In Ischemic Heart Disease, Reduced Sensitivity to Pressure at the Sternum Accompanies Lower Mortality after Five Years: Evidence from a Randomized Controlled Trial.

Background: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD). Elevated periosteal pressure sensitivity (PPS) at the sternum relates to ANSD and sympathetic hyperactivity. Two previous observational case-control studies of the effect of reduction of PPS suggested lower all-cause mortality from IHD and stroke. We now used a specific daily, adjunct, non-pharmacological program of reduction of elevated PPS to test the hypothetical association between the intervention and reduced all-cause mortality in patients with stable IHD in a randomized controlled trial (RCT). Methods: We completed active (n = 106) and passive interventions (n = 107) and compared the five-year mortalities. We also compared the five-year individual all-cause mortality of each participant to approximately 35.000 members of the general population of Denmark. Pooling the mortality data from the active group of the RCT with the two preliminary studies, we registered the mortality following active intervention of 1.168 person-years, compared to 40 million person-years of the pooled general population. Results: We recorded fewer deaths of the active RCT intervention group than of the corresponding control group from the general population (p = 0.01), as well as of the passive RCT intervention group (p = 0.035). The meta-analysis of the three studies together demonstrated reduced 4.2-year all-cause mortality of 60% (p = 0.007). Conclusions: The test of the hypothetical effect of an intervention aimed at the attenuation of ANSD accompanied by a lowered PPS revealed reduced all-cause mortality in patients with stable IHD.

Renin-angiotensin-system inhibitors and the risk of exacerbations in chronic obstructive pulmonary disease: a nationwide registry study.

OBJECTIVE: The renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD) because of the inflammatory properties of the system. Many patients with COPD use RAS-inhibiting (RASi) treatment. The aim was to determine the association between treatment with RASi and the risk of acute exacerbations and mortality in patients with severe COPD. METHODS: Active comparator analysis by propensity-score matching. Data were collected in Danish national registries, containing complete information on health data, prescriptions, hospital admissions and outpatient clinic visits. Patients with COPD (n=38 862) were matched by propensity score on known predictors of the outcome. One group was exposed to RASi treatment (cases) and the other was exposed to bendroflumethiazide as an active comparator in the primary analysis. RESULTS: The use of RASi was associated with a reduced risk of exacerbations or death in the active comparator analysis at 12 months follow-up (HR 0.86, 95% CI 0.78 to 0.95). Similar results were evident in a sensitivity analysis of the propensity-score-matched population (HR 0.89, 95% CI 0.83 to 0.94) and in an adjusted Cox proportional hazards model (HR 0.93, 95% CI 0.89 to 0.98). CONCLUSION: In the current study, we found that the use of RASi treatment was associated with a consistently lower risk of acute exacerbations and death in patients with COPD. Explanations to these findings include real effect, uncontrolled biases, and-less likely-chance findings.

High-intensity training in patients with lacunar stroke: A one-year follow-up.

OBJECTIVES: Physical inactivity is a major risk factor for stroke. It is a challenge for patients to initiate and adhere to regular exercise post-stroke. Early initiation of home-based high-intensity interval training (HIIT) may engage patients in physical activity, improve cardiorespiratory fitness, and reduce risk of recurrent stroke. MATERIALS AND METHODS: Post-intervention follow-up of patients with lacunar stroke, randomized to three-months HIIT including weekly motivational calls, or usual care. At follow-up (six- and 12-months post-stroke), we investigated changes in cardiorespiratory fitness, physical activity, fatigue, depression, mental well-being, stress, cognition, cardiovascular function, and recurrent stroke. RESULTS: We included 71 patients of whom 59 patients (mean age: 63.9 ± 8.8 years) completed six- and 12-month follow-up. No change was detected in cardiorespiratory fitness between groups from baseline to 12-months follow-up. At six months, vigorous-intensity activity (median hours/week [interquartile range]) was maintained in the intervention group (baseline, 0[0;2]; post-intervention, 2[0;3]; six-month, 2[0;4]) and increased in the usual care group (baseline, 0[0;1]; post-intervention, 1[0;2]; six-month, 1[0;3]), with no difference between groups. Vigorous-intensity activity declined to baseline levels at 12-months in both groups. Secondary outcomes improved from baseline to 12-months with no significant differences between groups. Similar rate of recurrent stroke (n=3) occurred in each group with a three-month delay in the intervention group. CONCLUSIONS: Early initiated HIIT did not increase long-term cardiorespiratory fitness, but increased time spent doing vigorous-intensity activities post-stroke. Decline to baseline activity level at 12 months warrants identification of motivators to initiate and sustain physical activity post-stroke.

Corrigendum: Patients with myeloproliferative neoplasms harbor high frequencies of CD8 T cell-platelet aggregates associated with T cell suppression.

[This corrects the article DOI: 10.3389/fimmu.2022.866610.].

Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group.

OBJECTIVE: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma. METHODS: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 â†’ 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86). RESULTS: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections. CONCLUSION: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.

Physical activity after colorectal cancer surgery-a cross sectional study of patients with a long-term stoma.

PURPOSE: Physical activity is recommended to cancer survivors by the World Health Organisation (WHO) and is associated with improved survival after colorectal cancer. It remains unclear whether having a stoma is a barrier for an active lifestyle. We examined the level of physical activity and explored factors impacting physical activity in survivors with a stoma. METHODS: A total of 1265 (65%) patients in the Danish Stoma Database completed a multidimensional survey. Physical activity of moderate- and vigorous-intensity was assessed using two validated questions. Based on WHO guidelines, physical activity was categorised into 'Meeting' or 'Not Meeting' recommendations. Multivariate regression analysis, adjusting for potential confounders, provided odds ratio (OR) and 95% confidence intervals (CI) for factors' association with'Not Meeting' guideline recommendations. RESULTS: In total, 571 patients with colorectal cancer reported on physical activity at a median of 4.3 years (interquartile range 3.1-5.8) after stoma surgery. Two hundred ninety-three patients (51%) were 'Meeting recommendations' and 63% of them were 'Highly active'. Two hundred seventy-eight were 'Not meeting' recommendations (49%). Of the factors analysed, patients without support garment were more likely (OR 1.72 [95% CI 1.16; 2.54] not to meet guideline recommendations. We found no association between stoma type, surgical procedure, parastomal bulging and 'problematic stoma' and level of physical activity, respectively. CONCLUSION: In this large sample of survivors with a stoma half of patients met or exceeded guideline recommendations. Of patients not meeting recommendations some could potentially meet the recommendations by modest increases in either moderate or vigorous activity.

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

BACKGROUND: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having in vitro antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19). METHODS: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14). RESULTS: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 versus 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group versus two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group versus six patients receiving placebo (p=0.57). CONCLUSIONS: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.

Discontinuation of Infliximab Therapy in Patients with Crohn's Disease.

Infliximab Discontinuation in Patients with Crohn's DiseaseThis randomized controlled trial explores infliximab withdrawal in patients with Crohn's disease in clinical, biochemical, and endoscopic remission with long-term infliximab maintenance therapy. Time to relapse was significantly shorter among patients who discontinued infliximab than among those who continued therapy.

A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma.

Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study ( https://clinicaltrials.gov/ , NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7-90.5%) was reached, with 43% (CI, 27.4-60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4-69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4+ and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.

The real-world outcomes of multiple myeloma patients treated with daratumumab.

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. METHODS: Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). RESULTS: Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). CONCLUSION: The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N = 635), we retrospective studied patients treated with carfilzomib (N = 251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N = 150) and after daratumumab (Da-Car; N = 101) with those not treated with carfilzomib (N = 384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p = 0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies.

A culinary twist of a two-course meals-on-wheels menu in a cluster-randomized controlled trial influencing health-related quality of life in nursing home residents.

BACKGROUND AND AIMS: Meals-on-wheels in nursing homes are sensory diminished because of the packaging and reheating of the food, which creates less appetite stimulation and an impaired meal experience for nursing home residents. This background is crucial since nursing home residents are a frail and often malnourished group that is physiologically affected by sensory, physical and mental alterations. The study aimed to increase health-related quality of life in nursing home residents receiving meals-on-wheels using an intervention menu with favourite meals that added a culinary twist and were sensory improved by chefs. METHODS: A double-blinded cluster-randomized controlled trial with two arms, one group receives an intervention menu, and the other group receives a non-optimized menu. The intervention menu included popular meals-on-wheels (a main meal for dinner and a starter/dessert before or after dinner with culinary improvements). The participants received the same meals without culinary improvements in the control group. Health-related quality of life (EQ5D3L) was the primary outcome of the study. Secondary outcomes were mental and nutritional status and muscle strength. The measurements were assessed at a baseline and end visit (12 weeks after baseline visit). RESULTS: Fifty-two nursing home residents were included in the study (There are 20 in the intervention group and 32 in the control group). Following the principle of intention-to-treat, a significant decreasing effect (p-value 0.026) was found between the groups on health-related quality of life. The treated group experienced the largest decrease from the baseline to the end visit. The intervention group had a significant decrease in the second item on Satisfaction With Food-related Life (SWFL2) (I am very pleased with my food). No changes were found either within or between the groups, on the rest of the measured parameters. CONCLUSIONS: Nursing home residents are a target group experiencing natural aggravation, why the health-related quality of life might be difficult to improve using a culinary meal intervention. The decreasing effect of Satisfaction With Food-related Life found in the intervention group could be related to these older adults being too unfamiliar with the culinary twist added to the intervention menu. The study was registered on ClinTrials.gov (Identifier NCT03133364).

Accuracy of the calculated serum osmolarity to screen for hyperosmolar dehydration in older hospitalised medical patients.

BACKGROUND AND AIMS: Simple hyperosmolar dehydration, also termed water-loss dehydration (HD), is common in older hospitalised patients, thus increasing the risk of morbidity and mortality. Directly measured serum osmolality is the reference standard to determine HD; however, it is not a routine test due to its complexity and cost. Thus, a simple valid objective diagnostic tool to detect HD is needed. Consequently, we aimed to validate the agreement between measured s-osmolality (mOsm/kg) and calculated s-osmolarity (mOsm/L). METHODS: Patients aged >65 were included from the emergency medical department at Herlev Hospital, Copenhagen, Denmark. Exclusion criteria were: eGFR< 30 mmol/L, severe heart failure, decompensated cirrhosis, alcohol intake or initiated rehydration treatment. We obtained data for measured s-osmolality as well as calculated osmolarity, using the by ESPEN recommended equation [1.86x (Na+ + K+)+1.15 ∗glucose + urea+14]. To determine accuracy, we used cut-off values of >295 mOsm/L versus >300 mOsm/kg. RESULTS: A total of 90 patients (female 53%), age median 78 yrs (72-86 yrs) were included. According to the measured mOsm/kg, impending HD was evident in 32% (n = 10), of these 11% (n = 10) had current HD. There was a significant association between calculated mOsm/L and measured Osm/kg (r2 = 0.7513, p < 0.0001). A sensitivity of 90% (95% CL: 56%-100%), a specificity of 68% (95% CL: 56%-78%), Positive predictive value (PPV) of 26% (95% CL: 12%-43%), and Negative predictive value (NPV) of 98% (95% CL: 90%-100%) were observed. Notably, only 20% (n = 2) of the patients who were dehydrated according to the measured Osm/kg were correctly clinically diagnosed with dehydration. CONCLUSIONS: The equation recommended by ESPEN to calculate osmolarity was found to be an accurate objective diagnostic tool to assess HD in older hospitalised medical patients. The method is markedly superior to the current clinical practice.

Quality of life in men with metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone: a systematic review and meta-analysis.

BACKGROUND: Enzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC), but different mechanisms of action. The aim was to compare patient-reported health-related quality of life (HRQoL) in men treated with enzalutamide vs AAP for mCRPC. METHODS: We systematically reviewed the literature in June 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Patient-reported outcomes (PROs) until the last follow-up were summarised in a narrative synthesis. Short-term changes (12 weeks) in HRQoL, measured by the Functional Assessment of Cancer Therapy-Prostate total score (FACT-P), were compared between treatment groups and were analysed for enzalutamide and AAP in separate meta-analyses. Higher FACT-P scores indicate better HRQoL. RESULTS: Eight studies were included in the systematic review, four of which were randomised clinical trials (RCTs) eligible for the meta-analyses. The meta-analyses showed mean within-subject FACT-P changes from baseline to week 12 of -1.3 points (95% confidence interval [CI] -2.7; 0.1) for enzalutamide and 4.7 points (95% CI -0.1; 9.6) for AAP. One RCT and three non-randomised studies directly compared enzalutamide with AAP. The RCT showed better short-term HRQoL for AAP (6.8 FACT-P-points, 95% CI 1.7; 11.8) and better long-term HRQoL for AAP in men ≥75 years (7.35 FACT-P-points, 95% CI 2.59; 12.11). The non-randomised studies showed no difference in long-term HRQoL but had all a serious risk of bias. Limitations of the included studies include that the PRO in the included trials were inconsistently reported and that only one study defined the HRQoL measures in their published protocol. CONCLUSIONS: AAP seems to be associated with better short-term HRQoL than enzalutamide. This difference was not apparent at longer follow-up, but the long-term studies had serious risks of bias.

Reduction mammoplasty and mastopexy in the previously irradiated breast - a systematic review and meta-analysis.

Breast cancer is the most common cancer diagnosed in women, and early stages are treated with lumpectomy and irradiation. Irradiation, however, leads to reduced vascularization and fibrosis, which may influence the cosmetic outcome unfavourably and increase complications after subsequent surgery on irradiated breasts. Patients with significant asymmetry after treatment may desire corrective reduction mammoplasty or mastopexy, but this may be associated with increased complication rates. This systematic review and meta-analysis aimed to investigate postoperative complication rates after bilateral reduction mammoplasty or mastopexy in women who had undergone unilateral lumpectomy and irradiation. PubMed, Medline, EMBASE and Cochrane databases were searched for eligible studies. After screening titles and abstracts, 14 full text studies were reviewed, and 7 of these were included in the analysis. The meta-analysis showed a significantly higher complication rate in the irradiated breast compared to the non-irradiated breast, rate ratio 4.82 (95% CI: 1.58, 14.70), p = 0.006. The complication rate was 54% in the irradiated breast (58/107) compared to 8% (9/107) in the non-irradiated breast (p = 0.034). This study suggests that reduction mammoplasty or mastopexy in the previously irradiated breast is associated with a significantly increased risk of complications. Careful patient selection and information are paramount in the treatment of this patient group.

Impact of a Parastomal Bulge on Quality of Life - A Cross-sectional Study of Patients From the Danish Stoma Database.

OBJECTIVE: To investigate stoma specific and generic HRQoL in patients with and without a parastomal bulge. BACKGROUND: Most patients have to live with their stoma complicated by a parastomal bulge. How this affects quality of life remains unclear. METHODS: Patients in the Danish Stoma Database completed the Short-form 36 health survey and the stoma-QOL questionnaire. Linear regression analysis, adjusted for potential confounding factors, provided mean and mean score differences and 95% confidence intervals for each HRQoL scale and item. Cohens d provided estimates of effect size. RESULTS: A total of 1265 patients (65%) completed the questionnaire 4.4 (interquartile range 3.1-6.0) years after stoma surgery. Of these, 693 (55%) patients with a parastomal bulge had significantly impaired (P < 0.01) HRQoL across all stoma specific and generic health domains compared to patients without a parastomal bulge. In patients with a benign diagnosis or an ileostomy, a parastomal bulge impacted significantly on Social Functioning and Mental Health resulting in a worse Mental Component Summary. A large bulge >10 cm impaired HRQoL (P < 0.01) across all stoma specific and generic domains. The impact on HRQoL was independent of time with the bulge. CONCLUSIONS: A novel finding in this large, unselected sample from high-quality regional registries was that parastomal bulging was associated with substantial and sustained impairment of HRQoL.

Association between women's age and stage, morphology, and implantation of the competent blastocyst: a multicenter cohort study.

OBJECTIVE: To study if the age of women undergoing assisted reproductive technology treatment associates with stage, morphology, and implantation of the competent blastocyst. DESIGN: Multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial human chorionic gonadotrophin [hCG] rise) from women undergoing single blastocyst transfer resulting in singleton pregnancy/birth. SETTING: Sixteen private and university-based facilities. PATIENT(S): In this study, 7,246 women who, between 2014 and 2018, underwent controlled ovarian stimulation (COS) or frozen-thawed embryo transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. Linking data to the Danish Medical Birth Registry resulted in a total of 4,842 women with a live birth being included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The competent blastocyst development stage (1-6), inner cell mass (A, B, C), trophectoderm (A, B, C), and initial serum hCG value. RESULT(S): Adjusted analysis of age and stage in COS treatments showed that for every 1-year increase in age there was a 5% reduced probability of the competent blastocyst assessed as being in a high stage at transfer. Comparison between hCG values in women 18-24 years and 25-29 years in both COS and FET showed significantly lower levels in the youngest women. CONCLUSION(S): The initial hCG rise was influenced by the age of the woman, with an identical pattern for hCG values in COS and FET treatments. In COS, the competent blastocyst had a reduced stage with increasing women's age.

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.