Outcomes at a Mean of 13 Years After Proximal Humeral Fracture During Adolescence.

BACKGROUND: The long-term outcomes of a proximal humeral fracture during adolescence are not well known. We investigated the course of primary treatment for these injuries and the long-term outcomes in adulthood, comparing the outcomes with those from age-matched controls. We also compared outcomes after operative and nonoperative treatment via propensity score matching. METHODS: We included children who sustained a proximal humeral fracture between the ages of 10.0 and 16.0 years and underwent treatment between 1995 and 2005. Data from primary treatment episodes were extracted from patient files. The patients were invited to a follow-up visit with outcome assessment and radiographs or to a telephone interview if unable to attend. The primary outcome was the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The secondary outcomes were the Simple Shoulder Test (SST), pain at rest and with strenuous use, shoulder range of motion, strength measurements, health-related quality of life (15D), and harms. Participant results were compared with the normal values of an age-matched population. The effect of operative treatment was assessed using propensity score matching and the average treatment effect was calculated. RESULTS: This study included 209 patients (210 fractures). The mean follow-up (and standard deviation) was 13.1 ± 3.2 years. Outcome data were obtained from 152 participants (153 fractures); 78 participants attended the follow-up visit. The primary treatment episodes were uneventful. The mean scores were 2.5 (95% confidence interval [CI], 1.8 to 3.3 [range, 0 to 13]) for the DASH and 11.7 (95% CI, 11.5 to 11.8 [range, 8 to 12]) for the SST. Other outcomes were similarly good. There were no differences in function compared with the normal population values. Propensity matching showed no treatment effect for operative treatment compared with nonoperative treatment. CONCLUSIONS: Proximal humeral fractures of adolescents heal well and rarely result in impairments whether treated operatively or nonoperatively. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia.

In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.

Return to work after subacromial decompression, diagnostic arthroscopy, or exercise therapy for shoulder impingement: a randomised, placebo-surgery controlled FIMPACT clinical trial with five-year follow-up.

BACKGROUND: Arthroscopic subacromial decompression is one of the most commonly performed shoulder surgeries in the world. It is performed to treat patients with suspected shoulder impingement syndrome, i.e., subacromial pain syndrome. Only few studies have specifically assessed return-to-work rates after subacromial decompression surgery. All existing evidence comes from open, unblinded study designs and this lack of blinding introduces the potential for bias. We assessed return to work and its predictors in patients with shoulder impingement syndrome in a secondary analysis of a placebo-surgery controlled trial. METHODS: One hundred eighty-four patients in a randomised trial had undergone arthroscopic subacromial decompression (n = 57), diagnostic arthroscopy, a placebo surgical intervention, (n = 59), or exercise therapy (n = 68). We assessed return to work, defined as having returned to work for at least two follow-up visits by the primary 24-month time point, work status at 24 and 60 months, and trajectories of return to work per follow-up time point. Patients and outcome assessors were blinded to the assignment regarding the arthroscopic subacromial decompression vs. diagnostic arthroscopy comparison. We assessed the treatment effect on the full analysis set as the difference between the groups in return-to-work rates and work status at 24 months and at 60 months using Chi-square test and the predictors of return to work with logistic regression analysis. RESULTS: There was no difference in the trajectories of return to work between the study groups. By 24 months, 50 of 57 patients (88%) had returned to work in the arthroscopic subacromial decompression group, while the respective figures were 52 of 59 (88%) in the diagnostic arthroscopy group and 61 of 68 (90%) in the exercise therapy group. No clinically relevant predictors of return to work were found. The proportion of patients at work was 80% (147/184) at 24 months and 73% (124/184) at 60 months, with no difference between the treatment groups (p-values 0.842 and 0.943, respectively). CONCLUSIONS: Arthroscopic subacromial decompression provided no benefit over diagnostic arthroscopy or exercise therapy on return to work in patients with shoulder impingement syndrome. We did not find clinically relevant predictors of return to work either. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00428870 .

Ad5/3 is able to avoid neutralization by binding to erythrocytes and lymphocytes.

Oncolytic adenoviruses are promising cancer therapeutic agents. Clinical data have shown adenoviruses' ability to transduce tumors after systemic delivery in human cancer patients, despite antibodies. In the present work, we have focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and human erythrocytes. Ad5/3 binding with human lymphocytes and erythrocytes was observed to occur in a reversible manner, which allowed viral transduction of tumors, and oncolytic potency of Ad5/3 in vitro and in vivo, with or without neutralizing antibodies. Immunodeficient mice bearing xenograft tumors showed enhanced tumor transduction following systemic administration, when Ad5/3 virus was bound to lymphocytes or erythrocytes (P < 0.05). In conclusion, our findings reveal that chimeric Ad5/3 adenovirus reaches non-injected tumors in the presence of neutralizing antibodies: it occurs through reversible binding to lymphocytes and erythrocytes.

Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples.

Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.

Perioperative Dexamethasone Is Associated With Higher Short-Term Mortality in Reconstructive Head and Neck Cancer Surgery.

PURPOSE: Studies of the effects of perioperative dexamethasone (DEX) during oncologic surgery are scarce. The first aim of the present study was to clarify whether perioperative DEX affects the short-term mortality in patients with head and neck cancer (HNC). The second aim was to analyze the causes of death and predictors affecting long-term mortality. PATIENTS AND METHODS: The present prospective, double-blind randomized, controlled study included patients with HNC who had undergone microvascular reconstruction from 2008 through 2013. The patients were randomized into 2 groups: the receipt of perioperative DEX for 3 days (study group) or no DEX (control group). The patients' data and cause of death were registered until the end of 2017. The primary cause of death was used in the analyses. RESULTS: A total of 93 patients were included in the present study: 51 in the DEX group (study group) and 42 in the NON-DEX group (control group). Altogether 38 patients died during a median follow-up period of 5.3 years. During the first year, more deaths had occurred in the DEX group than in the NON-DEX group: at 1 month, 4% versus 0%; at 6 months, 14% versus 0%; and at 12 months, 22% versus 5% (P = .043). The overall survival rate for all patients was 59%. HNC was the primary cause of death for most of the patients who died. On univariate analysis, the deceased patients had more advanced disease (higher T classification, P = .002; higher stage, P = .008), a greater need for a gastrostoma (P = .002), more often received postoperative chemotherapy (P = .005), and more often had locoregional (P = .025) or distal (P < .001) metastases. In the multivariate Cox model, the most important long-term predictors of death were the presence of distant metastases (P < .001), a Charlson comorbidity index (CCI) of 5 to 9 (P < .001), and the use of perioperative DEX (P = .004). CONCLUSIONS: The use of perioperative DEX was associated with higher short-term mortality after reconstructive HNC surgery. The most important long-term predictors of death were the receipt of DEX, the presence of distant metastases, and a CCI of 5 to 9. These findings do not encourage the routine use of perioperative DEX for these patients.

Finnish Trial on Practices of Anterior Cervical Decompression and Fusion (FACADE): a protocol for a prospective randomised non-inferiority trial comparing outpatient versus inpatient care.

INTRODUCTION: Although a great majority of patients with cervical radiculopathy syndrome can successfully be treated non-operatively, a considerable proportion experience persistent symptoms, severe enough to require neurosurgical intervention. During the past decade, cervical spine procedures have increasingly been performed on an outpatient basis and retrospective database analyses have shown this to be feasible and safe. However, there are no randomised controlled studies comparing outpatient care with inpatient care, particularly with emphasis on the patients' perception of symptom relief and their ability to return to normal daily activities and work. METHODS AND ANALYSIS: This is a prospective, randomised, controlled, parallel group non-inferiority trial comparing the traditional hospital surveillance (inpatient, patients staying in the hospital for 1-3 nights after surgery) with outpatient care (discharge on the day of the surgery, usually within 6-8 hours after procedure) in patients who have undergone anterior cervical decompression and fusion procedure. To determine whether early discharge (outpatient care) is non-inferior to inpatient care, we will randomise 104 patients to these two groups and follow them for 6 months using the Neck Disability Index (NDI) as the primary outcome. We expect that early discharge is not significantly worse than the current care in terms of change in NDI. Non-inferiority will be declared if the mean improvement for outpatient care is no worse than the mean improvement for inpatient care, by a margin of 17.3%. We hypothesise that a shorter hospital stay results in more rapid return to normal daily activities, shorter duration of sick leave and decreased secondary costs to healthcare system. Secondary outcomes in our study are arm pain and neck pain using the Numeric Rating Scale, operative success (Odom's criteria), patient's satisfaction to treatment, general quality of life (EQ-5D-5L), Work Ability Score, sickness absence days, return to previous leisure activities and complications. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of the Helsinki and Uusimaa Hospital District on 6 June 2019 (1540/2019) and duly registered at ClinicalTrials.gov. We will disseminate the findings of this study through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03979443.

Treatment of gynecological malignancies: long-term follow-up of health-related quality of life and healthcare costs.

Aim: To assess long-term health-related quality of life (HRQoL) and treatment-related costs in gynecological cancer patients, and to compare HRQoL between cancer types and to age-standardized general female population. Materials & methods: A prospective 8-10-year follow-up of 218 patients treated in Helsinki University Hospital in 2002-2004. Results: The most common malignancies were uterine, ovarian and cervical cancers. The mean HRQoL scores were 0.880 (baseline), 0.885 (6 months) and 0.884 for survivors in the end of the study. Depression, vitality and sexual activity were impaired at baseline but improved during follow-up. Total secondary healthcare costs during the follow-up averaged EUR 41342. Conclusion: The long-term HRQoL of surviving gynecological cancer patients was good and similar to that of age-standardized general female population.

Rates of serious infections and malignancies among patients with rheumatoid arthritis receiving either tumor necrosis factor inhibitor or rituximab therapy.

OBJECTIVE: Because of the role of tumor necrosis factor (TNF) in host defense, it was hypothesized that its inhibition might lead to an increased risk of malignancies and infections. The objective of our study was to assess the incidence of serious infections leading to hospitalization and malignancies among patients with rheumatoid arthritis (RA) receiving either TNF inhibitor or rituximab (RTX) therapy. METHODS: The study population was identified from the National Register for Biologic Treatment in Finland and the hospital records of Central Finland Central Hospital for conventional disease-modifying antirheumatic drug (cDMARD) users. Data on infections and malignancies were acquired from national healthcare registers. A Poisson model was used to calculate the adjusted incidence rate ratios (aIRR) and was composed of age, sex, time from diagnosis, year of the beginning of the followup, rheumatoid factor status, Disease Activity Score at 28 joints, Health Assessment Questionnaire, prior malignancy, prior serious infection, prior biologic use, and time-updated use of methotrexate, sulfasalazine, hydroxychloroquine, and oral corticosteroids as confounders. RESULTS: In total, during the followup of 10,994 patient-years, 92 malignancies and 341 serious infections were included in the analyses. The aIRR of infections compared to cDMARD users were 1.2 (95% CI 0.63-2.3), 0.84 (95% CI 0.53-1.3), 0.98 (95% CI 0.60-1.6), and 1.1 (95% CI 0.59-1.9) for the patients treated with infliximab (IFX), etanercept, adalimumab, and RTX, respectively. The crude rates of malignancies were highest among the users of cDMARD and RTX, and lowest among patients treated with IFX with no differences in aIRR. CONCLUSION: Our results provide some reassurance of the safety of biologic treatments in the treatment of RA.

The effectiveness of urinary incontinence treatments measured using the 15D Health-Related Quality of Life instrument.

INTRODUCTION AND HYPOTHESIS: The health-related quality of life (HRQoL) is significantly impaired among urinary incontinent women and the effectiveness of urinary incontinence (UI) treatment should be measured using an HRQoL instrument. METHODS: A prospective, observational study evaluating the HRQoL of 178 non-selected UI patients referred for routine treatment at the Helsinki University Central Hospital between the years 2004 and 2010. HRQoL was assessed using the generic 15D questionnaire on four occasions: before treatment, 6 and 18 months after treatment, and after a median follow-up of 5 years. The HRQoL of the patients was compared with that of an age-standardized Finnish female population. RESULTS: Compared with the general population, the baseline total HRQoL score of the patients was significantly impaired (p < 0.001). It was worse among the urge or mixed (UUI (±SUI)) incontinence patients than among the stress incontinence (SUI) patients (p = 0.035). During follow-up, HRQoL improved and the improvement was more substantial among the operatively than among the conservatively treated patients (p = 0.027). Statistically significant improvement was only seen in the SUI group (Δ + 0.021, 95 % CI 0.005-0.036), but clinically relevant improvement was also found in the operatively treated UUI (±SUI) group. The maximum benefit of treatment was reached between at 2 and 3 years. CONCLUSIONS: 15D is a sensitive tool for monitoring the change in HRQoL and could be implemented into clinical practice. Operative treatment of UI is effective when measured by improved HRQoL. Not only SUI patients, but also selected patients with an urgency component may benefit from surgery.

Economic evaluation of multidisciplinary rehabilitation after primary total knee arthroplasty based on a randomized controlled trial.

OBJECTIVE: To conduct an economic evaluation of a multidisciplinary, biopsychosocial outpatient rehabilitation program implemented 2-4 months after total knee arthroplasty (TKA), compared with conventional orthopedic care. METHODS: After surgery, 86 patients were randomized to a multidisciplinary rehabilitation group (n = 44) or a conventional orthopedic care group (n = 42). Alongside the randomized controlled trial, we estimated the costs of rehabilitation, health care resource use, and community support. Information about resource use was collected by means of a questionnaire together with data from hospital records. The primary outcome (effectiveness) measure was change in self-reported functional capacity and the secondary measure was quality-adjusted life years (QALYs) gained during the 12-month followup. Cost-effectiveness was assessed from between-group differences in costs, change in functional capacity, and QALYs gained. RESULTS: Both protocols of providing rehabilitation services turned out to be equally effective, but the conventional orthopedic care protocol was unequivocally cost saving: the saving was €1,830 per patient (95% confidence interval -548, 3,623) using the available direct cost data. CONCLUSION: Multidisciplinary rehabilitation for unselected osteoarthritis patients in the subacute period of recovery after TKA is not a cost-effective use of health care resources. Similar rehabilitation protocols cannot be recommended for clinical pathways of TKA in the future.

Cost effectiveness and cost utility of an organized screening programme for glaucoma.

PURPOSE: To assess the cost effectiveness and cost utility of an organized screening programme for glaucoma. The previous cost-effectiveness studies of screening show inconsistent results, and the cost utility of screening has not been assessed. METHODS: An organized screening programme was simulated using Markov modelling in a population aged 50-79 years at 5 year intervals. The programme ended when the subjects reached the age of 80 years. The comparator was opportunistic case finding. The main outcome measures were cases and years of severe visual disability avoided, quality-adjusted life years (QALYs) gained and direct healthcare and non-healthcare costs. RESULTS: The incremental cost of 1 year of avoided visual disability by screening was euro32 602. The cost of one QALY gained by screening was euro9023 with a discount rate of 5%. During the average 20 year time horizon considered, the cumulative incremental costs of screening in a population of 1 million people would be euro30 million, producing 3360 incremental QALYs and 930 years of avoided visual disability for 701 persons. The results were sensitive to the estimates of several parameters, especially screening cost and specificity of screening tests (96-99% specificity required). CONCLUSION: An organized screening programme could be a cost-effective strategy especially in older age groups, in which screening is clearly more likely to be acceptable to decision makers at any level in terms of their willingness to pay for a QALY. Modelling includes some uncertainty especially concerning the specificity of diagnostic tests and screening cost.