Multi-cancer risk stratification based on national health data: a retrospective modelling and validation study.

BACKGROUND: Health care is experiencing a drive towards digitisation, and many countries are implementing national health data resources. Although a range of cancer risk models exists, the utility on a population level for risk stratification across cancer types has not been fully explored. We aimed to close this gap by evaluating pan-cancer risk models built on electronic health records across the Danish population with validation in the UK Biobank. METHODS: In this retrospective modelling and validation study, data for model development and internal validation were derived from the following Danish health registries: the Central Person Registry, the Danish National Patient Registry, the death registry, the cancer registry, and full-text medical records from secondary care records in the capital region. The development data included adults aged 16-86 years without previous malignant cancers in the time period from Jan 1, 1995, to Dec 31, 2014. The internal validation period was from Jan 1, 2015, to April 10, 2018, and the data included all adults without a previous indication of cancer aged 16-75 years on Dec 31, 2014. The external validation cohort from the UK Biobank included all adults without a previous indication of cancer aged 50-75 years. We used time-dependent Bayesian Cox hazard models built on the combined medical history of Danish individuals. A set of 1392 covariates from available clinical disease trajectories, text-mined basic health factors, and family histories were used to train predictive models of 20 major cancer types. The models were validated on cancer incidence between 2015 and 2018 across Denmark and on individuals in the UK Biobank. The primary outcomes were discrimination and calibration performance. FINDINGS: From the Danish registries, we included 6 732 553 individuals covering 60 million hospital visits, 90 million diagnoses, and a total of 193 million life-years between Jan 1, 1978, and April 10, 2018. Danish registry data covering the period from Jan 1, 2015, to April 10, 2018, were used to internally validate risk models, containing a total of 4 248 491 individuals who remained at risk of a primary malignant cancer diagnosis and 67 401 cancer cases recorded. For the external validation, we evaluated the same time period in the UK Biobank covering 377 004 individuals with 11 486 cancer cases. The predictive performance of the models on Danish data showed good discrimination (concordance index 0·81 [SD 0·08], ranging from 0·66 [95% CI 0·65-0·67] for cervix uteri cancer to 0·91 [0·90-0·92] for liver cancer). Performance was similar on the UK Biobank in a direct transfer when controlling for shifts in the age distribution (concordance index 0·66 [SD 0·08], ranging from 0·55 [95% CI 0·44-0·66] for cervix uteri cancer to 0·78 [0·77-0·79] for lung cancer). Cancer risks were associated, in addition to heritable components, with a broad range of preceding diagnoses and health factors. The best overall performance was seen for cancers of the digestive system (oesophageal, stomach, colorectal, liver, and pancreatic) but also thyroid, kidney, and uterine cancers. INTERPRETATION: Data available in national electronic health databases can be used to approximate cancer risk factors and enable risk predictions in most cancer types. Model predictions generalise between the Danish and UK health-care systems. With the emergence of multi-cancer early detection tests, electronic health record-based risk models could supplement screening efforts. FUNDING: Novo Nordisk Foundation and the Danish Innovation Foundation.

Genomic reconstruction of the SARS-CoV-2 epidemic in England.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.

Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis.

We use deep transfer learning to quantify histopathological patterns across 17,355 hematoxylin and eosin-stained histopathology slide images from 28 cancer types and correlate these with matched genomic, transcriptomic and survival data. This approach accurately classifies cancer types and provides spatially resolved tumor and normal tissue distinction. Automatically learned computational histopathological features correlate with a large range of recurrent genetic aberrations across cancer types. This includes whole-genome duplications, which display universal features across cancer types, individual chromosomal aneuploidies, focal amplifications and deletions, as well as driver gene mutations. There are widespread associations between bulk gene expression levels and histopathology, which reflect tumor composition and enable the localization of transcriptomically defined tumor-infiltrating lymphocytes. Computational histopathology augments prognosis based on histopathological subtyping and grading, and highlights prognostically relevant areas such as necrosis or lymphocytic aggregates. These findings show the remarkable potential of computer vision in characterizing the molecular basis of tumor histopathology.

Long-term results of the threaded Weill cup in primary total hip arthroplasty: a 15-20-year follow-up study.

Uncemented, threaded acetabular components with smooth surface treatment were widely used in continental Europe in the 1970s and 1980s for primary total hip arthroplasty (THA). Previously published studies showed high failure rates in the mid-term. In a consecutive series of 116 patients, 127 threaded cups with smooth surface treatment (Weill cup; Zimmer, Winterthur, Switzerland) were implanted in combination with one type of uncemented stem. Patients were followed up clinically and radiographically. Mean time of follow-up was 17 years (range 15-20). At the time of follow-up, the acetabular component had been revised or was awaiting revision in 30 hips (24%). Two hips were revised for infection and 23 for aseptic loosening. Four polyethylene liners were exchanged because of excessive wear. One hip was awaiting revision. The survival rate for all acetabular revisions including one hip awaiting revision was 75% (95%CI: 65-85%) at 17 years. These results support the view that smooth, threaded acetabular components do not provide satisfactory long-term fixation and should be abandoned. It is important to closely monitor patients with these components as the failure rate remains high in the long-term.

Long-term results of the threaded Mecron cup in primary total hip arthroplasty : A 15-20-year follow-up study.

In the 1970s, high failure rates of cemented acetabular components, especially in young patients, in the middle- and long-term prompted a search for alternatives. The Mecring was one of the most popular first generation uncemented, threaded cups widely used in the 1980s for arthroplasty of the hip. First generation threaded cups commonly had smooth surface treatment and showed unacceptably high failure rates in the mid-term. In a consecutive series of 209 patients, 221 threaded uncemented acetabular cups with smooth surface treatment (Mecring) had been implanted in combination with one type of uncemented stem. Patients were followed up clinically and radiographically. The mean time of follow-up was 17 (range 15-20) years. In 91 (41%) hips the acetabular component had been revised or was awaiting revision: two hips for infection and 84 (38%) for aseptic loosening. Five hips were awaiting revision. The survival rate for all revisions including hips awaiting revision was 49% (95% CI: 41-57%) at 17 years. These results support the view that smooth, threaded acetabular components do not provide satisfactory long-term fixation and should be abandoned. Patients with these components must be closely monitored as the failure rate remains high in the long-term.

Survival of the cementless Spotorno stem in the second decade.

High survival rates have been reported for the uncemented CLS Spotorno stem up to 10 years. To confirm survival at longer followup we report the minimum 15-year (mean, 17 years; range, 15-20 years) for 257 hips using this stem. We retrospectively evaluated the clinical and radiographic results of all 326 patients (354 THAs) operated between 1985 and 1989. The patients had a mean age of 57 years using an uncemented grit-blasted, tapered titanium femoral stem. Eighty-six patients (89 hips) died and eight patients (eight hips) were lost to followup, leaving 240 patients (257 hips) for evaluation. The femoral component was revised in 35 hips: eight for infection, nine for periprosthetic fracture, one for traumatic loosening, and 17 for aseptic loosening. Survival of the stem was 88% at 17 years (95% confidence interval, 84%-92%), and survival with femoral revision for aseptic loosening as an end point was 94% (95% confidence interval, 91%-97%). The median Harris hip score at followup was 80 points. No thigh pain was reported. Small osteolytic lesions (< 1 cm(2)) were found in the proximal Gruen zones (1 or/and 7) in 28 hips (15%). No distal femoral osteolysis was found. The long-term survival with this type of femoral component remains high in the second decade.

Uncemented grit-blasted straight tapered titanium stems in patients younger than fifty-five years of age. Fifteen to twenty-year results.

BACKGROUND: Total hip arthroplasty without cement is frequently performed in young active patients, but only limited outcomes data are available after durations of follow-up of more than fifteen years. METHODS: We retrospectively evaluated the clinical and radiographic results of a consecutive series of 154 total hip arthroplasties (in 141 patients) performed with an uncemented grit-blasted straight tapered titanium femoral stem combined with a threaded socket in patients under the age of fifty-five years. The median duration of follow-up was seventeen years. Clinical results were evaluated with use of the Harris hip score. The canal fill index was used as the criterion to determine the adequacy of stem sizing. Kaplan-Meier survivorship analysis was performed to predict long-term outcomes. RESULTS: The stem was undersized, with a canal fill index of < or =80%, in forty-one hips (27%). Late aseptic loosening of the stem occurred in four femora, and the femoral component was undersized in all four. These four stems were stable for ten years and then underwent progressive subsidence, which was associated with pain. Five stems were revised because of a late postoperative periprosthetic fracture following trauma. Localized proximal femoral osteolysis was seen in seven hips without signs of loosening. Survivorship of the stem with revision for any reason as the end point was estimated to be 90% (95% confidence interval, 87% to 97%) at twenty years. Survivorship with aseptic loosening as the end point was estimated to be 95% (95% confidence interval, 91% to 99%) at twenty years. Sixty-seven (44%) of the threaded uncemented acetabular components were revised during the follow-up period. CONCLUSIONS: After a minimum duration of follow-up of fifteen years, the survival of this type of femoral component is excellent in individuals younger than fifty-five years. The main mode of stem failure was a periprosthetic fracture due to trauma, or late aseptic loosening in a small percentage of the hips in which the femoral implant was undersized. The high rate of failure of the acetabular components was attributable to a poor design that is no longer in use.

Good survival of uncemented tapered stems for failed intertrochanteric osteotomy: a mean 16 year follow-up study in 45 patients.

INTRODUCTION: Inferior survival of cemented total hip arthroplasty has been reported after previous femoral osteotomy. We previously presented 5-15 years results of uncemented femoral stems for this subgroup of patients. The purpose of the present study was to re-evaluate that same patient group at 10-20 years follow-up. MATERIALS AND METHODS: Forty-eight hips in 45 patients had undergone conversion THA for a failed intertrochanteric osteotomy of the hip after a mean of 12 years (2-33 years). Mean time of follow-up was 16 years (10-20 years). RESULTS: At the latest follow-up five patients had died (five hips), and one patient (one hip) remained lost to follow-up. Compared to the previous evaluation, one more patient required femoral revision for aseptic loosening giving a total of four patients (four hips) with femoral revision--one for infection and three for aseptic loosening of the stem. Survival of the stem was 91% at 15 and 20 years respectively; survival with femoral revision for aseptic loosening as an end point was 93%. The median Harris-Hip-Score at final follow-up was 76 points (previously 80 points). Radiolucent lines in Gruen zones 1 and 7 were present in 20 and 17% of hips, respectively. Radiolucencies in other zones were not detected. There was no radiographic evidence of femoral osteolysis, stress-shielding or loosening. CONCLUSION: The long-term results with this type of uncemented tapered titanium femoral component after proximal femoral osteotomy remain encouraging and compare favorably to those achieved in patients with regular femoral anatomy.