Phase III Clinical Trials in First-Line Follicular Lymphoma: A Review of Their Design and Interpretation

Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored

Distal radius fractures in the elderly population

We found no clear evidence of the clinical superiority of distal radius fracture surgery among older adults at one year.Surgical treatment, however, may yield a faster recovery to previous level of activity in elderly patients.With operative treatment, hardware-based problems may warrant secondary operations and implant removal, whereas in non-operative treatment, symptomatic loss of alignment and malunion can occur.In elderly patients, non-operative treatment can be considered to be the gold standard.Peer reviewe

Trends in scapular fractures- a nationwide 17-year study in Finland

Background: The aim of this study was to examine the trends in the number and incidence of scapular fractures causing hospitalization in the Finnish adult population between 1998 and 2014. Methods: We assessed the number and incidence of scapular fractures resulting in hospital admission and fixation with a plate in Finland in 1998 through 2014 using the Finnish National Hospital Discharge Register as the database. In each year, the study included the entire Finnish adult population. Results: A total of 3843 adult patients with scapular fractures were hospitalized, and the incidence of fracture increased from 4.8 (per 100,000 person-years) in 1998 to 6.6 in 2014. The fracture was operated on with plating in 476 cases (12.4%). The annual number and incidence of scapular fixation with plates did not show constant trend changes during the study period except in the years 2011 through 2013, when there was a sudden increase in the number of these operations. This increase leveled off in 2014. Conclusion: The incidence of hospital-treated scapular fractures increased in Finland in 1998 through 2014. Treatment of scapular fractures with a plate did not show consistent trend changes in Finland during this period.Peer reviewe

The impact of full-thickness rotator cuff tear on shoulder function and quality of life in patients who sustain a proximal humerus fracture—a prospective cohort study

Publisher Copyright: © 2021 The Author(s)Background: Only few studies have investigated the impact of rotator cuff integrity on patients with proximal humerus fracture (PHF). We aimed to determine if the presence of a rotator cuff tear impairs shoulder function and health-related quality of life (HRQoL) after nonsurgically treated PHF. Methods: Sixty-seven patients with PHF were recruited prospectively in a cohort. Presence of a full-thickness rotator cuff tear was determined by ultrasound examination. After 6 and 12 months, Constant-Murley Score; Disability of the Arm, Shoulder and Hand; the Visual Analog Scale; EuroQol-5 Domain; and the 15D scores were compared between the patients with a rotator cuff tear and patients with an intact rotator cuff. Results: The prevalence of a full-thickness rotator cuff tear was 34%. After 12 months, the mean Constant-Murley Score was 65.7 (standard deviation 16.3) in the intact rotator cuff group vs. 53.9 (16.0) in the rotator cuff tear group (mean diff. 11.8, 95% confidence interval 2.5; 21.2) and was found to be a clinically relevant difference. A significantly lower HRQoL was found on the EuroQol-5 Domain score after 12 months in the rotator cuff tear group with a median score of 1 (interquartile range 0.23) in the intact rotator cuff group vs. 0.75 (interquartile range 0.34) in the rotator cuff tear group (P = .03). In the remaining outcome measures, no statistically significant between-group differences were detected. Conclusion: Rotator cuff tear in older adults with nonsurgically treated PHF may be considered a prognostic factor for poorer shoulder function and HRQoL. This knowledge can support the planning of treatment.Peer reviewe

Two casting methods compared in patients with Colles' fracture: A pragmatic, randomized controlled trial

Background: Distal radius fractures are common fractures and the cornerstone of treatment remains immobilization of the wrist in a cast. At present, there is a scarcity of studies that compare different cast immobilization methods. The objective of the study was therefore to compare volar-flexion and ulnar deviation cast to functional cast position in the treatment of dorsally displaced distal radius fracture among elderly patients. Methods and findings: We performed a pragmatic, randomized, controlled trial in three emergency centers in Finland. After closed reduction of the fracture, the wrist was placed in either volar-flexion and ulnar deviation cast or functional cast position. The follow-up was 12 months. The primary outcome was patient-rated wrist evaluation (PRWE) score at 12 months. The secondary outcomes were Quick-DASH score, grip strength, health-related quality of life (15D), and pain catastrophizing scale. The number of complications was also recorded. In total, 105 participants were included in the study. Of these, 88% were female and the mean age was 73.5 (range 65-94) years. In the primary analysis, the mean difference in patient-rated wrist evaluation measure between groups was -4.9 (95% CI: -13.1.- 3.4., p = .24) in favor of the functional cast position. Operative treatment due to loss of reduction of fracture was performed for four patients (8%) in the FC group and for seven patients (13%) in the volar-flexion and ulnar deviation cast group (OR: 0.63, 95% CI: 0.16-2.1). Conclusion: In this study, the data were consistent with a wide range of treatment effects when comparing two different cast positions in the treatment of distal radius fracture among elderly patients at 12-month follow-up. However, the functional cast is more likely to be superior when compared to volar-flexion and ulnar deviation cast.Peer reviewe

Nordic Innovative Trials to Evaluate osteoPorotic Fractures (NITEP) Collaboration : The Nordic DeltaCon Trial protocol-non-operative treatment versus reversed total shoulder arthroplasty in patients 65 years of age and older with a displaced proximal humerus fracture: a prospective, randomised controlled trial

Introduction The proximal humerus fracture (PHF) is one of the most common fractures in the elderly. The majority of PHFs are treated non-operatively, while 15%-33% of patients undergo surgical treatment. Recent randomised controlled trial (RCT) and meta-analyses have shown that there is no difference in outcome between non-operative treatment and locking plate or hemi-arthroplasty. During the past decade, reverse total shoulder arthroplasty (RTSA) has gained popularity in the treatment of PHF, although there is a lack of RCTs comparing RTSA to non-operative treatment. Methods This is a prospective, single-blinded, randomised, controlled, multicentre and multinational trial comparing RTSA with non-operative treatment in displaced proximal humeral fractures in patients 65-85 years. The primary outcome in this study is QuickDASH-score measured at 2 years. Secondary outcomes include visual analogue scale for pain, grip strength, Oxford shoulder score, Constant score and the number of reoperations and complications. The hypothesis of the trial is that operative treatment with RTSA produces better outcome after 2 and 5 years measured with QuickDASH. Ethics and dissemination In this protocol, we describe the design, method and management of the Nordic DeltaCon trial. The ethical approval for the trial has been given by the Regional Committee for Medical and Health Research Ethics, Norway. There have been several examples in orthopaedics of innovations that result in failure after medium-term follow-ups. In order to prevent such failures and to increase our knowledge of RSTA, we feel a large-scale study of the effects of the surgery on the outcome that focuses on the complications and reoperations is warranted. After the trial 2-year follow-up, the results will be disseminated in a major orthopaedic publication.Peer reviewe

Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients

Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n=143) and Korean (n=167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT—PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P=0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P=0.066). LKB1 mutations associated with smoking history (P=0.007) and KRAS mutations (P=0.042) were almost mutually exclusive with EGFR mutations (P=0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations

Mortality following proximal humerus fracture—a nationwide register study of 147,692 fracture patients in Sweden

Summary: Little is known about survival after proximal humerus fracture. In this manuscript, we found the mortality to be high (almost four times higher than in age- and sex-matched controls). While frailty hip fracture has gained attention, we hope our manuscript will shed light on frailty proximal humerus fracture patients. Introduction: Proximal humerus fractures (PHF) are common and occur mostly after the 6th decade of life. While mortality following PHF has been reported previously, mortality data after longer follow-up on a national level is lacking. Methods: We obtained data from the Swedish Hospital Discharge Register (SHDR), on all adult patients (≥ 18 years) with a diagnosis of PHF (S42.2, S42.20, or S42.21) for the period between 2001 and 2016. We used the Swedish Cause of Death Register (SCDR) to investigate mortality in the fracture cohort. We compared the mortality of fracture patients with age- and sex-matched population-based mortality data obtained from Statistics Sweden. Results: A total of 147 692 PHF patients were identified, with a male to female ratio of 1:3. The mean age was 69 years (range, 18 to 111). Most patients were treated non-surgically (n = 126,487, 86%). The crude mortality rate was 2.2% at 1 month, 4.1% at 3 months, 8.5% at 12 months, and 24% at 48 months after sustaining a PHF. Mortality increased with age; however, the standardized mortality rate (SMR) was highest among young patients. SMR was 5.4 in the 18- to 39-year age group, 3.9 in the 40- to 64-year age group, 1.8 in the 65–79-year age group, and 1.2 in the ≥ 80-year-old population. The age-adjusted SMR was 3.9 in the whole adult PHF population. Conclusion: The mortality rate and SMR suggest that PHF patients are heterogeneous. Some older PHF patients may benefit from specialized care (e.g., orthogeriatric), and this should be evaluated in future studies.publishedVersionPeer reviewe

Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial

Background Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures. Methods and findings The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant–Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group’s 5- dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI −7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded. Conclusions This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial. Trial registration ClinicalTrials.gov NCT01246167.Peer reviewe