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.

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.

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.

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.

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.

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.

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.

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.

Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial.

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10-5) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation.

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.

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.

Distal Femoral Replacement for Fractures Allows for Early Mobilization with Low Complication Rates: A Multicenter Review.

Periprosthetic fractures around a total knee arthroplasty (TKA), comminuted and intra-articular femur fractures, or fracture nonunions in osteoporotic bone represent technically challenging problems. This is particularly true when the fracture involves a loose femoral component or the pattern results in suboptimal fixation potential. These clinical indications often arise in an older and comorbid patient population in whom a principal goal of treatment includes allowing for early mobilization. Limited data indicate that arthroplasty via distal femoral replacement (DFR) is a reasonable alternative to open reduction and internal fixation, allowing for early ambulation with low complication rates. We performed a retrospective review of trauma and arthroplasty surgeries at three tertiary referral institutions. Adult patients treated for the above with a DFR were included. Patients with active infection, open and/or high-energy injuries and revisions unrelated to fracture were excluded. Patient demographics, treatment details, and outcomes were assessed. Between 2002 and 2017, 90 DFR's were performed for the above indications with a mean follow-up of 24 months. Postoperatively, 80 patients (88%) were allowed to weight bear as tolerated, and at final follow-up, 9 patients (10%) remained dependent on a wheelchair. The average arc of motion at final follow-up was 95 degrees. There were seven (8%) implant-related complications requiring secondary surgeries: two infections, one with associated component loosening; one fracture of the hinge mechanism and one femoral component failure in conjunction with a patellofemoral dislocation (both requiring revision); one case of patellofemoral arthrosis in a patient with an unresurfaced patella; one periprosthetic fracture with associated wound dehiscence; and one case of arthrofibrosis. In each of these cases, only modular components of the DFR were exchanged. All nonmodular components cemented into the femur or tibia were retained. DFR provides a viable reconstruction option in the treatment of acute distal femur fractures, periprosthetic femur fractures, and fracture nonunions. We noted that in an elderly patient population with high comorbidities, the complication and secondary surgery rates remained relatively low, while allowing for immediate weight bearing.

Remote consultations: experiences of UK patients with prostate cancer during the COVID-19 pandemic.

Aim: Explore UK prostate cancer patients' experiences and preferences for in-person and remote consultations. Materials & methods: In January-March 2021, patients completed a survey of consultation format preferences. Results: Of 971 patients, most preferred in-person consultations when receiving diagnosis and results (92.3 and 66.5%, respectively) and discussing first and further treatment options (92.0 and 84.0%, respectively). Fewer patients considered follow-up (40.9%) or side effect consultations (47.7%) should be in person. Patients with longer travel preferred telephone consultations for receiving test results post-treatment. Patients over 55 preferred in-person consultations for discussing first treatment. Conclusion: To optimize prostate cancer care in the wake of COVID-19, we recommend patients have the option of consultation format, although key decisions should be made in person.

During the COVID-19 pandemic, there was a move away from in-person to remote consultations for patients with prostate cancer. However, it is not clear if remote consultations work well for every interaction. We surveyed UK-based men with prostate cancer about their preferences for consultation format. Patients wanted in-person consultations when receiving their diagnosis, discussing treatment options or getting test results after treatment. They were more accepting of remote consultations for regular follow-up or support with treatment side effects. Patients should ideally be offered a choice between in-person and remote consultations, although consultations should be in person when key decisions have to be made. These findings will be of value in planning care for patients with prostate cancer post pandemic.

A genetic model for central chondrosarcoma evolution correlates with patient outcome.

BACKGROUND: Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. METHODS: In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. RESULTS: IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. CONCLUSIONS: Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

BACKGROUND: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. METHODS: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). RESULTS: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. CONCLUSIONS: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data.

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

BACKGROUND: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). METHODS AND FINDINGS: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. CONCLUSIONS: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.