Blended online learning for oncologists to improve skills in shared decision making about palliative chemotherapy: a pre-posttest evaluation.

PURPOSE: To improve shared decision making (SDM) with advanced cancer patients, communication skills training for oncologists is needed. The purpose was to examine the effects of a blended online learning (i.e. e-learning and online training session) for oncologists about SDM in palliative oncological care and to compare this blended format with a more extensive, fully in-person face-to-face training format. METHODS: A one-group pre-posttest design was adopted. Before (T0) and after (T2) training, participants conducted simulated consultations (SPAs) and surveys; after the e-learning (T1), an additional survey was filled out. The primary outcome was observed SDM (OPTION12 and 4SDM). Secondary outcomes included observed SDM per stage, SPA duration and decision made as well as oncologists' self-reported knowledge, clinical behavioural intentions, satisfaction with the communication and evaluation of the training. Additionally, outcomes of the blended learning were compared with those of the face-to-face training cohort. Analyses were conducted in SPSS by linear mixed models. RESULTS: Oncologists (n = 17) showed significantly higher SDM scores after the blended online learning. The individual stages of SDM and the number of times the decision was postponed as well as oncologists' beliefs about capabilities, knowledge and satisfaction increased after the blended learning. Consultation duration was unchanged. The training was evaluated as satisfactory. When compared with the face-to-face training, the blended learning effects were smaller. CONCLUSION: Blended online SDM training for oncologists was effective. However, the effects were smaller compared to face-to-face training. The availability of different training formats provides opportunities for tailoring training to the wishes and needs of learners.

Perinatal loss and parental loneliness: Narratives of late termination of pregnancy.

Advances in perinatal medicine, present increasing numbers of women with difficult decisions about their pregnancy. We explored the views of 5 parents and 5 perinatal healthcare professionals regarding late termination of pregnancy following the principles of qualitative content analysis. Parents deciding on whether to (dis)continue pregnancy needed more time and decisional support. Decentralized care and lacking continuity between caregivers led to negative experiences. No standardized bereavement services were offered after leaving the hospital. Integrating principles of perinatal palliative care to care might help to offer further decisional support and to overcome the fragmentation of care.

Novelty processing depends on medial temporal lobe structures.

OBJECTIVES: The goal of the present study was to identify the role of the medial temporal lobe (MTL) in the detection and later processing of novelty. METHODS: Twenty-one epilepsy patients with unilateral MTL resection (10 left-sided; 11 right-sided) and 26 matched healthy controls performed an adapted visual novelty oddball task. In this task two streams of stimuli were presented on the left and right of fixation while the patients' electroencephalogram was measured. The participants had to respond to infrequent target stimuli, while ignoring frequent standard, and infrequent novel stimuli that were presented to the left or right, appearing either contra- or ipsilateral to the patients' resections. RESULTS: Novelty detection, as indexed by the N2 ERP component elicited by novels, was reduced by the MTL resections, as evidenced by a smaller N2 for patients than healthy controls. Later processing of novels, as indexed by the novelty P3 ERP component, was reduced for novels presented contra- versus ipsilateral to the resected side. Moreover, at a frontal electrode site, the N2-P3 complex showed reduced novelty processing in patients with MTL resections compared to healthy controls. The ERP differences were specific for the novel stimuli, as target processing, as indexed by the P3b, was unaffected in the patients: No P3b differences were found between targets presented ipsi- or contralaterally to the resected side, nor between patients and healthy controls. CONCLUSIONS: The current results suggest that MTL structures play a role in novelty processing. In contrast, target processing was unaffected by MTL resections.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group.

BACKGROUND: Hand-foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m2 orally for patients <70 years; 1000 mg/m2 for patients ≥70 years, twice daily on days 1-14) or S-1 (30 mg/m2 orally twice daily on days 1-14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival. RESULTS: A total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16-0.60), P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%, P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates. CONCLUSION: Treatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01918852.

The influence of right ventricular stimulation on acute response to cardiac resynchronisation therapy.

BACKGROUND: The contribution of right ventricular (RV) stimulation to cardiac resynchronisation therapy (CRT) remains controversial. RV stimulation might be associated with adverse haemodynamic effects, dependent on intrinsic right bundle branch conduction, presence of scar, RV function and other factors which may partly explain non-response to CRT. This study investigates to what degree RV stimulation modulates response to biventricular (BiV) stimulation in CRT candidates and which baseline factors, assessed by cardiac magnetic resonance imaging, determine this modulation. METHODS AND RESULTS: Forty-one patients (24 (59 %) males, 67 ± 10 years, QRS 153 ± 22 ms, 21 (51 %) ischaemic cardiomyopathy, left ventricular (LV) ejection fraction 25 ± 7 %), who successfully underwent temporary stimulation with pacing leads in the RV apex (RVapex) and left ventricular posterolateral (PL) wall were included. Stroke work, assessed by a conductance catheter, was used to assess acute haemodynamic response during baseline conditions and RVapex, PL (LV) and PL+RVapex (BiV) stimulation. Compared with baseline, stroke work improved similarly during LV and BiV stimulation (∆+ 51 ± 42 % and ∆+ 48 ± 47 %, both p < 0.001), but individual response showed substantial differences between LV and BiV stimulation. Multivariate analysis revealed that RV ejection fraction (ß = 1.01, p = 0.02) was an independent predictor for stroke work response during LV stimulation, but not for BiV stimulation. Other parameters, including atrioventricular delay and scar presence and localisation, did not predict stroke work response in CRT. CONCLUSION: The haemodynamic effect of addition of RVapex stimulation to LV stimulation differs widely among patients receiving CRT. Poor RV function is associated with poor response to LV but not BiV stimulation.

Consumer Quality Index Chronic Skin Disease (CQI-CSD): a new instrument to measure quality of care from the patient's perspective.

BACKGROUND: Assessing quality of care from the patient's perspective is considered to be highly relevant. As a standardized instrument in dermatology was lacking, we developed a patient experience questionnaire regarding chronic skin disease care: the Consumer Quality Index Chronic Skin Disease (CQI-CSD). OBJECTIVES: (i) To evaluate the dimensional structure of the CQI-CSD, (ii) to assess its ability to distinguish between hospitals according to patients' experiences with quality of care, (iii) to explore patients' experiences with dermatological care and priorities for quality improvement according to the patients, and (iv) to optimize the questionnaire based on psychometric results and stakeholders' input. METHODS: In a cross-sectional study 5647 adult patients who received dermatological care in the past 12 months in 20 hospitals were randomly selected and invited to fill out the questionnaire. RESULTS: Overall 1160 of 3989 eligible respondents (29% response rate, 30-87 per hospital) were included for analysis. The CQI-CSD comprised seven scales with high internal consistency (Cronbach's α = 0·74-0·92). The instrument's discriminative power was limited. Patients were positive about the care provided by nurses and doctors, but the provision of information by healthcare providers, accessibility of care and patient involvement could be improved. We optimized the CQI-CSD, resulting in a revised questionnaire containing 65 items. CONCLUSIONS: In conclusion, the CQI-CSD is a useful instrument to measure patient experiences with dermatological care.

Integrating metabolomics profiling measurements across multiple biobanks.

To optimize the quality of large scale mass-spectrometry based metabolomics data obtained from semiquantitative profiling measurements, it is important to use a strategy in which dedicated measurement designs are combined with a strict statistical quality control regime. This assures consistently high-quality results across measurements from individual studies, but semiquantitative data have been so far only comparable for samples measured within the same study. To enable comparability and integration of semiquantitative profiling data from different large scale studies over the time course of years, the measurement and quality control strategy has to be extended. We introduce a strategy to allow the integration of semiquantitative profiling data from different studies. We demonstrate that lipidomics data generated in samples from three different large biobanks acquired in the time course of 3 years can be effectively combined when using an appropriate measurement design and transfer model. This strategy paves the way toward an integrative usage of semiquantitative metabolomics data sets of multiple studies to validate biological findings in another study and/or to increase the statistical power for discovery of biomarkers or pathways by combining studies.

Short-term changes in hormonal profiles after laparoscopic ovarian laser evaporation compared with diagnostic laparoscopy for PCOS.

STUDY QUESTION: Which reproductive endocrine changes are attributed exclusively to laparoscopic ovarian drilling in polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Laser evaporation-specific endocrine effects were the prevention of an immediate increase in inhibin B and a sustained decrease in testosterone, androstenedione and anti-Müllarian hormone (AMH). WHAT IS KNOWN ALREADY: All ovarian drilling procedures result in reproductive endocrine changes. It is not known which of these changes are the result of ovarian drilling and which are related to the surgery per se. STUDY DESIGN, SIZE, DURATION: This prospective controlled study was performed at an outpatient academic fertility clinic. Between 2007 and 2010, a total of 21 oligo- or amenorrheic PCOS patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were oligo- or amenorrheic PCOS patients with all three of the Rotterdam criteria and luteinizing hormone (LH) >6.5 U/l. All PCOS patients had an indication for diagnostic surgery due to subfertility. There were 12 PCOS patients who chose to undergo ovarian laser evaporation (CO2 laser, 25 W, 20 times/ovary) and 9 PCOS who chose a diagnostic laparoscopy only (controls). Reproductive endocrinology was measured before, and until 5 days after, surgery, and four gonadotrophin-releasing hormone (GnRH) 'double pulse' tests were included. The main outcome measures were changes in reproductive endocrinology and pituitary sensitivity/priming to GnRH after laser evaporation compared with diagnostic laparoscopy only. MAIN RESULTS AND THE ROLE OF CHANCE: In the first hours after surgery, both groups showed an increase in LH, follicle stimulating hormone, estrogen and a decrease in testosterone, androstenedione, AMH and insulin growth factor-1 (P < 0.05). Inhibin B increased in the laparoscopy only group (P < 0.05). In the first days after surgery, testosterone, androstenedione and AMH remained at lower than baseline levels exclusively in the laser group (P < 0.05). Pituitary sensitivity/priming to GnRH was not altered after either laser evaporation or laparoscopy only. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study are the short follow-up period and the relatively small groups. WIDER IMPLICATIONS OF THE FINDINGS: The strength of this study is the integrally measured endocrine profiles in combination with an optimal control group of PCOS patients undergoing diagnostic laparoscopy only. Interestingly, most of the immediate endocrine changes after laser evaporation could be related to the surgical context and not to the ovarian drilling procedure itself. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Foundation of Scientific Research in Obstetrics and Gynaecology and the study medication, Lutrelef, was donated by Ferring, The Netherlands, Hoofdorphe There were no conflicts of interests mentioned by the authors.

How long should we continue clomiphene citrate in anovulatory women?

STUDY QUESTION: What is the effectiveness of continued treatment with clomiphene citrate (CC) in women with World Health Organization (WHO) type II anovulation who have had at least six ovulatory cycles with CC but did not conceive? SUMMARY ANSWER: When women continued CC after six treatment cycles, the cumulative incidence rate of the ongoing pregnancy rate was 54% (95% CI 37-78%) for cycles 7-12. WHAT IS KNOWN ALREADY: If women with WHO type II anovulation fail to conceive with CC within six ovulatory cycles, guidelines advise switching to gonadotrophins, which have a high risk of multiple gestation and are expensive. It is however not clear what success rate could be achieved by continued treatment with CC. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of women with WHO II anovulation who visited the fertility clinics of five hospitals in the Netherlands between 1994 and 2010. We included women treated with CC who had had at least six ovulatory cycles without successful conception (n = 114) after which CC was continued using dosages varying from 50 to 150 mg per day for 5 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follow-up was a total of 12 treatment cycles. Primary outcome was the cumulative incidence rate of an ongoing pregnancy at the end of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: We recruited 114 women that had ovulated on CC for at least six cycles but had not conceived. Of these 114 women, 35 (31%) had an ongoing pregnancy resulting in a cumulative incidence rate of an ongoing pregnancy of 54% after 7-12 treatment cycles with CC. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are its retrospective approach. WIDER IMPLICATIONS OF THE FINDINGS: Randomized trials comparing continued treatment with CC with the relatively established second line treatment with gonadotrophins are justified. In the meantime, we suggest to only begin this less convenient and more expensive treatment for women who do not conceive after 12 ovulatory cycles with CC. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.

High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Minor H antigen matches and mismatches are equally distributed among recipients with or without complications after HLA identical sibling renal transplantation.

Studies of the effect of minor H antigen mismatching on the outcome of renal transplantation are scarce and concern mainly single center studies. The International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 16 laboratories of the IHIW, the role of 15 autosomal, 10 Y-chromosome encoded minor H antigens and 3 CD31 polymorphisms, was investigated in relation to the incidence of renal graft rejection and graft loss in 444 human leukocyte antigens (HLA)-identical sibling renal transplantations. Recipient and donor DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, C19Orf48, LB-ECGF-1, CTSH, LRH-1, LB-ADIR and HY. The correlation between minor H antigen mismatch and the primary outcome graft rejection or graft loss was statistically analyzed. The incidence of rejection was very low and no correlation was observed between one or more minor H antigen mismatch(es) and a rejection episode (n = 36), of which only eight resulted in graft loss. In summary, in our study cohort of 444 renal transplants, mismatching for neither autosomal nor HY minor H antigens correlate with rejection episodes or with graft loss.

Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.

STUDY QUESTION: Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER: Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY: In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION: A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS: Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Dutch trial register (ISRCTN10841210).

False aminoglycoside resistance in Enterobacterales and non-fermenters by an automated testing system: a descriptive study.

IMPORTANCE: Antimicrobial sensitivity data are important to guide antimicrobial therapy. In microbiological laboratories, routine sensitivity measurements are typically performed with automated testing systems such as VITEK2 and Phoenix. Using data from the Dutch national surveillance system for antimicrobial resistance over a 6-year period, we found that the measured minimum inhibitory concentrations for aminoglycosides in Enterobacterales and non-fermenters were too high for the Phoenix system. In addition, we observed a yearly increase in resistance for several species measured by Phoenix. These findings might have consequences for clinical treatment of patients with sepsis.

The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer-results from the RAPIDO trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial. PATIENTS AND METHODS: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression. RESULTS: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included 1. CONCLUSIONS: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

Purification of a candidate gonadotrophin surge-inhibiting/attenuating factor (GnSIF/AF) showing MAPK as a possible target.

Gonadotrophin surge-inhibiting/attenuating factor (GnSIF/AF) has been known for over two decades, but its molecular structure has not been completely characterized yet. In the last 20 years, five different putative GnSIF/AF sequences have been published. In this article, we describe a procedure to isolate and characterize GnSIF/AF from bovine follicular fluid, a GnSIF/AF-derived synthetic peptide (SP-GnSIF/AF) was produced, and the intracellular bioactivity of GnSIF/AF was tested for intracellular action with a MAPK-assay. Two different bioactive molecular weight forms of GnSIF/AF were isolated, a 160 kDa heteromeric and a monomeric 40 kDa protein. The 40 kDa form appeared to be a subunit of the 160 kDa protein. The synthetic peptide mimicked the actions of GnSIF/AF, such as inhibition of GnRH-induced LH secretion and attenuation of the MAPK phosphorylation. The two GnSIF/AF candidates do not show similarities with previously published GnSIF/AF sequences. These are the first data showing the influence of GnSIF/AF on intracellular processes involved in GnRH self-priming and that the biological action of GnSIF/AF was preserved in the produced synthetic peptide. The results provide strong evidence that the identified candidate proteins are the true GnSIF/AF.

Registration of magnetic resonance and computed tomography images in patients with oral squamous cell carcinoma for three-dimensional virtual planning of mandibular resection and reconstruction.

The aim of this study was to evaluate and present an automated method for registration of magnetic resonance imaging (MRI) and computed tomography (CT) or cone beam CT (CBCT) images of the mandibular region for patients with oral squamous cell carcinoma (OSCC). Registered MRI and (CB)CT could facilitate the three-dimensional virtual planning of surgical guides employed for resection and reconstruction in patients with OSCC with mandibular invasion. MRI and (CB)CT images were collected retrospectively from 19 patients. MRI images were aligned with (CB)CT images employing a rigid registration approach (stage 1), a rigid registration approach using a mandibular mask (stage 2), and two non-rigid registration approaches (stage 3). Registration accuracy was quantified by the mean target registration error (mTRE), calculated over a set of landmarks annotated by two observers. Stage 2 achieved the best registration result, with an mTRE of 2.5±0.7mm, which was comparable to the inter- and intra-observer variabilities of landmark placement in MRI. Stage 2 was significantly better aligned compared to all approaches in stage 3. In conclusion, this study demonstrated that rigid registration with the use of a mask is an appropriate image registration method for aligning MRI and (CB)CT images of the mandibular region in patients with OSCC.