Assessing the Change in Operative Treatment Rates for Acute Midshaft Clavicle Fractures: Incorporation of Evidence-Based Surgery Results in Orthopaedic Practice.

In 2007, a randomized controlled trial (RCT) by the Canadian Orthopaedic Trauma Society (COTS) demonstrated better functional outcomes and a lower proportion of patients who developed malunion or nonunion following operative, compared with nonoperative, treatment of midshaft clavicle fractures. The primary aim of the present study was to compare the proportion of midshaft clavicle fractures treated operatively prior to and following the publication of the COTS RCT. An additional exploratory aim was to assess whether the proportion of midshaft clavicle fractures that were treated with surgery for malunion or nonunion decreased. Methods: This retrospective cohort analysis used population-level administrative health data on the residents of British Columbia, Canada. Cases were identified by International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes and procedure fee codes. Adult patients (≥18 years) with closed middle-third clavicle fractures between 1997 and 2018 were included. Multivariable logistic regression modeling compared the proportion of clavicle fractures treated operatively before and after January 1, 2007, controlling for patient factors. The Pearson chi-square test compared the proportion of fractures treated operatively for malunion or nonunion in the cohorts. Results: A total of 52,916 patients were included (mean age, 47.5 years; 65.6% male). More clavicle fractures were treated operatively from 2007 onward: 6.9% compared with 2.2% prior to 2007 (odds ratio [OR] = 3.35, 95% confidence interval [CI] = 3.03 to 3.70, p < 0.001). Male sex, moderate-to-high income, and younger age were associated with a greater proportion of operative fixation. The rate of surgery for clavicle malunion or nonunion also increased over this time period (to 4.1% from 3.4%, OR = 1.26, 95% CI = 1.15 to 1.38, p < 0.001). Conclusions: We found a significant change in surgeon practice regarding operative management of clavicle fractures following the publication of a Level-I RCT. With limited high-quality trials comparing operative and nonoperative management, it is important that clinicians, health-care institutions, and health-authority administrations determine what steps can be taken to increase responsiveness to new clinical studies and evidence-based guidelines. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Preliminary efficacy and safety analysis: 12-month results in 83 patients using a novel approach of widefield radiation therapy for extensive skin field cancerization with or without keratinocyte cancers.

PURPOSE: Evaluate the use of widefield radiation therapy (RT) in the management of extensive skin field cancerization (ESFC) with/without keratinocyte cancer (KC). METHODS: The National Dermatology Radiation Oncology Registry is a multidisciplinary collaboration (dermatologists and radiation oncologists). It captures disease description, prior therapies, radiation prescription, clinical effect, skin cosmesis scores, and toxicity data. This analysis included 12-month follow-up data on 89 treated fields from a subset of 83 patients. RESULTS: Clinical success (>90% field clearance) was 96% (ESFC, n = 63) and 88% (ESFC with KC, n = 26). Complete lesion response was seen in 96% of evaluable (n = 25) ESFC with KC. Recurrence (4/89 [5%]) and appearance of new lesions (10/89 [11%]) were minimal. Cosmetic outcome was excellent/good in 98% ESFC and 96% ESFC with KC. Grade 1-2 acute radiation dermatitis occurred in up to 80% of treated fields. The frequency of Grade 3 acute skin toxicities was low. CONCLUSIONS: Registry data demonstrate the potential for widefield RT to treat patients with significant skin pathology who have exhausted other therapies and require durable, minimally invasive treatment options. At 12 months, observed clinical success rates were higher than those reported for topical interventions for ESFC. Ongoing follow-up is required to determine longer term outcomes.

Use of intraoperative impression smear cytology to guide successful treatment of a large renal cyst in a dog: a case report.

A 13-yr-old Shih tzu was referred for surgical management of right-sided cranial abdominal mass, which corresponded to large, cavitated renal mass on ultrasonography, and was suspected to represent neoplasia. Intraoperative impression smear cytology (ISC) of the renal mass wall was consistent with benign renal cyst (RC), without evidence of neoplasia or infection. Deroofing and omentalisation were performed and histopathology was consistent with benign RC. Chronic kidney disease was diagnosed 4 mon postoperatively, however, the dog was asymptomatic, without cyst reoccurrence. Intraoperative ISC is an expedient and inexpensive diagnostic technique that can guide most appropriate treatment in dogs with large RCs.

Prospective Phase II trial of radiation therapy in localised non-gastric marginal zone lymphoma with prospective evaluation of autoimmunity and Helicobacter pylori status: TROG 05.02/ALLG NHL15.

BACKGROUND: This Phase 2 multicentre trial in localised non-gastric marginal zone lymphoma (MZL) evaluated the effectiveness and safety of radiotherapy and documented markers of autoimmunity and Helicobacter pylori infection. PATIENTS AND METHODS: Eligible patients had Stages I and II or paired-organ, non-gastric MZL. Bone marrow evaluation, autoantibody panel, and H. pylori evaluation were mandatory. Involved-field or involved-site radiotherapy was delivered to 24-30.6 Gy. Detected H. pylori infections underwent eradication. RESULTS: Between 2006 and 2014, six centres enrolled 70 patients, and 68 commenced treatment. The median age was 59 (range: 23-84) years, and 31 (46%) were male. Overall, 55 patients had Stage I disease, nine patients had Stage II disease, and four patients had paired organ-confined disease. Involved extranodal sites with three or more cases were orbital (n = 18), conjunctiva (n = 13), lacrimal (n = 8), skin (n = 8), salivary (n = 7), and muscle (n = 4). Eight patients had primary nodal MZL. At the median follow-up of 5 years (range 0.7-9.4), progression-free survival and overall survival were 79% and 95%, respectively. One lymphoma-related death and two in-field failures (after 25 and 30 Gy, respectively) occurred. Distant relapse sites were skin (n = 2), lymph nodes (n = 2), duodenum, stomach, muscle, and conjunctiva (1 each). No paired-organ MZL relapsed. Apart from cataracts (n = 18), only three treatment-related late grade ≥3 adverse events occurred. Autoantibodies or autoimmune events were detected in 26 of 68 patients (38%). H. pylori infection was detected in 15 of 63 patients (24%) tested. Neither autoimmunity nor H. pylori was detected in 27 of 68 patients (40%). CONCLUSIONS: Radiotherapy was a potentially curative treatment with low toxicity in localised non-gastric MZL. Autoimmunity, H. pylori infection or both were detected in 60% of patients.

Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

A head-to-head Caco-2 assay comparison of the mechanisms of action of the intestinal permeation enhancers: SNAC and sodium caprate (C10).

Salcaprozate sodium (SNAC) and sodium caprate (C10) are the two leading intestinal permeation enhancers (PEs) in oral peptide formulations in clinical trials. There is debate over their mechanism of action on intestinal epithelia. The aims were: (i) to compare their effects on the barrier function by measuring transepithelial electrical resistance (TEER), permeability of FITC-4000 (FD4) across Caco-2 monolayers, and on immunohistochemistry of tight junction (TJ)-associated proteins; and (ii) to compare cellular parameters using conventional end-point cytotoxicity assays and quantitative high content analysis (HCA) of multiple sub-lethal parameters in Caco-2 cells. C10 (8.5 mM) reversibly reduced TEER and increased FD4 permeability across monolayers, whereas SNAC had no effects on either parameter except at cytotoxic concentrations. C10 exposure induced reorganization of three TJ proteins, whereas SNAC only affected claudin-5 localization. High concentrations of C10 and SNAC were required to cause end-point toxicology changes in vitro. SNAC was less potent than C10 at inducing lysosomal and nuclear changes and plasma membrane perturbation. In parallel, HCA revealed that both agents displayed detergent-like features that reflect initial membrane fluidization followed by changes in intracellular parameters. In conclusion, FD4 permeability increases in monolayers in response to C10 were in the range of concentrations that altered end-point cytotoxicity and HCA parameters. For SNAC, while HCA parameters were also altered in a similar overall pattern as C10, they did not lead to increased paracellular flux. These assays show that both agents are primarily surfactants, but C10 has additional TJ-opening effects. While these in vitro assays illucidate their epithelial mechanism of action, clinical experience suggests that they over-estimate their toxicology in the dynamic intestinal environment.

Measuring Outcomes Over Time in Distal Radius Fractures: A Comparison of Generic, Upper Extremity-Specific and Wrist-Specific Outcome Measures.

Purpose: This study compared the responsiveness of a generic (Short Form-36 [SF-36]), an upper extremity-specific (Disabilities of the Arm, Shoulder, and Hand [DASH]) and a wrist-specific (Patient-Rated Wrist Evaluation [PRWE]) outcome score when evaluating distal radius fractures over time. Methods: We observed 235 patients who met the inclusion criteria of an isolated distal radius fracture treated surgically or nonsurgically and greater than age 50 years for 12 months in this prospective study. Standardized assessments were performed at baseline and at 6 and 12 months. Exclusion criteria included subjects with concomitant injuries in the ipsilateral limb and follow-up of less than 1 year. Responsiveness was evaluated through the standardized response mean and the proportion who met a minimal clinically important difference. Floor and ceiling effects were also calculated. Results: The standardized response mean was significantly greatest for the DASH between baseline and 6 months (P < .001), and the PRWE between both baseline and 6 months (P < .01) and 6 and 12 months (P < .01) compared with the SF-36. The proportion of patients who met a minimal clinically important difference between baseline and 6 months was greater in the PRWE, but it did not meet statistical significance (P = .12). The PRWE demonstrated a high ceiling effect at baseline (76.6%) but less so at 12 months (16.9%). The DASH demonstrated similar ceiling effects at baseline (62.9%) and 12 months (18.6%). The SF-36 had no ceiling effect. Conclusions: In the first 6 months, both the DASH and PRWE have greater responsiveness in assessing change over the SF-36 in distal radius fractures. From 6 to 12 months, the wrist-specific PRWE has greater responsiveness over both the DASH and SF-36. This supports the use of the anatomy- and injury-specific outcome measures over the generic outcome measure in detecting change over a patient's early recovery. However, as the time from injury increases, the absence of a ceiling effect from the generic outcome measure may become more useful. Clinical relevance: This study demonstrates the responsiveness of the DASH, PRWE, and SF36 in assessing distal radius fractures treated in patients greater than age 50 in the first year. In establishing the most responsive measure, respondent burden can be decreased in future research.

Adoption of hypofractionated radiation therapy for early breast cancer in private practice: the GenesisCare experience 2014­2016.

INTRODUCTION: Cancer Australia guidelines recommend that hypofractionation should be considered for women over the age of 50 years with early breast cancer. GenesisCare is the largest provider of radiation therapy services in Australia. This study aimed to investigate variation in hypofractionation across 4 states encompassing the period when the most recent guidelines had been released. METHODS: Patients with T1 N0 and T2 N0 breast cancer who received radiation therapy as adjuvant therapy after breast conservation surgery between 2014 and 2016 were reviewed. Patient, treatment and disease-related variables were included in the univariate and multivariate models together with other potential explanatory variables such as the state, in which the patient was treated, radiation oncologist and distance from the treatment centre. RESULTS: Of 3374 patients included, 44% received a hypofractionated schedule. There was an increase in the use of hypofractionation from 32% in 2014 to 56% in 2016. Older patients were more likely to receive a hypofractionated treatment schedule - 75% for patients 80 years and over. Multivariate modelling revealed older age, year of treatment, higher T stage and grade, chemotherapy and the individual radiation oncologist (and state) as independent predictors of the use of hypofractionation. There was no difference in hypofractionation based on laterality. CONCLUSIONS: Guidelines from Cancer Australia may impact clinician behaviour. The influence of the individual radiation oncologist remains paramount, and their practice is affected by their immediate colleagues. Subsequent analysis of hypofractionation rates after presentation of these data has resulted in a significant increase in its use.

The Feasibility of a Randomized Controlled Trial for Open Tibial Fractures at a Regional Hospital in Uganda.

BACKGROUND: The inclusion of low and middle-income country (LMIC) hospitals in multicenter orthopaedic trials expands the pool of eligible patients and improves the external validity of the evidence. Furthermore, promoting studies in LMIC hospitals defines the optimal treatments for low-resource settings, the conditions under which the majority of musculoskeletal injuries are treated. The objective of this study was to determine the feasibility of a randomized controlled trial comparing external fixation with intramedullary (IM) nailing in patients with an isolated open tibial fracture who presented to a regional hospital in Uganda. METHODS: From July 2016 to July 2017, skeletally mature patients who presented to a Ugandan regional hospital with an isolated Gustilo-Anderson type-II or IIIA open fracture of the tibial shaft were eligible for inclusion. The primary feasibility outcomes were the enrollment rate, the recruitment rate, and the 3 and 12-month follow-up rates. The secondary outcomes included a comparison of 3 and 12-month follow-up rates between the treatment arms and a qualitative assessment of barriers to enrollment, timely treatment, and missed follow-up. RESULTS: During the 12-month enrollment period, 37.5% (30 of 80) of eligible patients were successfully enrolled and operatively treated on the basis of their random allocation, with an enrollment rate of 2.5 patients per month. Of the 30 enrolled patients, 53% completed their 3-month follow-up appointment, and 40% completed their 1-year follow-up appointment. Rates of 1-year follow-up were significantly higher for patients receiving IM nails than for those receiving external fixation (absolute difference, 52%; 95% confidence interval [CI], 21 to 83, p < 0.01). The main reasons that patients declined to participate in the trial were preferences for treatment by traditional bonesetters and prehospital delays that were related to a disorganized referral system. Barriers to follow-up included prohibitive transportation costs and community pressure to turn to traditional forms of treatment. CONCLUSIONS: A regional hospital in Uganda can successfully enroll, randomize, and operatively treat multiple patients with an open tibial fracture each month. Patient follow-up presents substantial concerns over trial feasibility in this setting. Cultural pressure to utilize traditional treatments remains a particularly common barrier to study-participant enrollment and retention.

High rate of reoperation and conversion to total hip arthroplasty after internal fixation of young femoral neck fractures: a population-based study of 796 patients.

Background and purpose - Most often, the goal of non-geriatric femoral neck fracture surgery is to preserve the native hip joint. However, reoperations for painful implants, osteonecrosis, and nonunion are common. We determined the reoperation rate and time-to-reoperation following internal fixation of these fractures in a large population cohort. Patients and methods - This retrospective cohort study included patients between the ages of 18 and 50 years old who underwent internal fixation for a femoral neck fracture during 1997-2013. Patients were followed until December 2013. Primary outcomes were reoperation rate and time-to-reoperation. Time-to-event analysis was performed to estimate the rate of any reoperation and for THA specifically, while testing the dependency of time-to-reoperation on secondary variables. Results - 796 young femoral neck fracture patients were treated with internal fixation during the study period (median age 43 years, 39% women). Median follow-up was 8 years (IQR 4-13). One-third underwent at least 1 reoperation at a median 16 months after the index surgery (IQR 8-31). Half of reoperations were for implant removal, followed by conversion to total hip arthroplasty. 14% of the cohort were converted to THA. The median time to conversion was 2 years (IQR 1-4). Neither female sex nor older age had a statistically significant effect on time-to-reoperation or time-to-THA conversion. Interpretation - Following internal fixation of young femoral neck fracture, 1 in 3 patients required a reoperation, and 1 in 7 were converted to THA. These data should be considered by patients and surgeons during treatment decision-making.

A Prospective, Multicenter Study of Involved-Field Radiation Therapy With Autologous Stem Cell Transplantation for Patients With Hodgkin Lymphoma and Aggressive Non-Hodgkin Lymphoma (ALLG HDNHL04/TROG 03.03).

PURPOSE: The role of involved-field radiation therapy (IFRT) with autologous stem cell transplantation (ASCT) for lymphomas remains uncertain. METHODS AND MATERIALS: In this prospective, multicenter study, patients undergoing ASCT for relapsed/refractory lymphoma received peritransplant IFRT to disease sites identified at study registration (SR) (before salvage chemotherapy [SC]). Radiation dose was adapted to SC response. Survival, relapse rates/pattern, toxicity, and prognostic factors were evaluated. RESULTS: Forty-five patients were enrolled (23 with Hodgkin lymphoma, 22 with aggressive non-Hodgkin lymphoma). Three-year overall survival and cumulative incidence of posttransplant progression rates were 72% (95% confidence interval [CI], 59%-87%) and 42% (95% CI, 27%-57%), respectively. Stage (P = .03) and elevated lactate dehydrogenase (P = .05) were significant risk factors for disease progression on multivariable analysis. Three-year actuarial in-field, marginal, and distant progression rates were 7% (95% CI, 0%-15%), 9% (95% CI, 0%-18%), and 36% (95% CI, 21%-51%), respectively. Progression occurred in 8 of 30 patients with all sites irradiated and in 13 of 15 patients without all sites irradiated. There were 117 disease sites at SR and 64 post-ASCT progression sites, of which 15 were involved at SR and 12 only at initial diagnosis. Posttransplant relapse occurred in 3 of 83 irradiated and 12 of 34 unirradiated involved sites. Of 28 sites in complete response to SC on computed tomography, there was no relapse in any of the 21 irradiated sites and in 1 of 7 unirradiated sites. Of 72 sites in complete response on positron emission tomography, relapse occurred in 1 of 50 irradiated and 10 of 22 unirradiated sites. No grade 4 nonhematologic radiation therapy toxicities were observed. CONCLUSIONS: IFRT was well tolerated and associated with a low rate of in-field progression. Progression rates were lower for patients with all disease sites irradiated. Response to SC on both computed tomography and positron emission tomography warrants further study to select sites for IFRT.

Predicting completion of follow-up in prospective orthopaedic trauma research.

OBJECTIVE: Orthopaedic trauma studies that collect long-term outcomes are expensive and maintaining high rates of follow-up can be challenging. Knowing what factors influence completion of follow-up could allow interventions to improve this. We aimed to assess which factors influence completion of follow-up in the 12 months following surgery in prospective orthopaedic trauma research. DESIGN: Prospective Cohort Study. SETTING: Level 1 Trauma Center, Vancouver, Canada. PARTICIPANTS: Eight hundred seventy patients recruited to 4 prospective studies investigating the outcomes of operatively treated lower extremity fractures. MAIN OUTCOME MEASUREMENTS: Completion of follow-up defined as completion of all outcome measures at all time points up to 12 months following injury. RESULTS: Univariate analysis and subsequent analysis by building a reductive multivariate regression model allowed for estimation of the influence of factors in completion of follow-up.Eight hundred seventy patients with complete data had previously been recruited and were included in the analysis. Seven hundred seven patients (81.2%) completed follow-up to 12 months. Factors associated with completion of follow up included higher physical component score of SF-36 at baseline, not being on social assistance at the time of injury, being married and having a higher level of educational attainment. CONCLUSIONS: Our study has demonstrated several important factors identifiable at baseline which are associated with a failure to complete follow-up. Although these factors are not modifiable themselves, we advocate that researchers designing studies should plan for additional follow-up resources and interventions for at risk patients. LEVEL OF EVIDENCE: Level IV.

Comparison of Generic, Musculoskeletal-Specific, and Foot and Ankle-Specific Outcome Measures Over Time in Tibial Plafond Fractures.

BACKGROUND: This study performed a psychometric analysis assessing and comparing the responsiveness of the relevant components of a generic (Short Form-36 [SF36]), a musculoskeletal-specific (Short Musculoskeletal Functional Assessment [SMFA]), and a foot and ankle-specific (Foot and Ankle Outcome Score [FAOS]) outcome score when evaluating surgically treated tibial plafond fractures over time. METHODS: Fifty-one patients were followed for 12 months after their tibial plafond fracture. Responsiveness, or the ability to detect clinical change in a disease, was evaluated through the standardized response mean (SRM), the proportion meeting a minimal clinically important difference (MCID), and floor and ceiling effects. RESULTS: The SRM of the SF36-Physical Component Summary (PCS) was significantly greater than the SMFA-dysfunction index (DI) (P < .01) and FAOS-Activities of Daily Living (ADL) (P = .01) between baseline and 6 months, whereas the SRMs of only SF36-PCS and FAOS-ADL differed (P = .01) between 6 and 12 months. The proportion of patients achieving an MCID for SF36-PCS was higher than FAOS-ADL (P = .03) between baseline and 6 months and higher than SMFA-DI (P = .04) between 6 and 12 months. The FAOS-ADL showed substantial ceiling effects at baseline (88.2%) but much less at 6 months (5.9%) and 12 months (9.8%). Smaller ceiling effects were observed for the SMFA-DI (11.8%) at baseline, whereas none were observed for the SF36-PCS. CONCLUSIONS: This study found that the SF36-PCS had greater responsiveness in assessing tibial plafond fractures compared to the SMFA-DI and FAOS-ADL, particularly in the first 6 months after surgery. In addition, limitations were revealed in the SMFA-DI and FAOS-ADL. This study illustrates the necessary diligence required for selection of outcome measures, as musculoskeletal and anatomy specific scores are not necessarily superior. LEVEL OF EVIDENCE: Level II, prospective cohort study.

Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03.

PURPOSE: Follicular lymphoma (FL) is curable by involved-field radiotherapy (IFRT) in < 50% of patients with stage I to II disease. We hypothesized that adding systemic therapy to IFRT would improve long-term progression-free survival (PFS). PATIENTS AND METHODS: A multicenter randomized controlled trial enrolled patients with stage I to II low-grade FL after staging computed tomography scans and bone marrow biopsies. 18F-labeled fluorodeoxyglucose-positron emission tomography (PET) was not mandatory. Patients were randomly assigned to either arm A (30 Gy IFRT alone) or arm B (IFRT plus six cycles of cyclophosphamide, vincristine, and prednisolone [CVP]). From 2006, rituximab was added to arm B (R-CVP). RESULTS: Between 2000 and 2012, 150 patients were enrolled, 75 per arm. In arm B, 44 patients were allocated to receive CVP and 31 were allocated to receive R-CVP. At randomization, 75% had stage I, the median age was 57 years, 52% were male, and 48% were PET staged. With a median follow-up of 9.6 years (range, 3.1 to 15.8 years), PFS was superior in arm B (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = .033). Ten-year PFS rates were 59% (95% CI, 46% to 74%) and 41% (95% CI, 30% to 57%) for arms B and A, respectively. Patients in arm B who received R-CVP had markedly superior PFS compared with contemporaneous patients in arm A (hazard ratio, 0.26; 95% CI, 0.07 to 0.97; P = .045). Fewer involved regions ( P = .047) and PET staging ( P = .056) were associated with better PFS. Histologic transformation occurred in four and 10 patients in arms B and A, respectively ( P = .1). Ten deaths occurred in arm A versus five in arm B, but overall survival was not significantly different ( P = .40; 87% and 95% at 10 years, respectively). CONCLUSION: Systemic therapy with R-CVP after IFRT reduced relapse outside radiation fields and significantly improved PFS. IFRT followed by immunochemotherapy is more effective than IFRT in early-stage FL.

The Socioeconomic Implications of Isolated Tibial and Femoral Fractures from Road Traffic Injuries in Uganda.

BACKGROUND: The purpose of this study was to determine the socioeconomic implications of isolated tibial and femoral fractures caused by road traffic injuries in Uganda. METHODS: This prospective longitudinal study included adult patients who were admitted to Uganda's national referral hospital with an isolated tibial or femoral fracture. The primary outcome was the time to recovery following injury. We assessed recovery using 4 domains: income, employment status, health-related quality of life (HRQoL) recovery, and school attendance of the patients' dependents. RESULTS: The majority of the study participants (83%) were employed, and they were the main income earner for their household (74.0%) at the time of injury, earning a mean annual income of 2,375 U.S. dollars (USD). All of the patients had been admitted with the intention of surgical treatment; however, because of resource constraints, only 56% received operative treatment. By 2 years postinjury, only 63% of the participants had returned to work, and 34% had returned to their previous income level. Overall, the mean monthly income was 62% less than preinjury earnings, and participants had accumulated 1,069 USD in debt since the injury; 41% of the participants had regained HRQoL scores near their baseline, and 62% of school-aged dependents, enrolled at the time of injury, were in school at 2 years postinjury. CONCLUSIONS: At 2 years postinjury, only 12% of our cohort of Ugandan patients who had sustained an isolated tibial or femoral fracture from a road traffic injury had recovered both economically and physically. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Outcomes and relapse patterns following chemotherapy in advanced Hodgkin lymphoma in the positron emission tomography era.

BACKGROUND: This study evaluated relapse patterns and survival in advanced Hodgkin lymphoma (HL) patients treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with positron emission tomography (PET) used for staging and response assessment. PATIENTS AND METHODS: Patients aged 18 years or above with newly diagnosed histologically proven Stage III or IV HL treated with ABVD at Calvary Mater Newcastle from January 2005 to December 2012 were included in this study. All patients underwent pre-chemotherapy staging with 18F-fluorodeoxyglucose PET or PET/computed tomography and post-chemotherapy PET or PET/computed tomography for the assessment of response. RESULTS: Forty-three patients were included in the study. The 5-year disease-free survival, progression-free survival and overall survival were 88%, 74% and 86%, respectively. PET complete response was seen in 35 patients (81%), and the 5-year overall survival for this group was 94%. Relapse following a PET complete response was low (three patients) and occurred predominantly at the initial sites of disease. Four of five patients with bulky disease received consolidative radiotherapy and no in-field relapses were observed. CONCLUSION: Advanced stage HL with a PET complete response following ABVD is associated with an excellent prognosis.

Methotrexate induced mitochondrial injury and cytochrome c release in rat liver hepatocytes.

Methotrexate (MTX) is a folic acid antagonist that is widely used to treat a variety of diseases. One of the most serious side effects of MTX therapy is hepatotoxicity. The potential molecular cytotoxic mechanisms of MTX toward isolated rat hepatocytes were investigated using Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques. A concentration and time dependent increase in cytotoxicity and reactive oxygen species (ROS) formation and a decrease in mitochondrial membrane potential (MMP) were observed with MTX. Furthermore, a significant increase in MTX (300 µM)-induced cytotoxicity and ROS formation were observed when glutathione (GSH)-depleted hepatocytes were used whereas addition of N-acetylcysteine (a GSH precursor) decreased cytotoxicity. Catalase inactivation also increased MTX-induced cytotoxicity, while the direct addition of catalase to the hepatocytes decreased cytotoxicity. MTX treatment in isolated rat mitochondria caused swelling and significantly decreased adenosine triphosphate (ATP) and GSH content, and cytochrome c release. Potent antioxidants such as mesna, resveratrol and Trolox decreased MTX-induced cytotoxicity and ROS formation and increased MMP. This study suggests that MTX-induced cytotoxicity caused by ROS formation and GSH oxidation leads to oxidative stress and mitochondrial injury in rat hepatocytes.