A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial).

BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO). PATIENTS AND METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year. RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9). CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

Reduced risk of serious pneumococcal infections up to 10 years after a dose of pneumococcal conjugate vaccine in established arthritis.

BACKGROUND: To examine rates of serious pneumococcal infections up to 10 years after vaccination with 7-valent conjugated pneumococcal vaccine (PCV7) in patients with arthritis compared to non-vaccinated arthritis patients. METHODS: In total, 595 adult arthritis patients (rheumatoid arthritis; RA = 342, 80 % women and spondylarthropathy; SpA = 253, 45 % women) received one dose of PCV7. Mean age/disease duration were 62/16 and 51/14 years, respectively. For each patient, 4 matched reference subjects were identified. At vaccination, 420 patients received bDMARDs (anti-TNF = 330, tocilizumab = 15, abatacept = 18, anakinra = 1, rituximab = 56). Methotrexate was given as monotherapy (n = 86) or in combination with bDMARD (n = 220). 89 SpA patients received NSAIDs without DMARD. The Skåne Healthcare Register was searched for ICD-10 diagnostic codes for pneumococcal infections (pneumonia, lower respiratory tract infection, septicemia, meningitis, septic arthritis) between January 2000 and December 2018. Frequency of infections after vs before vaccination were calculated (relative risks). Relative risk ratio (RRR) and relative risk reduction (1-RRR) were calculated comparing patients vs non-vaccinated references. Kaplan-Meier and Cox regression were used to investigate time to first event and predictors of infections. RESULTS: Among vaccinated RA and SpA patients, there was a significant relative risk reduction of pneumonia and all serious infections; 53% and 46%, respectively. There was no significant difference in time to first pneumonia or all serious infections after vaccination between patients and references. Higher age, RA diagnosis and concomitant prednisolone were associated with infections. CONCLUSION: One dose of pneumococcal conjugate vaccine may decrease risk of serious pneumococcal infection up to 10 years in patients with arthritis receiving immunomodulating treatment.

The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis.

BACKGROUND: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. OBJECTIVE: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. METHODS: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan-Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. RESULTS: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 -1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 -1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 -1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 -1.117], p = 0.017). CONCLUSION: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.

Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models.

BACKGROUND: The mouse strains usually used to generate patient-derived xenografts (PDXs) are immunocompromised, rendering them unsuitable for immunotherapy studies. Here we assessed the value of immune-PDX mouse models for predicting responses to anti-PD-1 checkpoint inhibitor therapy in patients. PATIENTS AND METHODS: Melanoma biopsies contained in a retrospective biobank were transplanted into NOG mice or NOG mice expressing interleukin 2 (hIL2-NOG mice). Tumor growth was monitored, and comparisons were made with clinical data, sequencing data, and current in silico predictive tools. RESULTS: Biopsies grew readily in NOG mice but growth was heterogeneous in hIL2-NOG mice. IL2 appears to activate T-cell immunity in the biopsies to block tumor growth. Biopsy growth in hIL2-NOG mice was negatively associated with survival in patients previously treated with PD-1 checkpoint blockade. In two cases, the prospective clinical decisions of anti-PD-1 therapy or targeted BRAF/MEK inhibitors were supported by the observed responses in mice. CONCLUSIONS: Immune-PDX models represent a promising addition to future biomarker discovery studies and for clinical decision making in patients receiving immunotherapy.

A biomarker of collagen type I degradation is associated with cardiovascular events and mortality in patients with atherosclerosis.

OBJECTIVE: Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix (ECM) proteins in the arterial wall. Collagen type I (COL1), a component of the arterial ECM, is cleaved by matrix metalloproteinases (MMPs) and known to be remodelled in atherosclerosis. We explored whether the MMP-mediated COL1 biomarker, C1M, was associated with cardiovascular events, cardiovascular mortality and all-cause mortality in a large prospective cohort of patients with known atherosclerosis. METHODS: Serum from 787 patients who underwent a carotid endarterectomy was included. Circulating levels of C1M were measured in serum. A total of 473 patients were followed for 6 years after surgery. Associations between C1M and incidence of cardiovascular events, cardiovascular mortality and all-cause mortality were assessed by Kaplan-Meier curves and Cox regression analysis. RESULTS: A total of 101 (21.4%) patients suffered from nonfatal cardiovascular events during the follow-up period, and 64 (13.5%) patients died. Of these, 39 (60.9%) died from cardiovascular diseases. Patients with C1M levels above the median were significantly associated with cardiovascular events, cardiovascular mortality and all-cause mortality (P < 0.001, P = 0.004 and P < 0.001, respectively). C1M was included in the final model for prediction of cardiovascular events (HR 2.15, 95% CI 1.40-3.32, P = 0.001), cardiovascular mortality (HR 2.20, 95% CI 1.07-4.51, P = 0.031) and all-cause mortality (HR 2.98 95% CI 1.67-5.33, P = < 0.001). CONCLUSIONS: In patients with atherosclerotic carotid lesions, high levels of C1M predicted cardiovascular events, cardiovascular mortality and all-cause mortality. These findings emphasize the importance of remodelling mechanisms in atherosclerosis that are now becoming more and more explored.

Anti-ApoA-I IgG antibodies are not associated with carotid artery disease progression and first-time cardiovascular events in middle-aged individuals.

OBJECTIVE: IgG antibodies against apolipoprotein A-I (ApoA-I) have been found to be elevated in subjects from the general population with clinically manifest cardiovascular disease and in myocardial infarction patients with an adverse prognosis. Here, we investigated whether these antibodies are prospectively associated with carotid artery disease progression and with the risk for first-time cardiovascular events in individuals with no previous history of cardiovascular disease. APPROACH AND RESULTS: We selected 383 subjects from the cardiovascular cohort of Malmö Diet and Cancer study who suffered a coronary event during a median follow-up period of 15.4 (10.3-16.4) years and 395 age- and sex-matched controls. None of the study participants had a previous history of coronary artery disease or stroke. Anti-ApoA-I IgG were measured by ELISA in serum samples collected at baseline. Intima-media thickness (IMT) was measured in the common carotid artery and in the carotid bifurcation at baseline and after 15.9 (±1.5) years. We found no associations between anti-ApoA-I IgG and carotid artery IMT at baseline or with IMT progression during follow-up. In Cox proportional hazards analyses adjusted for traditional cardiovascular risk factors, the hazard ratio (HR 95%CI) for the primary outcome, incident coronary events, was 0.97 (0.75-1.25), P = 0.782, in subjects with anti-ApoA-I IgG within the highest tertile compared with the lowest tertile. Similarly, we did not find any associations with the secondary outcome, incident first-time stroke. CONCLUSIONS: Serum autoantibodies against ApoA-I do not correlate with disease progression and adverse events in cardiovascular disease-free individuals from the general population.

Differences in regional cerebral oximetry during cardiac surgery for patients with or without postoperative cerebral ischaemic lesions evaluated by magnetic resonance imaging.

BACKGROUND: Near infrared spectroscopy (NIRS) is widely used to monitor regional cerebral tissue oxygenation (rScO2). We compared rScO2 values during cardiac surgery in patients with or without new cerebral ischaemic lesions on diffusion weighted magnetic resonance imaging (DWI). We hypothesised patients with new cerebral lesions would have impaired tissue oxygenation reflected in their rScO2 values. METHODS: NIRS and DWI data were collected in 152 elective cardiac surgery patients. Absolute rScO2 values, duration of desaturation below thresholds (baseline, 10%, and 20%), and accumulated cerebral desaturation load were compared between patients with or without new cerebral lesions on DWI. Primary outcome was time below 10% from rScO2 baseline. RESULTS: The time below 10% from rScO2 baseline was significantly longer for patients with new cerebral lesions than for patients without [median (inter-quartile range): 11.0 (0.4; 37.5) min vs 1.8 inter-quartile range: (0.05; 20.9) min, P=0.02]. Furthermore, they had a higher accumulated desaturation load below baseline (P=0.02) and 10% below baseline (P=0.02). Finally, their absolute minimum rScO2 value was significantly lower (P=0.01). However, the frequency of patients with desaturation below 10% and 20% was comparable between patients with and without new cerebral lesions. Receiver-operating characteristic curve analysis did not identify a clear-cut critical threshold among the investigated rScO2 variables. CONCLUSIONS: Use of NIRS identified significant group differences in rScO2 values between patients with or without new ischaemic lesions. However, a critical threshold could not be identified because of a high variation in NIRS values across both groups. CLINICAL TRIAL REGISTRATION: NCT 02185885.

Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality.

BACKGROUND: Diabetes mellitus is linked to premature mortality of virtually all causes. Furin is a proprotein convertase broadly involved in the maintenance of cellular homeostasis; however, little is known about its role in the development of diabetes mellitus and risk of premature mortality. OBJECTIVES: To test if fasting plasma concentration of furin is associated with the development of diabetes mellitus and mortality. METHODS: Overnight fasted plasma furin levels were measured at baseline examination in 4678 individuals from the population-based prospective Malmö Diet and Cancer Study. We studied the relation of plasma furin levels with metabolic and hemodynamic traits. We used multivariable Cox proportional hazards models to investigate the association between baseline plasma furin levels and incidence of diabetes mellitus and mortality during 21.3-21.7 years follow-up. RESULTS: An association was observed between quartiles of furin concentration at baseline and body mass index, blood pressure and plasma concentration of glucose, insulin, LDL and HDL cholesterol (|0.11| ≤ ß ≤ |0.31|, P < 0.001). Plasma furin (hazard ratio [HR] per one standard deviation increment of furin) was predictive of future diabetes mellitus (727 events; HR = 1.24, CI = 1.14-1.36, P < 0.001) after adjustment for age, sex, body mass index, systolic and diastolic blood pressure, use of antihypertensive treatment, alcohol intake and fasting plasma level of glucose, insulin and lipoproteins cholesterol. Furin was also independently related to the risk of all-cause mortality (1229 events; HR = 1.12, CI = 1.05-1.19, P = 0.001) after full multivariable adjustment. CONCLUSION: Individuals with high plasma furin concentration have a pronounced dysmetabolic phenotype and elevated risk of diabetes mellitus and premature mortality.

The feasibility of tricuspid annular plane systolic excursion performed by transesophageal echocardiography throughout heart surgery and its interchangeability with transthoracic echocardiography.

Tricuspid annular plane systolic excursion (TAPSE) is a robust measure of RV function, but the performance of transesophageal echocardiography (TEE) measured TAPSE during surgery is not well established. We aim to evaluate feasibility of various TEE views before, during and after surgery. Furthermore, we compare performance of individual TEE measurements depending on view and method (AMM- and M-mode as well as 2D) as well as TAPSE measured using TEE with transthoracic echocardiography (TTE) TAPSE. The study was conducted from January 2015 through September 2016. In 47 patients with normal left ventricular ejection fraction, TEE was prospectively performed during coronary artery bypass grafting surgery. TAPSE and tricuspid annulus tissue Doppler imaging (TDI) were recorded in five different views at pre-specified time points during surgery. Data were analyzed for availability (obtainable/readable images) and reliability (intra-/inter-observer bias and precision). Finally, TEE TAPSE was compared to TTE TAPSE immediately before and after surgery. TAPSE and TDI with TEE was achievable in > 90% of patients in the transgastric view during surgery. The AM- and M-mode had the best reliability and the best correlation with TAPSE measured with TTE. The deep transgastric view was achievable in less than 50% after sternotomy, and TAPSE measured from 2D had a poorer performance compared to the AM- and M-mode. TDI demonstrated a high reliability throughout surgery. RV function can be evaluated by TAPSE and TDI using TEE during surgery. TEE values from the transgastric view demonstrated high performance throughout surgery and a good agreement with TTE TAPSE measurements.

Threatened fertility: A longitudinal study exploring experiences of fertility and having children after cancer treatment.

Infertility is a recognised potential sequel of cancer treatment which impacts negatively on the quality of survival. The aim of this study was to explore how men and women experience the threat of infertility by cancer treatment and individuals' thoughts about having children after cancer during the first 2 years following diagnosis. Nine women and seven men (aged 24-41) participated in two interviews in this longitudinal interview study, after the initiation of cancer treatment and 2 years thereafter. The interviews focused on participants' thoughts and feelings about threatened fertility and having children. The interviews were analysed with qualitative content analysis with a particular focus on identifying experiences over time. The Traits-Desires-Intentions model was used to reflect upon the study findings. The analysis resulted in the identification of four themes: Continue calmly on chosen path, Abandoning plans for children, Avoiding the subject of fertility and Struggling towards life goals. The results emphasise the need to offer individualised fertility-related treatment communication and counselling, both at the time of cancer diagnosis and also in connection with follow-up care. Appropriate fertility-related communication should be included in young cancer patients' survivor care plans.

Successful treatment of SAPHO syndrome with apremilast.

SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome is a rare disease with inflammatory osteoarticular and skin involvement. The pathogenesis of SAPHO syndrome remains unclear, but evidence suggests it may be an autoinflammatory disease triggered upon exposure to infectious agents in genetically predisposed individuals. Induction of the interleukin (IL)-23/T helper 17 axis in addition to neutrophil activation seem to play a key role, and therapies targeting these immunological pathways, including tumour necrosis factor (TNF) inhibitors, ustekinumab, secukinumab and the IL-1 inhibitor anakinra, are potential treatment options that need further investigation. Here we report a case of a 24-year-old woman with SAPHO syndrome who presented at our clinic with palmoplantar pustulosis and sternoclavicular joint involvement. Previous treatments with topical steroids and keratolytics combined with nonsteroidal anti-inflammatory drugs, intravenous methylprednisolone, methotrexate and sulfasalazine had all failed to improve symptoms. Therapy with etanercept was not tolerated, and because of a previous demyelinating peripheral neuropathy, further treatment with TNF inhibitors was avoided. We initiated ustekinumab 45 mg, which improved skin manifestations but not joint pain. Dose escalation to 90 mg initially improved joint pain, but the dose had to be reduced to 45 mg again because of increased infections. During subsequent 45-mg ustekinumab treatment, joint pain exacerbated so we switched to adalimumab which caused an exacerbation of the disease, so we switched to secukinumab, which improved skin and joint symptoms significantly but was associated with a pustular hypersensitivity reaction. Finally, we began treatment with apremilast, a pan-cytokine approach, resulting in stabilization of the skin and joint symptoms without side-effects. To our knowledge, this is the first case report of apremilast as a treatment for SAPHO syndrome.

The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy.

Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting.

Autoantibodies against aldehyde-modified collagen type IV are associated with risk of development of myocardial infarction.

BACKGROUND: Oxidation of LDL particles entrapped in the extracellular matrix of the arterial wall is a key factor in the development of atherosclerosis. Lipid oxidation products, such as malondialdehyde (MDA), react with surrounding extracellular matrix proteins and cause modifications that are recognized by the immune system. MDA modification of collagen type IV is increased in carotid lesions from symptomatic patients and correlates with autoantibodies against MDA-modified collagen type IV in plasma. OBJECTIVE: The aim of this study was to determine whether autoantibodies against MDA-modified collagen type IV predict risk of development of myocardial infarction (MI). METHODS: Plasma levels of MDA-modified collagen type IV IgM and IgG antibodies were analysed by enzyme-linked immunosorbent assay in 385 subjects with incident MI during 13 years of follow-up and 410 age- and sex-matched controls in the Malmö Diet and Cancer study. RESULTS: MDA-modified collagen type IV IgG levels were higher in cases with incident MI than in controls. Subjects in the highest tertile of MDA-modified collagen type IV IgG had an increased risk of MI (hazard ratio 1.56, 95% confidence interval 1.22-2.00, P for trend 0.0004). This association remained significant after adjusting for factors included in the Framingham risk score and diabetes. High levels of MDA-collagen type IV IgG were associated with increased carotid intima-media thickness and elevated plasma levels of matrix metalloproteinase 10 and 12. CONCLUSIONS: Immune responses against MDA-modified collagen type IV are associated with more severe carotid disease and increased risk of MI. These immune responses may reflect LDL oxidation in the artery wall, but could also affect the atherosclerotic disease process.

Plasma stem cell factor levels are associated with risk of cardiovascular disease and death.

OBJECTIVE: Stem cell factor (SCF) is a key growth factor for several types of stem and progenitor cells. There is experimental evidence that such cells are of importance for maintaining the integrity of the cardiovascular system. We investigated the association between circulating levels of SCF and risk for development of cardiovascular events and death. METHODS: SCF was analysed by the proximity extension assay technique in plasma from 4742 subjects participating in the Malmö Diet and Cancer Study. Cardiovascular events and death were monitored through national registers with a mean follow-up time of 19.2 years. RESULTS: Subjects with high baseline levels of SCF had lower cardiovascular (n = 340) and all-cause mortality (n = 1159) as well as a lower risk of heart failure (n = 177), stroke (n = 318) and myocardial infarction (n = 452). Smoking, diabetes and high alcohol consumption were associated with lower levels of SCF. Single nucleotide polymorphisms in the gene region encoding PDX1 C-terminal inhibiting factor 1 (PCIF1) and matrix metalloproteinase-9 were associated with plasma SCF levels. The highest SCF quartile remained independently associated with a lower risk of a lower risk of cardiovascular [hazard ratio and 95% confidence interval 0.59 (0.43-0.81)] and all-cause mortality [0.68 (0.57-0.81)], heart failure [0.50 (0.31-0.80)] and stroke [0.66 (0.47-0.92)], but not with MI [0.96 (0.72-1.27)] as compared with the lowest quartile when adjusting for traditional cardiovascular risk factors in Cox proportional hazard regression models. CONCLUSIONS: This prospective population-based study demonstrates that subjects with high levels of SCF have a lower risk of cardiovascular events and death. The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity.

Physicians' self-reported practice behaviour regarding fertility-related discussions in paediatric oncology in Sweden.

OBJECTIVE: The aim of this study was to investigate practice behaviours of Swedish physicians with regard to discussing the impact of cancer treatment on fertility with paediatric oncology patients and their parents, and to identify factors associated with such discussions. METHODS: A cross-sectional survey study was conducted targeting all physicians in Sweden working in paediatric oncology care settings. Participants responded to a questionnaire measuring practice behaviour, attitudes, barriers, and confidence in knowledge. Multivariable logistic regression was used to determine factors associated with seldom discussing fertility. RESULTS: More than half of the physicians routinely talked with their patients/parents about the treatment's potential impact on fertility (male patients: 62%; female patients: 57%; P = 0.570). Factors associated with less frequently discussing fertility with patients/parents were working at a non-university hospital (male patients: OR 11.49, CI 1.98-66.67; female patients: OR 33.18, CI 4.06-271.07), concerns that the topic would cause worry (male patients: OR 8.23, CI 1.48-45.89; female patients: OR 12.38, CI 1.90-80.70), and perceiving the parents as anxious (male patients: OR 7.18, CI 1.20-42.85; female patients: OR 11.65, CI 1.32-103.17). CONCLUSIONS: Based on our findings, we recommend structured training in how to communicate about fertility issues in stressful situations, which in turn might increase fertility-related discussions in paediatric oncology.

Functionality testing of stem cell grafts to predict infectious complications after allogeneic hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Allogeneic hematopoietic stem cell transplantation (HSCT) is a routine clinical procedure performed to treat patients with haematological malignancies, primary immune deficiencies or metabolic disorders. Infections during lymphopenia after allogeneic HSCT are associated with high mortality and morbidity. Typical infectious agents are Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus and fungi. The study aim was to evaluate whether measurement of the responses of antigen-specific T-cells, recognizing infectious pathogens would correlate to protective functions in the stem cell recipient post-transplant. MATERIALS AND METHODS: Twenty-one grafts were analysed by flow cytometry and cells were stimulated in vitro with relevant infectious antigens, followed by evaluation of T-cell proliferation and cytokine production. Results were compared to the recipients' clinical records 1-year post-transplantation. RESULTS: We show that an extensive repertoire of transferred antigen-specific T-cells from allogeneic donor grafts against infectious agents, involved in post-transplant infections, are linked to an absence of infectious complications for the recipient up-to 1-year post-transplant. The protective effect was associated with antigen-specific T-cell proliferation and IL-1ß secretion. CONCLUSION: Our results suggest that assaying T-cell function before HSCT could determine individual risks for infectious complications and thus aid in clinical decision-making regarding prophylactic and pre-emptive anti-infective therapy.

Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis.

BACKGROUND AND OBJECTIVES: The T-cell response to low-density lipoprotein (LDL) in the vessel wall plays a critical role in atherosclerotic plaque formation and stability. In this study, we used a new translational approach to investigate epitopes from human apolipoprotein B100 (ApoB100), the protein component of LDL, which triggers T-cell activation. We also evaluated the potential of two selected native ApoB100 epitopes to modulate atherosclerosis in human ApoB100-transgenic Ldlr-/- (HuBL) mice. METHODS AND RESULTS: HuBL mice were immunized with human atherosclerotic plaque homogenate to boost cellular autoimmune response to tissue-derived ApoB100 epitopes. In vitro challenge of splenocytes from immunized mice with a library of overlapping native peptides covering human ApoB100 revealed several sequences eliciting T-cell proliferation. Of these sequences, peptide (P) 265 and P295 were predicted to bind several human leucocyte antigen (HLA) haplotypes and induced high levels of interferon (IFN)-γ. Vaccination of HuBL mice with these peptides mounted a strong adaptive immune response to native ApoB100, including high levels of epitope-specific plasma IgGs. Interestingly, P265 and P295 vaccines significantly decreased plaque size, reduced macrophage infiltration and increased IgG1 deposition in the plaques. Purified IgGs from vaccinated mice displayed anti-inflammatory properties against macrophages in vitro, reducing their response to LPS in a dose-dependent manner. CONCLUSION: We identified two specific epitopes from human native ApoB100 that trigger T-cell activation and protect HuBL mice against atherosclerosis when used in a vaccine. Our data suggest that vaccination-induced protective mechanisms may be mediated at least in part through specific antibody responses to LDL that inhibit macrophage activation.

Predictors of work disability after start of anti-TNF therapy in a national cohort of Swedish patients with rheumatoid arthritis: does early anti-TNF therapy bring patients back to work?

OBJECTIVES: To examine predictors of work ability gain and loss after anti-tumour necrosis factor (TNF) start, respectively, in working-age patients with rheumatoid arthritis (RA) with a special focus on disease duration. METHODS: Patients with RA, aged 19-62 years, starting their first TNF inhibitor 2006-2009 with full work ability (0 sick leave/disability pension days during 3 months before bio-start; n=1048) or no work ability (90 days; n=753) were identified in the Swedish biologics register (Anti-Rheumatic Treatment In Sweden, ARTIS) and sick leave/disability pension days retrieved from the Social Insurance Agency. Outcome was defined as work ability gain ≥50% for patients without work ability at bio-start and work ability loss ≥50% for patients with full work ability, and survival analyses conducted. Baseline predictors including disease duration, age, sex, education level, employment, Health Assessment Questionnaire, Disease Activity Score 28 and relevant comorbidities were estimated using Cox regression. RESULTS: During 3 years after anti-TNF start, the probability of regaining work ability for totally work-disabled patients was 35% for those with disease duration <5 years and 14% for disease duration ≥5 years (adjusted HR 2.1 (95% CI 1.4 to 3.2)). For patients with full work ability at bio-start, disease duration did not predict work ability loss. Baseline disability pension was also a strong predictor of work ability gain after treatment start. CONCLUSIONS: A substantial proportion of work-disabled patients with RA who start anti-TNF therapy regain work ability. Those initiating treatment within 5 years of symptom onset have a more than doubled 3-year probability of regaining work ability compared with later treatment starts. This effect seems largely due to the impact of disease duration on disability pension status.