy on persistent pain in women treated for primary breast cancer - explorative analyses from a randomized controlled trial.

BACKGROUND: Mindfulness-based intervention has been found efficacious in reducing persistent pain in women treated for breast cancer. Little, however, is known about possible moderators of the effect. We explored clinical and psychological moderators of the effect on pain intensity previously found in a randomized controlled trial of mindfulness-based cognitive therapy (MBCT) with women treated for breast cancer with persistent pain. MATERIAL AND METHODS: A total of 129 women treated for breast cancer reporting persistent pain were randomized to MBCT or a wait-list control. The primary outcome of pain intensity (11-point numeric rating scale) was measured at baseline, post-intervention, three, and six months follow-up. Proposed clinical moderators included age, axillary lymph node dissection (ALND), radiotherapy, and endocrine treatment. Psychological moderators included psychological distress [the Hospital Anxiety and Depression Scale (HADS)], the adult attachment dimensions anxiety and avoidance [the Experiences in Close Relationships Short Form (the ECR-SF)], and alexithymia [the Toronto Alexithymia Scale (TAS-20)]. Multi-level models were used to test moderation effects over time, i.e. time × group × moderator. RESULTS: Only attachment avoidance (p = 0.03, d = 0.36) emerged as a statistically significant moderator. Higher levels of attachment avoidance predicted a larger effect of MBCT in reducing pain intensity compared with lower levels attachment avoidance. None of the remaining psychological or clinical moderators reached statistical significance. However, based on the effect size, radiotherapy (p = 0.075, d = 0.49) was indicated as a possible clinical moderator of the effect, with radiotherapy being associated with a smaller effect of MBCT on pain intensity over time compared with no radiotherapy. CONCLUSION: Attachment avoidance, and potentially radiotherapy, may be clinically relevant factors for identifying the patients who may benefit most from MBCT as a pain intervention. Due to the exploratory nature of the analyses, the results should be considered preliminary.

Socio-demographic, treatment-related, and health behavioral predictors of persistent pain 15 months and 7-9 years after surgery: a nationwide prospective study of women treated for primary breast cancer.

The purpose of this study was to investigate and report prevalence and risk factors for persistent pain in breast cancer patients at 15 months and 7-9 years post surgery. A nationwide inception cohort study including 3343 women treated for primary breast cancer between 2001 and 2004, who returned a questionnaire 3 months post surgery. Socio-demographic and clinical information was obtained from registries. Questionnaire data on pain and health behaviors were obtained 15 months and 7-9 years post surgery. A total of 1905 women were eligible for analysis. At 15-month post surgery, 32.7 % reported pain "almost every day" or more frequently. At 7-9 years post surgery, the prevalence decreased to 20.4 %. Socio-demographic (young age, lower education, lower income, lower occupational status), treatment-related (being lymph node positive, axillary lymph node dissection (ALND), post-menopausal endocrine treatment), and health behavioral factors (smoking ≥ 10 cigarettes/day, obesity (BMI ≥ 30 and < 35), comorbidity, poor physical function) were significantly associated with pain at 15 months. Being physically active and moderate alcohol intake (<3 units/day) were negatively associated with pain. At 7-9 years post surgery, only ALND (OR:1.41, p = 0.03), post-menopausal endocrine treatment (OR:1.62, p = 0.01), poorer physical function (ORs:2.00-2.40, p = 0.003), and weight training (h/week) at 15 months (OR:1.10, p = 0.008) were significant predictors of pain when adjusting for age and pain 15 months post surgery. No socio-demographic predictors remained statistically significant. Younger age, lower socio-economic status, more invasive surgery, endocrine treatment, and adverse health behaviors emerged as risk factors for persistent pain. The influence of risk factors changed over time, suggesting a complex course of pain development and maintenance.

The efficacy of psychosocial intervention for pain in breast cancer patients and survivors: a systematic review and meta-analysis.

Persistent pain after breast cancer treatment is prevalent, and not all patients respond sufficiently to pharmacological treatment. Pain is recognized as a multi-dimensional phenomenon, which includes psychological and social components, and several clinical trials have investigated the efficacy of psychosocial interventions on pain in cancer patients and survivors. Our aim was to systematically review and quantify the existing research on the effect of psychosocial interventions on pain in breast cancer patients and survivors. Two independent raters reviewed 474 abstracts for eligibility, leading to the identification of 26 independent and eligible studies published between 1983 and 2012, which were assessed for their methodological quality and subjected to meta-analytic evaluation. A total of 1786 participants were included in the analyses. A statistically significant and robust overall effect size was found across all included studies (Hedges g = 0.37, 95 % CI: 0.20-0.40; p < 0.001). However, the effect size was considerably smaller (0.21), when adjusted for possible publication bias. Furthermore, the results were heterogeneous, and when exploring the sources of heterogeneity, studies of higher methodological quality were found to yield a more conservative effect size (g = 0.21, 95 % CI: 0.02-0.41) than studies of poorer quality (g = 0.65, 95 % CI: 0.25-1.04). The results also indicated that patient educational approaches yielded a larger effect size (g = 0.64) than relaxation-based interventions (g = 0.31, 95 % CI: -0.05-0.67) and supportive group therapy (g = 0.17, 95 % CI: 0.02-0.32). Taken together, while suggestive of psychosocial intervention as an effective tool in the management of pain among breast cancer patients and survivors, the results should be interpreted as preliminary. The methodological quality of the existing research varied considerably, and only few studies had selected patients on the basis of the presence of pain and included pain as the primary outcome.

Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy.

BACKGROUND: It is unknown if discontinuation of targeted therapy (TT) and readministration in case of recurrence is feasible in patients with metastatic renal cell carcinoma (mRCC) in which complete response (CR) is achieved by TT alone or no evidence of disease (NED) with additional resection of residual metastases. PATIENTS AND METHODS: Patients in whom TT was discontinued after CR to TT alone or NED after additional metastasectomy were included in this retrospective analysis. Outcome criteria evaluated were time off TT, recurrence of metastases and response to re-exposure to TT. Univariate and multivariate analyses were carried out to identify variables potentially predictive of outcome. RESULTS: In 36 patients with CR or NED under TT with sunitinib (22), sorafenib (11), bevacizumab/interferon (2) and temsirolimus (1), TT was discontinued. Recurrence was observed in 24 patients (66.7%). Re-exposure to TT was effective in 86.9% of these cases. Twelve patients (33.3%) remained recurrence free at a median follow-up of 12 months (range 3-31). Median time off TT was 7 months (range 1-31). Factors that correlate with outcome could not be identified. CONCLUSIONS: In the majority of patients with mRCC and CR or NED, discontinuation of TT was followed by recurrence, but re-exposure to TT was effective.

[Self-reported and measured height and weight in adolescents]. / Schätz- und Messwerte von Größe und Gewicht bei Jugendlichen.

OBJECTIVES: The aim of this study was to assess the validity of self-reported height and weight and resulting body-mass-index (BMI) in adolescents, to identify influencing factors and to generate appropriate algorithms for the correction of self-reported values. METHODS: In the Kiel Obesity Prevention Study (KOPS) height and weight were assessed in 2,706 12- to 17-year-old adolescents by self-report and by measurements. Differences between self-reported and measured values were calculated. Algorithms for correction of self-reported data were generated in a random sample (n=941) and validated in another random sample (n=946). RESULTS: Overestimation of height and underestimation of weight resulted in a remarkable underestimation of BMI. Girls underestimated BMI more than boys (-0.8±1.0 kg/m² vs. -0.4±1.1 kg/m²; p<0.01), overweight adolescents underestimated more than normal weight adolescents (boys: -1.4±1.4 kg/m² vs. -0.3±0.9 kg/m²; p<0.01; girls:-1.6±1.3 kg/m² vs. -0.7±0.8 kg/m²; p<0.01). Prevalence of overweight and obesity was underestimated by 2.0% and 1.5%, respectively, in boys and by 2.2% and 2.0%, respectively in girls. Differences between self-reported and measured values were influenced by gender and weight status. Correction of self-reported data resulted in approaching the valid overweight prevalence. However, underestimations persisted. CONCLUSIONS: Self-reported height, weight and BMI calculated from these values are discrepant from measured data and cause underestimation of the prevalence of overweight and obesity in adolescents. Correction of self-reported values is possible. However, valid data can only be assessed by measurements of height and weight.

Infrared flashing light through the cricothyroid membrane to guide flexible bronchoscopic tracheal intubation.

Flexible bronchoscopic tracheal intubation is a fundamental technique in the management of the difficult airway but requires specific skills which may be both difficult to achieve and maintain. Therefore, techniques to improve its success should be developed. We present two cases, one where the ear, nose and throat surgeon could not view the glottis due to laryngeal pathology, and one where pathology in the oropharynx obscured access to the trachea during attempts at flexible bronchoscopic and videolaryngoscopic tracheal intubation. In both cases, tracheal intubation was subsequently successful due to the use of the Infrared Red Intubation System. This is an infrared light source that is secured to the anterior neck. It emits a flashing infrared light that is captured by the flexible bronchoscope, thus guiding the way to the trachea. These are the first reports of this technology being used for flexible bronchoscopic tracheal intubation in patients with severe airway pathology where conventional approaches had failed. Both cases emphasise that this technique can be of benefit in avoiding a surgical airway.

[Radium-223 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) : The androgen receptor-independent active agent in the therapeutic sequence]. / Radium-223 zur Therapie des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) : Der androgenrezeptorunabhängige Wirkstoff in der therapeutischen Sequenz.

BACKGROUND: Radium-223 improves overall survival and preserves quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases and no known visceral metastases. Radium-223 can be used in combination with a luteinizing hormone releasing hormone (LHRH) analogue and as part of a sequential treatment scheme if disease progresses after at least two prior lines of systemic mCRPC therapies or if no other available systemic treatment is eligible. OBJECTIVES: Today physicians are faced with a previously unknown multitude and complexity of options for the treatment of mCRPC. An increasing number of clinical trials contribute to the dynamics of the therapeutic landscape. Radium-223 was approved for mCRPC treatment in 2013. Up to now the recommendations of use have been adjusted several times. Highlighting recent clinical trials and practice, this paper explores the position of radium-223 within the therapeutic sequence and outlines key elements for the interdisciplinary cooperation between uro-oncologists and nuclear medicine specialists. RESULTS: The mode of action of radium-223 does not depend on the androgen receptor (AR) pathway. Thus, it is an option in the therapeutic sequence when the efficacy of other agents is reduced by resistance. Furthermore, the efficacy of prior or subsequent medications are neither reduced nor enhanced by radium-223. The opportunity of an AR-independent and survival-prolonging medication should be taken as soon as the indication criteria are met because the incidence of visceral metastases increases during disease progression. According to current mCRPC guidelines, the osteoprotective use of bisphosphonates or denosumab is recommended, before treatment with radium-223 is started or resumed.

Psychological interventions for grief in adults: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The present meta-analysis evaluates the efficacy of psychological interventions for grief in bereaved adults and explores the possible moderating influence of various study characteristics. METHODS: A systematic literature search was conducted by two reviewers who independently searched electronic databases, reviewed and selected eligible studies, and evaluated their methodological quality. RESULTS: A total of 31 randomized controlled trials (RCTs) were included in the meta-analysis. Statistically significant pooled effects of psychological intervention on grief symptoms were found for both post-intervention (Hedges's g = 0.41, p > .001, K = 31) and follow-up (g = 0.45, p > .001, K = 18). While generally robust, the effect was smaller at post-intervention when adjusting for possible publication bias (g = 0.31). Compared with the remaining studies, larger post-intervention effect sizes were found for studies with (1) individually delivered interventions (Beta = 0.49, p < .001), (2) the ICG-(R)/PG-13 questionnaire as the grief instrument (Beta = 0.46, p < .001), (3) participants who were ≥6 months post-loss (Beta = 0.58, p < .001), (4) participants included based on high baseline symptom levels (Beta = 0.40, p = .002) and (5) higher study quality (Beta = 0.06, p = .013). LIMITATIONS: The included studies were methodologically heterogeneous and their methodological quality varied considerably. Moreover, there were some indications of publication bias. CONCLUSIONS: Given the recent introduction of Prolonged Grief Disorder in the ICD-11, the results of the present meta-analysis are timely and of clinical relevance. Based on our results, psychological intervention appears efficacious for alleviating grief symptoms in bereaved adults, with several study characteristics as possible moderators of the effect. The interpretability of the results, however, is challenged by some limitations of the available research, including possible publication bias.

Associations between active commuting to school, fat mass and lifestyle factors in adolescents: the Kiel Obesity Prevention Study (KOPS).

OBJECTIVE: To examine possible associations between active commuting (walking or cycling) to school, parameters of adiposity and lifestyle factors in 14-year-old adolescents of the Kiel Obesity Prevention Study. SUBJECTS: A total of 626 14-year-old adolescents. METHODS: Measured body mass index (BMI), fat mass (FM), distance to school as well as self-reported modes and duration of commuting to school, time spent in structured and unstructured physical activities (PAs), media use, nutrition, alcohol consumption and smoking. RESULTS: Parameters of adiposity did not differ between different commuting modes after stratifying by gender. Active commuters reported higher overall PA, which was caused by commuting activity and time spent in unstructured PA in girls and just by commuting activity in boys. In active commuters, 28.4% of overall PA was explained by commuting activity. Additionally, TV viewing was lower in active commuters. Compared to their inactively commuting counterparts, actively commuting boys were less likely to smoke. After controlling for potential confounders the interaction term 'active commuting by distance to school' and 'time spent in structured PA' were independent predictors of FM, whereas active commuting by itself showed no effect. CONCLUSION: The present data suggest that active commuting to school per se does not affect FM or BMI until considering distance to school. Increasing walking or cycling distance results in decreasing FM. However, the everyday need to get to and from school may enhance adolescents' overall PA.

Psychosocial predictors of posttreatment pain after nonmetastatic breast cancer treatment: a systematic review and meta-analysis of prospective studies.

BACKGROUND: The search for risk factors of pain after breast cancer, which affects a considerable proportion of the women, has primarily focused on clinical factors. The aim of this meta-analysis was to explore the less well-studied psychosocial predictors of pain after breast cancer treatment. METHODS: Two independent searches were conducted in PubMed, PsycINFO, Web of Science, and CINAHL. Eligible studies were prospective, observational studies of women aged ≥18 years, diagnosed and treated for nonmetastatic breast cancer ≥3 months previously. Additional inclusion criteria were that studies had assessed at least one pain outcome and at least one psychosocial predictor. The psychosocial predictors investigated included: 1) psychological-behavioral states, 2) psychological traits, and 3) social support. Effect size correlations (ESr) were chosen as the effect size and pooled using a random effects model. We also explored a number of study characteristics as possible moderators of the effect with meta-regression. RESULTS: Of the total of 13 eligible studies identified, most studies measured psychosocial predictors at presurgery. Neither psychological-behavioral states (ESr: 0.05; p=0.13; K=11) nor psychological traits (ESr: 0.02; p=0.48; K=6) emerged as statistically significant predictors of pain. In contrast, higher levels of social support were statistically significantly associated with less pain (ESr: -0.24; p<0.001; K=4). In studies of psychological-behavioral states, longer follow-up was associated with smaller effect sizes (p=0.023). Furthermore, older mean sample age was associated with larger effect sizes for both psychological-behavioral states (p=0.0004) and psychological traits (p=0.035). CONCLUSION: The results of this meta-analysis suggest that psychosocial factors measured at presurgery may only be of modest predictive value in identifying women at risk of developing pain after breast cancer treatment. While speculative, psychosocial factors may play a larger role in the postsurgery trajectory, which could be valuable to investigate in future studies.

Treatment of varicocele with reference to age: a retrospective comparison of three minimally invasive procedures.

BACKGROUND: This study investigated whether the therapeutic efficacy and morbidity of three minimally invasive techniques for varicocele correction--laparoscopic varicocelectomy (LV), antegrade sclerotherapy (AS), and retrograde embolization (RE)--differed between children and adults. METHODS: During a 10-year period, 356 procedures for varicocele correction, including 122 cases of LV, 108 cases of AS, and 126 cases of RE, were performed for 314 patients at our institution. Of these patients, 223 were 19 years of age or younger (group 1), and 133 were older than 19 years (group 2). Diagnosis and postoperative results were established clinically and with the use of Doppler ultrasonography. The failure rates and complications for each procedure were retrospectively evaluated and compared between the two age groups. RESULTS: The median follow-up period was 69 months (range, 6-122 months). For 25 patients (19.8%), RE was not feasible for technical reasons. In both groups, LV had a lower failure rate than AS or RE, but the difference between LV and AS was not significant in group 1 (7.7(% vs 11.9%; p > 0.5). Also in group 1, AS was associated with fewer complications than LV 1 (4.5% vs 15.4%; p < 0.05). In group 2, LV was significantly more effective in correcting varicoceles than the other two techniques (p < 0.01). In this group, the complication rates for all three procedures did not differ significantly (p > 0.05). CONCLUSIONS: In our experience, LV was more effective than AS or RE in correcting varicoceles. For children and adolescents, AS may be more indicated because of the slightly lower complication rate and similar recurrence rates, as compared with LV, for this age group. The higher incidence of postoperative hydrocele formation after LV warrants more refined techniques such as the lymphatic-sparing approach.

[Cytokine-based and targeted therapy of metastatic renal cell carcinoma--a current analysis]. / Zytokinbasierte und molekulare Therapie des metastasierten Nierenzellkarzinoms--eine aktuelle Analyse.

The systemic treatment of renal cell cancer represents a challenge for uro-oncologists. Although no internationally recognised treatment regime has been defined, cytokine therapy has been the standard of care for metastatic disease. The growing understanding of the relevant mechanisms in the molecular biology of renal cell carcinoma has led to the development of targeted therapies. Novel tyrosine kinase and angiogenesis inhibitors have had a beneficial effect on progression-free and overall survival in patients with advanced renal cell cancer and represented a significant progress. Even though several important aspects regarding treatments and combinations of these drugs with each other as well as with cytokines still remain unclear, cytokine therapy will probably become less important as a first-line treatment. With increasing therapeutic options becoming available as potential new standards and with the old standards being poorly defined, a critical analysis of the role of different systemic therapies for renal cell carcinoma is warranted. A better knowledge of molecular markers and their prognostic relevance could allow the rational use of different targeted therapies in individual patients in the future. Until such therapies become available, the systemic treatment options should be selected carefully in individual patients.

Associations between body composition, physical capabilities and pulmonary function in healthy older adults.

BACKGROUND/OBJECTIVES: There are positive associations between pulmonary function (PF) and fat-free mass as well as muscle strength. Contrarily, negative associations were found with indirect measures of visceral adipose tissue (VAT). We aimed to differentiate between associations of body composition and PF by assessing mediating and moderating effects of physical capabilities. SUBJECTS/METHODS: Cross-sectional data were assessed among 40 healthy, free-living elderly (20 males) aged 65.1-81.2 years (mean±s.d. age: 72.2±4.3 years; body mass index: 25.6±3.7 kg/m2). Total and regional skeletal muscle (SM), and adipose tissue (AT) were measured using whole-body magnetic resonance imaging. Muscle strength by handgrip dynamometry, physical activity (PA) by questionnaire, and physical performance by gait speed and sit-to-stand test (STS). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were assessed by spirometry. RESULTS: Positive associations between height-standardized FVC (FVCI) as well as FEV1 (FEVI), and SM (r=0.435-0.520, P<0.05) were found; subcutaneous AT (SAT) and FVCI correlated negatively (r=-0.374; P<0.05). HGS and PA correlated positively with FEVI (r=0.456-0.608, P<0.05), HGS also with FVCI (r=0.595, P<0.05). Stepwise multiple regression using FVCI and FEVI as dependent variables, and total/thoracic SM, VAT, SAT, HGS, PA and physical performance as independent variables showed that (i) only HGS entered the regression for predicting FVCI (R2=0.351; standard error of estimation (SEE)=0.32 l), and (ii) HGS and PA explained 50% of FEVI (SEE=0.23 l). HGS mediated the relationship between SM and PF; the STS moderated the relationship between SM and FVCI. CONCLUSIONS: In healthy elderly, PF is positively associated with SM; physical capabilities mediate and moderate these relationships.

IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP.

Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.