The genomic landscape of 2,023 colorectal cancers.

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

Salvage of failed subtrochanteric fracture fixation in the elderly: revision internal fixation or hip arthroplasty?

PURPOSE: This study aimed to compare reoperation rate and clinical outcomes between revision open reduction and internal fixation and hip arthroplasty following failed subtrochanteric fracture fixation. METHODS: A retrospective review was conducted of patients > 50 years old treated for failed fixation of subtrochanteric fractures with revision ORIF or hip arthroplasty from 2003 to 2023. Primary outcomes included rate of fracture union and reoperations after initial salvage therapy. Secondary outcomes included complications (infection, dislocation, bursitis, implant prominence, implant failure, nonunion), pain, and gait-aid requirements by final follow-up. RESULTS: Forty-four patients were identified: 34 treated with revision ORIF and 10 with hip arthroplasty. The arthroplasty cohort was older (75.4 vs. 66.0 years, p = 0.016) but did not differ from the ORIF cohort in sex, type of initial fixation, or reason for fixation failure. Patients treated with revision ORIF and patients treated with arthroplasty had similar rates of fracture union (85.3% vs. 80.0%, p = 0.772) and reoperation (35.3% vs. 30.0%, p = 0.710). There was no significant difference in rate of additional complications not requiring reoperation (0.0% vs. 40.0%, p = 0.071). The arthroplasty cohort achieved full weightbearing in significantly shorter time than the revision ORIF cohort (3.8 vs. 6.8 weeks, p = 0.005). CONCLUSION: Both revision ORIF and hip arthroplasty are acceptable options for salvage of failed subtrochanteric fracture fixation in patients greater than 50 years old, but patients should be counseled that although the rate of fracture union is high whether revision ORIF or hip arthroplasty is selected, the rate of reoperation can exceed 1-in-4 patients. LEVEL OF EVIDENCE:  : Level III, Retrospective Comparative Study.

Impact of Intraoperative Femoral Fractures During Cemented Hemiarthroplasty for Femoral Neck Fractures.

BACKGROUND: There have been several studies on intraoperative femoral fractures (IFFs) during primary total hip arthroplasty, but it is not well understood how this complication affects the patient population undergoing cemented hemiarthroplasty. This study aimed to analyze the impact of IFFs sustained during cemented hemiarthroplasty for the treatment of femoral neck fractures. METHODS: A retrospective review was conducted of all patients who were treated for Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association 31B fractures with cemented hemiarthroplasty between January 1, 2000 and December 31, 2021, at a single academic level 1 trauma center. An initial cohort was constructed of all patients who sustained an IFF during their surgery, yielding 31 patients after excluding those who sustained a pathologic fracture or had incomplete data. These patients were matched 1:2 on age, sex, and body mass index to patients in a control cohort. The primary outcome measure was implant failure. Secondary outcome measures included complications, all-cause mortality, and radiographic outcomes (subsidence, femoral component loosening, acetabular wear, and heterotopic ossification) postoperatively. RESULTS: Subsequent implant revision was required in 3.2% (n = 1) of patients who sustained an IFF and 1.6% (n = 1) of patients who did not. After adjusting for comorbidities, there was no observed excess risk of implant failure in the fracture cohort when compared to the control cohort (hazard ratio [HR] = 0.30, P = 0.740). There was no observed excess risk of morbidity (HR = 0.69, P = 0.621) or all-cause mortality (HR = 0.23, P = 0.330). Radiographic outcomes also did not significantly differ between the 2 cohorts (P > 0.05). CONCLUSIONS: Intraoperative fractures during cemented hemiarthroplasty do not contribute to an increased risk of secondary surgery, morbidity, or mortality after surgery. They also do not adversely affect radiographic outcomes postoperatively. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047).

BACKGROUND AND OBJECTIVE: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term. METHODS: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations. ADT was allocated for 0, 6, or 24 mo. The primary outcome measure (OM) was metastasis-free survival (MFS). The secondary OMs included freedom from distant metastasis, overall survival, and initiation of nonprotocol ADT. Sample size was determined by two-way comparisons. Analyses followed standard time-to-event approaches and intention-to-treat principles. KEY FINDINGS AND LIMITATIONS: Between 2007 and 2015, 492 participants were randomised one of three groups: 166 None, 164 Short, and 162 Long. The median age at randomisation was 66 yr; Gleason scores at surgery were as follows: <7 = 64 (13%), 3+4 = 229 (47%), 4+3 = 127 (26%), and 8+ = 72 (15%); T3b was 112 (23%); and T4 was 5 (1%). The median follow-up was 9.0 yr and, with MFS events reported for 89 participants (32 None, 31 Short, and 26 Long), there was no evidence of difference in MFS overall (logrank p = 0.98), and, for Long versus None, hazard ratio = 0.948 (95% confidence interval 0.54-1.68). After 10 yr, 80% None, 77% Short, and 81% Long patients were alive without metastatic disease. The three-way randomisation was not powered to conventional levels for assessment, yet provides a fair comparison. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term outcomes after radical prostatectomy are usually favourable. In those indicated for postoperative RT and considered suitable for no, short-term, or long-term ADT, there was no evidence of improvement with addition of ADT. Future research should focus on patients at a higher risk of metastases in whom improvements are required more urgently.

Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Serosurvey for Japanese encephalitis virus antibodies following an outbreak in an immunologically naïve population, Victoria, 2022: a cross-sectional study.

OBJECTIVES: To investigate the distribution and prevalence of Japanese encephalitis virus (JEV) antibody (as evidence of past infection) in northern Victoria following the 2022 Japanese encephalitis outbreak, seeking to identify groups of people at particular risk of infection; to investigate the distribution and prevalence of antibodies to two related flaviviruses, Murray Valley encephalitis virus (MVEV) and West Nile virus Kunjin subtype (KUNV). STUDY DESIGN: Cross-sectional serosurvey (part of a national JEV serosurveillance program). SETTING: Three northern Victorian local public health units (Ovens Murray, Goulburn Valley, Loddon Mallee), 8 August - 1 December 2022. PARTICIPANTS: People opportunistically recruited at pathology collection centres and by targeted recruitment through community outreach and advertisements. People vaccinated against or who had been diagnosed with Japanese encephalitis were ineligible for participation, as were those born in countries where JEV is endemic. MAIN OUTCOME MEASURES: Seroprevalence of JEV IgG antibody, overall and by selected factors of interest (occupations, water body exposure, recreational activities and locations, exposure to animals, protective measures). RESULTS: 813 participants were recruited (median age, 59 years [interquartile range, 42-69 years]; 496 female [61%]); 27 were JEV IgG-seropositive (3.3%; 95% confidence interval [CI], 2.2-4.8%) (median age, 73 years [interquartile range, 63-78 years]; 13 female [48%]); none were IgM-seropositive. JEV IgG-seropositive participants were identified at all recruitment locations, including those without identified cases of Japanese encephalitis. The only risk factors associated with JEV IgG-seropositivity were age (per year: prevalence odds ratio [POR], 1.07; 95% CI, 1.03-1.10) and exposure to feral pigs (POR, 21; 95% CI, 1.7-190). The seroprevalence of antibody to MVEV was 3.0% (95% CI, 1.9-4.5%; 23 of 760 participants), and of KUNV antibody 3.3% (95% CI, 2.1-4.8%; 25 of 761). CONCLUSIONS: People living in northern Victoria are vulnerable to future JEV infection, but few risk factors are consistently associated with infection. Additional prevention strategies, including expanding vaccine eligibility, may be required to protect people in this region from Japanese encephalitis.

Closing the loop - the role of pathologists in digital and computational pathology research.

An increasing number of manuscripts related to digital and computational pathology are being submitted to The Journal of Pathology: Clinical Research as part of the continuous evolution from digital imaging and algorithm-based digital pathology to computational pathology and artificial intelligence. However, despite these technological advances, tissue analysis still relies heavily on pathologists' annotations. There are three crucial elements to the pathologist's role during annotation tasks: granularity, time constraints, and responsibility for the interpretation of computational results. Granularity involves detailed annotations, including case level, regional, and cellular features; and integration of attributions from different sources. Time constraints due to pathologist shortages have led to the development of techniques to expedite annotation tasks from cell-level attributions up to so-called unsupervised learning. The impact of pathologists may seem diminished, but their role is crucial in providing ground truth and connecting pathological knowledge generation with computational advancements. Measures to display results back to pathologists and reflections about correctly applied diagnostic criteria are mandatory to maintain fidelity during human-machine interactions. Collaboration and iterative processes, such as human-in-the-loop machine learning are key for continuous improvement, ensuring the pathologist's involvement in evaluating computational results and closing the loop for clinical applicability. The journal is interested particularly in the clinical diagnostic application of computational pathology and invites submissions that address the issues raised in this editorial.

Computational validation of clonal and subclonal copy number alterations from bulk tumor sequencing using CNAqc.

Copy number alterations (CNAs) are among the most important genetic events in cancer, but their detection from sequencing data is challenging because of unknown sample purity, tumor ploidy, and general intra-tumor heterogeneity. Here, we present CNAqc, an evolution-inspired method to perform the computational validation of clonal and subclonal CNAs detected from bulk DNA sequencing. CNAqc is validated using single-cell data and simulations, is applied to over 4000 TCGA and PCAWG samples, and is incorporated into the validation process for the clinically accredited bioinformatics pipeline at Genomics England. CNAqc is designed to support automated quality control procedures for tumor somatic data validation.

Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme.

The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.

Patient-Reported Outcomes and Computed Tomography Review After Minimally Invasive Fusion of the Sacroiliac Joint With Aggressive Joint Decortication and Joint Compression.

The sacroiliac joint (SIJ) is a common, underrecognized source of low back pain. We evaluated outcomes in patients undergoing sacroiliac joint fusion (SIJF) using a novel, minimally invasive SIJF system emphasizing compressive forces across an aggressively debrided SIJ. We retrospectively reviewed data from a continuous set of patients presenting to a large, tertiary care hospital from September 2017 to August 2019. All patients received the novel SIJF device. Outcomes were assessed at 8 weeks, 6 months, and 12 months using the Oswestry Disability Index (ODI) score, Numerical Rating Scale (NRS) score, Single Assessment Numerical Evaluation (SANE) score, and Patient-Reported Outcomes Measurement Information System (PROMIS) measures, plus radiographic evaluation of fusion status. Data from 75 patients were analyzed. At 8 weeks, 6 months, and 12 months, the ODI score improved by 10.5 points (P=.002), 17.4 points (P<.0001), and 23.6 points (P<.0001), respectively, while the NRS score improved by 4.6 points (P<.0001), 4.4 points (P<.0001), and 4.6 points (P<.0001), respectively. SANE scores indicated high levels of patient satisfaction (81.0%, 92.18%, and 89.2%, respectively). PROMIS physical function scores improved by 2.65 points, 3.30 points, and 3.63 points, respectively, while PROMIS mental health scores showed changes of -1.93 points, 1.57 points, and -0.47 points, respectively. A review of computed tomography scans demonstrated grade 3 fusion (complete) in 81% of cases at a mean of 371 days postoperatively. There was one revision case for a malpositioned implant. The use of a novel SIJF device emphasizing compressive forces provided early, durable improvements in patient-reported outcomes and extremely high patient satisfaction. [Orthopedics. 2024;47(2):101-107.].

Sacral insufficiency fractures are a frequent and painful consequence of pubic symphysis osteomyelitis.

BACKGROUND: Pubic symphysis osteomyelitis can result from urosymphyseal fistula formation. High rates of sacropelvic insufficiency fractures have been reported in this population. The aim of this study was to describe the presentation and risk factors for sacral insufficiency fractures (SIF) associated with surgical treatment of pubic symphysis osteomyelitis. METHODS: A retrospective review was performed for 54 patients who underwent surgery for pubic symphysis osteomyelitis associated with a urosymphyseal fistula at a single institution from 2009 to 2022. Average age was 71 years and 53 patients (98%) were male. All patients underwent debridement or partial resection of the pubic symphysis at the time of fistula treatment. Average width of the symphyseal defect was 65 mm (range 9-122) after treatment. RESULTS: Twenty patients (37%) developed SIF at a mean time of 4 months from osteomyelitis diagnosis. Rate of sacral fracture on Kaplan-Meier analysis was 31% at 6 months, 39% at 12 months, and 41% at 2 years. Eleven patients developed SIF prior to pubic debridement and 12 patients developed new or worsening of pre-existing SIF following surgery. Width of pubic resection was higher in patients who developed SIF (76 mm vs. 62 mm), but this did not meet statistical significance (p = 0.18). CONCLUSION: Sacral insufficiency fracture is a common sequela of pubic symphysis osteomyelitis. These fractures are often multifocal within the pelvis and can occur even prior to pubic resection. Pubectomy further predisposes these patients to fracture. Clinicians should maintain a high index of suspicion for these injuries in patients with symphyseal osteomyelitis.

Winquist View of the Femoral Neck: Ideal Visualization of Femoral Neck Fixation.

Background: Despite the increased frequency of cephalomedullary fixation for unstable intertrochanteric hip fractures, failure with screw cut-out and varus collapse remains a significant failure mode. Proper positioning of implants into the femoral neck and head directly influences the stability of fracture fixation. Visualization of the femoral neck and head can be challenging and failure to do so may lead to poor results; Obstacles include patient positioning, body habitus, and implant application tools. We present the "Winquist View," an oblique fluoroscopic projection that shows the femoral neck in profile, aligns the implant and cephalic component, and assists in implant placement. Methods: With the patient in the lateral position, the legs are scissored when possible. Following standard reduction techniques, the Winquist view is used to check reduction prior to surgical draping. Intraoperatively, we rely on a perfect image to place implants in the ideal portion of the femoral neck, with a trajectory that achieves the center-center or center-low position of the femoral neck. This is achieved by incorporating the anterior-posterior, lateral, and Winquist view. Results: We present 3 patients who underwent fixation with a cephalomedullary nail for intertrochanteric hip fractures. The Winquist view facilitated excellent visualization and positioning in all cases. All postoperative courses were uneventful, without failures or complications. Conclusion: While standard intraoperative imaging may be adequate in many cases, the Winquist view facilitates optimal implant positioning and fracture reduction. With lateral imaging, implant insertion guides may obscure visualization of the femoral neck during which Winquist view is the most helpful. Level of Evidence: V.

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Salvage Radiation Therapy After Radical Prostatectomy: Analysis of Toxicity by Dose-Fractionation in the RADICALS-RT Trial.

PURPOSE: Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT. METHODS AND MATERIALS: Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test. RESULTS: Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups. CONCLUSIONS: Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules.

A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus.

Background: The primary objective of the present study was to evaluate the effects of a Nerve Support Formula NeuropAWAY® on diabetic neuropathic pain. Methods: This double-blind, placebo-controlled, randomized trial was conducted between August 2020 and February 2021. Patients aged ≥40 and ≤65 years with a history of type 2 diabetes (T2D) with a confirmed diagnosis of diabetic neuropathic pain were included in the study. The primary efficacy endpoint was to assess the effect of the 42 days administration of the Nerve Support Formula on the neuropathic pain as assessed by the 11 point Pain Intensity Numeric Rating Scale (PI-NRS). The secondary objectives were to assess the effect on plasma vitamin B12 levels, nerve conduction velocity, blood flow velocity, Brief Pain Inventory, Neuropathy Total Symptom Score, and Insomnia Severity Index. Results: The enrolled study population (n=59) was randomized in two study groups; the Investigational Product (IP) group - Nerve Support Formula (n=27) and placebo group (n=32). The mean age of these participants was 52.63 and 53.72 for IP and placebo group, respectively. The mean (SD) HbA1c levels for IP and placebo group were 8.37 (0.85) and 8.16 (0.86), respectively. By the end of the study (Day 42) the decrease in PI-NRS scores for the IP group was maximal (↓61.32%) and highly significant (p<0.001) in comparison to the placebo group (↑2.47%). Significant improvements (p<0.05) were also noted in the secondary efficacy variables after 42 days of IP intake. Conclusion: The formula was found to be significantly effective as compared to placebo in reducing pain and other sensory symptoms related to the diabetic peripheral neuropathy.

Cephalomedullary Nailing of Unstable Geriatric Intertrochanteric Fractures on a Traction Table Combined With Percutaneous Reduction Techniques Is Safe and Results in a Low Rate of Cutout.

OBJECTIVES: To describe a reproducible technique for reduction assessment and percutaneous reduction of unstable intertrochanteric fractures treated with a cephalomedullary nail on a traction table. DESIGN: Retrospective cohort study. SETTING: Level-1 trauma center. PATIENTS: Two-hundred 20 consecutive patients with intertrochanteric fractures. INTERVENTION: Initial closed reduction performed on a traction table. Accessory incisions were used to facilitate a reduction in 77 patients (35%). All fractures were stabilized with a cephalomedullary nail. MAIN OUTCOME MEASUREMENTS: Radiographic outcome including union, cutout, and fracture collapse (FC). Surgical outcomes including infection and hematoma were also reported. RESULTS: Mechanical complications (nonunion, cutout, and varus collapse) occurred in 8.8% of patients at 1 year. Eleven of 13 patients who developed these complications had either suboptimal implant placement (tip-to-apex distance >25 mm) or a varus reduction. There was no difference in the incidence of reoperation, nonunion, lag screw cutout, or posttraumatic arthritis based on the use of an accessory incision for fracture reduction. There was a significant increase in FC in patients who received an accessory incision (6.8 mm vs. 5.4 mm, P = 0.04). One patient (1%) developed a hematoma in the accessory incision cohort, and 1 patient (0.7%) who did not have an accessory incision developed a postoperative infection. CONCLUSIONS: The current study suggests utilization of accessory incisions assist in reduction is safe and is associated with a low rate of complications. The surgeon should prioritize fracture reduction and optimal implant placement and not hesitate to use an accessory incision to assist with fracture reduction. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Patient-Reported and Radiographic Outcomes After Revision Sacroiliac Joint Fusion.

BACKGROUND: Sacroiliac joint fusion (SIJF) has been established as an effective treatment for sacroiliac joint dysfunction. However, failure necessitating revision has been reported in up to 30% of cases. Little is known regarding outcomes of revision SIJF. METHODS: We retrospectively reviewed all revision SIJF at a single academic center between 2017 and 2020. Revision surgery was performed using the principles of joint decortication, bone grafting, compression, and rigid internal fixation. Outcomes were assessed at 6 months and 1 year after surgery using the Oswestry Disability Index (ODI), Numeric Pain Rating Scale (NPRS), and Single Assessment Numeric Evaluation (SANE) scale. Fusion was assessed using computed tomography at 12 months postoperatively. RESULTS: Eighteen revision SIJFs in 13 patients were included. The mean age was 55.8 years (range 35-75). Mean body mass index was 27.9 (range 21.7-36.7). Sixty-two percent of the patients were women. The indications for revision were pseudarthrosis without fixation failure in 14 cases (77.8%), hardware failure (loosening) in 3 cases (16.7%), and continued pain after partial fusion in 1 case (5.6%). ODI and NPRS scores demonstrated significant statistical and clinical improvements at all timepoints. Mean (SD) ODI scores improved from 53.8 (19.9) preoperative to 37.5 (19.8) at 6 months and 32.9 (21.7) at 12 months. Improvement in ODI was found in 15 joints (83.3%), and the minimal clinically important difference (MCID) was achieved in 12 joints (66.7%). Mean (SD) NPRS scores improved from 6.5 (1.4) preoperative to 3.2 (2.8) at 6 months and 3.4 (2.6) at 12 months. Improvement in NPRS was also identified in 17 joints (94.4%), and 10 joints (55.6%) achieved MCID for NPRS. Mean (SD) SANE score was 72.0% (30.8) at 6 months and 70.0% (33.8) at 12 months. There were no radiographic lucencies, implant subsidence, or implant fractures at final follow-up. We identified an 88.9% fusion rate with definitive bridging bone across the sacroiliac joint. CONCLUSION: Utilizing a principles-based technique of joint decortication, compression, and rigid internal fixation, revision SIJF showed an improvement in patient-reported outcomes as well as high rate of fusion at 12 months. The most common indications for revision SIJF are symptomatic pseudarthrosis and implant loosening. This is the largest series of revision SIJF to date.

Patella Fracture Fixation With Novel Wagon Wheel Construct Versus Tension-Band Construct: A Technical Trick.

SUMMARY: Internal fixation of patella fractures remains technically challenging. Cannulated screws with an anterior tension band have been associated with high rates of implant prominence, and fracture comminution can make appropriate application of a tension band impractical. We present the results of a novel technique using a transtendinous/transligamentous mini-fragment plate positioned peripherally around the patella with radially directed screws: termed the wagon-wheel (WW) construct. Compared with a cohort of fractures treated with cannulated screws with an anterior tension band, there was no difference in final range of motion and rate of nonunion. The WW construct had a significantly decreased incidence of symptomatic implants (5% vs. 32%, P = 0.02), rate of reoperation (9% vs. 38%, P = 0.018), dependency on gait aids (10% vs. 38%, P = 0.031), and a faster time to union (HR: 2.2; 95% CI, 1.28-3.95, P = 0.005). In summary, the WW was designed with the goal of obtaining peripheral plate fixation to maximize fragment-specific fixation while minimizing implant prominence. Patients treated with the WW demonstrated reduced rates of implant prominence and reoperation.