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.

A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer.

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Synthetic Apparent Diffusion Coefficient for High b-Value Diffusion-Weighted MRI in Prostate.

PURPOSE: It has been reported that diffusion-weighted imaging (DWI) with ultrahigh b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher Materials and Methods. Fifteen patients (7 malignant and 8 benign) were included in this study retrospectively with the institutional ethical committee approval. All images were acquired at a 3T MR scanner. The ADC values were calculated using a monoexponential model. Synthetic ADC (sADC) for higher b-value increases the diagnostic power of prostate cancer. DWI with higher. RESULTS: No significant difference was observed between actual ADC and sADC for b-value increases the diagnostic power of prostate cancer. DWI with higher p=0.002, paired t-test) in sDWI as compared to DWI. Malignant lesions showed significantly lower sADC as compared to benign lesions (p=0.002, paired t-test) in sDWI as compared to DWI. Malignant lesions showed significantly lower sADC as compared to benign lesions (Discussion/. CONCLUSION: Our initial investigation suggests that the ADC values corresponding to higher b-value can be computed using log-linear relationship derived from lower b-values (b ≤ 1000). Our method might help clinicians to decide the optimal b-value for prostate lesion identification.b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher b-value increases the diagnostic power of prostate cancer. DWI with higher.

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.

Focal therapy using magnetic resonance image-guided focused ultrasound in patients with localized prostate cancer.

BACKGROUND: The purpose of this study is to evaluate and report the feasibility, safety, and initial outcomes of patients with limited localized prostate cancer treated using a trans-rectal magnetic resonance image-guided focused ultrasound (MRGFUS) device. Attempts to focally treat only the index lesion for prostate cancer have been explored to reduce side effects while maintaining oncologic control. MRGFUS allows for precise targeting of thermal ablative therapy with real-time thermometry. METHODS: Three patients underwent multiparametric 3T MRI and TRUS-guided 16-sector mapping biopsies of the prostate. The patients were eligible if they had Gleason 6 or 7 (3 + 4) disease, no MRI-visible tumor ≥15 mm, no extracapsular extension, and no more than two discrete cancerous lesions ≤10 mm in length. Acoustic power was adjusted to achieve temperatures of 65 to 85 °C. RESULTS: Age ranged from 60 to 64 years. The number of biopsy-positive sectors treated ranged from 2 to 4. Post therapy, 16-sector biopsies at 6 months were negative in two patients with one patient still with Gleason 6 cancer (10 %, 2 mm) in one core. 16-sector biopsy in the first patient remains negative at 24 months. PSA continues to remain stable in all patients. IPSS in all patients either remained stable or decreased then stabilized. Erectile function according to the International Index of Erectile Function (IIEF) was excellent for all patients and demonstrated no decline up to the time of last follow-up at 12-24 months. CONCLUSIONS: MRGFUS is a feasible alternative for focal therapy in a select subset of patients with prostate cancer. The treatment is well tolerated with no evidence of decline in functional outcomes. Initial post-therapy biopsy results are promising. Long-term treatment efficacy requires further study.

Intracerebral mass lesion diagnosed as cryptococcoma in a patient with sarcoidosis, a rare opportunistic manifestation induced by immunosuppression with corticosteroids.

Cryptococcal infection of the central nervous system (CNS) typically affects patients with HIV infection. In addition, opportunistic infections can also occur during immunosuppressive therapies. Some patients develop cryptococcal meningitis. Cryptococcomas, however, are rarely observed. A 42-year-old patient with sarcoidosis known for 2½ years presented with a cerebral mass lesion primarily thought to be CNS sarcoidosis. Stereotactic biopsy and extensive micro- and macrobiological investigations revealed a cryptococcoma which had emerged from cryptococcal meningitis despite 3 months of treatment. Differential diagnosis of cerebral cryptococcoma is difficult due to the unspecific findings in the CSF analysis if C. neoformans fails to be detected using Indian ink staining or PCR studies. In this case, stereotactic biopsy and pathohistological examination revealed C. neoformans causing intracerebral mass lesion. Intensive treatment with antifungal drugs was followed by remission of all symptoms. In conclusion, cryptococcoma of the CNS represents a very important indication of mass lesions in patients suffering from sarcoidosis and treated with corticosteroids.

Ultrasound-guided fine needle aspiration of major salivary gland masses and adjacent lymph nodes.

Ultrasound has an established role in the detection of masses in the major salivary glands and potentially malignant adjacent lymph nodes. Because there is overlap in their sonographic features, tissue diagnosis plays an important role in management. This review assesses ultrasound-guided fine needle aspiration biopsy as a diagnostic tool in the characterization of these lesions. The literature, and the authors' experience, suggests that ultrasound-guided fine needle aspiration is a safe and accurate technique, with definable implications for management, when performed in conjunction with cytopathologic expertise.

US-guided fine-needle aspiration of major salivary gland masses and adjacent lymph nodes: accuracy and impact on clinical decision making.

PURPOSE: To determine whether ultrasonography (US)-guided fine-needle aspiration (FNA) is an effective technique for diagnosing masses in the salivary gland and adjacent lymph nodes. MATERIALS AND METHODS: The institutional review board waived the requirement to obtain informed consent and approved this HIPAA-compliant retrospective study. Radiology records of 50 patients (28 female patients aged 25-85 years [median age, 58 years], 22 male patients aged 11-82 years [median age, 62 years]) who underwent 52 consecutive US-guided FNA procedures from 2004 to 2009 were reviewed. In 46 cases, lesions were sampled for biopsy under real-time US guidance by means of three passes with a 25-gauge needle. In six cases, two subsequent passes were performed with a 22-gauge needle after the first pass showed minimal or no aspirate. Findings from cytopathologic analysis, clinical follow-up, and surgery were evaluated and compared. RESULTS: A diagnostically adequate biopsy specimen was obtained in 48 of the 52 cases (92%). Among the 20 patients who underwent surgical intervention after diagnostic US-guided FNA findings, results of surgical-pathologic analysis helped confirm the cytologic diagnosis in 19 (95%). Twenty of the 50 patients (40%) were spared surgical intervention on the basis of findings from US-guided FNA. US-guided FNA did not result in any intra- or postprocedural complications. CONCLUSION: The diagnostic accuracy of US-guided FNA is similar to that of core needle biopsy, and there were no complications in this study. Information yielded with FNA cytology plays an integral role in clinical decision making in the management of masses in the major salivary glands and adjacent structures.

A stature-specific concept for uncemented, primary total hip arthroplasty.

BACKGROUND AND PURPOSE: Variations in hip anatomy limit the femoral canal fit of standard uncemented hip stems. In addition, there are still issues with leg length discrepancy and offset reconstruction, potentially resulting in impingement, dislocation, and wear. Modular stems with different shapes for femoral canal fit and multiple neck options may improve the outcome and reduce complications. PATIENTS AND METHODS: 173 patients (190 hips) received an uncemented THA with 1 of 2 different stem shapes for canal fit and a modular neck for stature-specific hip reconstruction. Median follow-up time was 9 (7-13) years. During the follow-up period, 20 patients died (22 hips) and 12 patients (13 hips) were lost to follow-up. 155 hips were available for evaluation, including clinical and radiological outcome. RESULTS: 1 stem was revised for a periprosthetic fracture following trauma; 10 cups and 2 modular necks were revised (1 for breakage and 1 during cup revision). At 10 years, stem survival was 100%, modular neck survival was 99% (CI: 95-100), and cup survival was 94% (CI: 87-97). No leg length discrepancies were measured in 96% of cases. Offset with anatomic lateralization was achieved in 98%. Median Harris hip score was 94 (47-100) and median Merle d'Aubigné score was 16 (10-18). Relevant radiolucent lines and osteolysis were not found. INTERPRETATION: The uncemented modular neck, dual-stem system used in this series allows accurate reconstruction of the joint by adapting the implant to the needs of the patient. This may improve the outcome of primary THA, which is supported by the results of this medium-term follow-up evaluation.

Interaction of Inhibitor of DNA binding 3 (Id3) with Gut-enriched Krüppel-like factor (GKLF) and p53 regulates proliferation of vascular smooth muscle cells.

Enhanced proliferation of vascular smooth muscle cells (VSMCs) is one of the key features of the pathogenesis of atherosclerosis. The helix-loop-helix protein Inhibitor of DNA binding 3 (Id3) contributes to regulation of VSMC proliferation in a redox-sensitive manner. We investigated the role of Id3 and its interaction with other redox-sensitive genes, the transcription factor Gut-enriched Krüppel-like factor (GKLF, KLF4) and the tumor suppressor gene p53 in the regulation of VSMC proliferation. Cultured rat aortic VSMCs were transfected with Id3 sense and antisense constructs. Overexpression of Id3 significantly enhanced VSMC proliferation. Id3 antisense transfection inhibited VSMC proliferation induced by the physiological stimuli insulin and platelet-derived growth factor (PDGF). Because p53 is essential for the regulation of proliferation processes, the effect of Id3 on p53 expression was investigated. Id3 overexpression led to decreased p53 protein expression. Co-transfection of p53 sense constructs inhibited the enhanced VSMC mitogenicity induced by Id3 sense transfection. GKLF overexpression, which causes growth arrest in VSMCs, reduced Id3 promoter activity and led to decreased Id3 expression. Id3-induced VSMC proliferation was abolished by GKLF sense co-transfection. Finally, strong Id3 expression was found in the neointima of human coronary artery atherosclerotic plaques but not in healthy coronary arteries. These findings reveal a relevant interaction of GKLF, Id3, and p53 for VSMC proliferation which might constitute a general mechanism of growth control in vascular cells.

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.

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.

Induction of p53 by GKLF is essential for inhibition of proliferation of vascular smooth muscle cells.

Proliferation of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and restenosis. Recent studies have demonstrated that the transcription factor gut-enriched Krüppel-like factor (GKLF, KLF4) is involved in redox-sensitive growth arrest of VSMC. We investigated the role of GKLF in VSMC proliferation and differentiation and the potentially important interaction with the tumor suppressor gene p53. Cultured rat aortic VSMC were transfected with GKLF sense and antisense constructs by electroporation. GKLF enhanced the mRNA expression of the differentiation marker SM22-alpha, but had no effect on the expression of alpha-smooth muscle actin (real-time RT-PCR, Western blot). Overexpression of GKLF significantly reduced VSMC proliferation (cell count, BrdU FACS analysis). Because p53 is essential for proliferation processes, the effect of GKLF on p53 gene expression was investigated. GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression (luciferase reporter assay, real-time PCR, Western blot). Consistently, GKLF overexpression induced an enhanced expression of the p53 target genes p21(WAF1/Cip1) and Mdm2. Co-transfection experiments revealed that the growth arrest induced by GKLF sense transfection was completely abolished by co-transfection of p53 antisense constructs, whereas the reduced proliferation exerted by p53 sense transfection was not inhibited by GKLF antisense transfection, suggesting that p53 induction is essential for the interference of GKLF with VSMC proliferation. Finally, stimulation of VSMC with hydroxyl radicals increased expression of GKLF and p53 and reduced cell proliferation. The transcription factor GKLF induces inhibition of proliferation of VSMC which is mechanistically linked to a GKLF-induced enhancement of the expression of the tumor suppressor gene p53.

Quantitative PCR based expression analysis on a nanoliter scale using polymer nano-well chips.

The analysis of gene expression is an essential element of functional genomics. Expression analysis is mainly based on DNA microarrays due to highly parallel readout and high throughput. Quantitative PCR (qPCR) based expression profiling is the gold standard for the precise monitoring of selected genes, and therefore used for validation of microarray data. Doing qPCR-based expression analysis in an array-like format can combine the higher sensitivity and accuracy of the qPCR methodology with a high data density at relatively low costs. This paper describes the development of an open-well based miniaturized platform for liquid PCR-based assays on the nanoliter scale using cost-effective polypropylene micro reactors (microPCR Chip). We show the quantification ability and reliability of qPCR in 200 nl with the microPCR chip down to 5 starting target molecules using TaqMan chemistry. An RNA expression analysis of four genes in mouse brain, liver and kidney tissues showed similar results in 200 nl as compared to standard 10 microl assays. The high sensitivity and quantification capability of the microPCR chip platform developed herein makes it a promising technology for performing high-throughput qPCR-based analysis in the nanoliter volume range.