Enhancement of Subcutaneous Islet Transplant Performance by Collagen 1 Gel.

Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell-derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site.

Leveraging AI and patient metadata to develop a novel risk score for skin cancer detection.

Melanoma of the skin is the 17th most common cancer worldwide. Early detection of suspicious skin lesions (melanoma) can increase 5-year survival rates by 20%. The 7-point checklist (7PCL) has been extensively used to suggest urgent referrals for patients with a possible melanoma. However, the 7PCL method only considers seven meta-features to calculate a risk score and is only relevant for patients with suspected melanoma. There are limited studies on the extensive use of patient metadata for the detection of all skin cancer subtypes. This study investigates artificial intelligence (AI) models that utilise patient metadata consisting of 23 attributes for suspicious skin lesion detection. We have identified a new set of most important risk factors, namely "C4C risk factors", which is not just for melanoma, but for all types of skin cancer. The performance of the C4C risk factors for suspicious skin lesion detection is compared to that of the 7PCL and the Williams risk factors that predict the lifetime risk of melanoma. Our proposed AI framework ensembles five machine learning models and identifies seven new skin cancer risk factors: lesion pink, lesion size, lesion colour, lesion inflamed, lesion shape, lesion age, and natural hair colour, which achieved a sensitivity of 80.46 ± 2.50 % and a specificity of 62.09 ± 1.90 % in detecting suspicious skin lesions when evaluated using the metadata of 53,601 skin lesions collected from different skin cancer diagnostic clinics across the UK, significantly outperforming the 7PCL-based method (sensitivity 68.09 ± 2.10 % , specificity 61.07 ± 0.90 % ) and the Williams risk factors (sensitivity 66.32 ± 1.90 % , specificity 61.71 ± 0.6 % ). Furthermore, through weighting the seven new risk factors we came up with a new risk score, namely "C4C risk score", which alone achieved a sensitivity of 76.09 ± 1.20 % and a specificity of 61.71 ± 0.50 % , significantly outperforming the 7PCL-based risk score (sensitivity 73.91 ± 1.10 % , specificity 49.49 ± 0.50 % ) and the Williams risk score (sensitivity 60.68 ± 1.30 % , specificity 60.87 ± 0.80 % ). Finally, fusing the C4C risk factors with the 7PCL and Williams risk factors achieved the best performance, with a sensitivity of 85.24 ± 2.20 % and a specificity of 61.12 ± 0.90 % . We believe that fusing these newly found risk factors and new risk score with image data will further boost the AI model performance for suspicious skin lesion detection. Hence, the new set of skin cancer risk factors has the potential to be used to modify current skin cancer referral guidelines for all skin cancer subtypes, including melanoma.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSION: Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Non-inferiority Study Design: Application to Clinical Trials.

SUMMARY: Non-inferiority trials, a distinct category within randomized controlled trials, are garnering increased attention in medical research. Their unique and evolving role comes to the forefront in scenarios where new treatments, despite not surpassing the efficacy of an existing standard, bring additional benefits like reduced side effects, enhanced compliance, or cost savings. As the field of surgery witnesses a growing number of published non-inferiority trials, it becomes imperative for surgeons to grasp the intricacies of this trial type to accurately decipher and interpret their outcomes.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

An updated PREDICT breast cancer prognostic model including the benefits and harms of radiotherapy.

PREDICT Breast ( www.breast .predict.nhs.uk ) is a prognostication tool for early invasive breast cancer. The current version was based on cases diagnosed in 1999-2003 and did not incorporate the benefits of radiotherapy or the harms associated with therapy. Since then, there has been a substantial improvement in the outcomes for breast cancer cases. The aim of this study was to update PREDICT Breast to ensure that the underlying model is appropriate for contemporary patients. Data from the England National Cancer Registration and Advisory Service for invasive breast cancer cases diagnosed 2000-17 were used for model development and validation. Model development was based on 35,474 cases diagnosed and registered by the Eastern Cancer Registry. A Cox model was used to estimate the prognostic effects of the year of diagnosis, age at diagnosis, tumour size, tumour grade and number of positive nodes. Separate models were developed for ER-positive and ER-negative disease. Data on 32,408 cases from the West Midlands Cancer Registry and 100,551 cases from other cancer registries were used for validation. The new model was well-calibrated; predicted breast cancer deaths at 5-, 10- and 15-year were within 10 per cent of the observed validation data. Discrimination was also good: The AUC for 15-year breast cancer survival was 0.809 in the West Midlands data set and 0.846 in the data set for the other registries. The new PREDICT Breast model outperformed the current model and will be implemented in the online tool which should lead to more accurate absolute treatment benefit predictions for individual patients.

Association between adverse pregnancy outcome and placental biomarkers in the first trimester: A prospective cohort study.

OBJECTIVE: To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs). DESIGN: Prospective cohort study of nulliparous singleton pregnancy. SETTING: Cambridge, UK. POPULATION OR SAMPLE: 4056 pregnancy outcome prediction study participants. METHODS: The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross-validation. MAIN OUTCOME MEASURES: Pre-eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre-viable loss and stillbirth, plus combinations of outcomes. RESULTS: Lower values of PAPP-A, PlGF and sFlt-1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48-0.74], OR 0.56 [95% CI 0.44-0.70], OR 0.68 [95% CI 0.54-0.87] and OR 1.53 [95% CI 1.25-1.88]), severe SGA (OR 0.59 [95% CI 0.49-0.72], OR 0.71 [95% CI 0.57-0.87], OR 0.74 [95% CI 0.60-0.91] and OR 1.41 [95% CI 1.17-1.71]), sPTB (OR 0.61 [95% CI 0.50-0.73], OR 0.79 [95% CI 0.66-0.96], OR 0.57 [95% CI 0.47-0.70] and OR 1.41 [95% CI 1.18-1.67]) and iPTB (OR 0.72 [95% CI 0.57-0.91], OR 0.62 [95% CI 0.49-0.78], OR 0.71 [95% CI 0.56-0.90] and OR 1.44 [95% CI 1.16-1.78]), respectively. When combinations of biomarkers were assessed, PAPP-A and AFP were independently associated with severe SGA; PAPP-A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta-hCG, AFP and PAPP-A with the combination of PE and SGA; AFP and sFlt-1 with sPTB; and AFP and PlGF with iPTB. CONCLUSIONS: Combinations of first-trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways.

Developing a Pipeline of African Global Surgery Scholars.

Global surgery is developing as new discipline in many countries. Global surgery primarily aims to improve access to quality surgery in low-and-middle Income countries (LMICs). Thus, ensuring appropriate LMIC representation and leadership in global surgery research, projects, and innovations, is essential. There is a paucity of pathways for students and young clinicians in LMICs to attain training in and exposure to global surgery research and projects. If equity in global surgery leadership and scholarship is truly desired, steps need to be taken to ensure that more students and young clinicians in LMICs are exposed to global surgery as an academic discipline and are offered pathways to practice and leadership. This paper explores ways of ensuring this through increased exposure, increased training and increased funding.

Objective measures of smoking and caffeine intake and the risk of adverse pregnancy outcomes.

BACKGROUND: In pregnancy, women are encouraged to cease smoking and limit caffeine intake. We employed objective definitions of smoking and caffeine exposure to assess their association with adverse outcomes. METHODS: We conducted a case cohort study within the Pregnancy Outcome Prediction study to analyse maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age. Objective smoking status was defined based on detectable cotinine levels at each time point and objective caffeine exposure was based on tertiles of paraxanthine levels at each time point. We used logistic and linear regression to examine the association between cotinine, paraxanthine and the risk of pre-eclampsia, spontaneous pre-term birth (sPTB), fetal growth restriction (FGR), gestational diabetes mellitus and birthweight. RESULTS: There were 914 and 915 women in the smoking and caffeine analyses, respectively. Compared with no exposure to smoking, consistent exposure to smoking was associated with an increased risk of sPTB [adjusted odds ratio (aOR) = 2.58, 95% CI: 1.14 to 5.85)] and FGR (aOR = 4.07, 95% CI: 2.14 to 7.74) and lower birthweight (ß = -387 g, 95% CI: -622 g to -153 g). On univariate analysis, consistently high levels of paraxanthine were associated with an increased risk of FGR but that association attenuated when adjusting for maternal characteristics and objective-but not self-reported-smoking status. CONCLUSIONS: Based on objective data, consistent exposure to smoking throughout pregnancy was strongly associated with sPTB and FGR. High levels of paraxanthine were not independently associated with any of the studied outcomes and were confounded by smoking.

The effect of Dipeptidyl peptidase 4 (DPP-4) inhibitors on hemoglobin level in diabetic kidney disease: A retrospective cohort study.

Anemia typically develops early in the course of diabetic kidney disease (DKD). There are data to show that dipeptidyl-peptidase-4 (DPP-4) inhibitors affect hematopoietic growth factor activity and hemoglobin level. We retrospectively reviewed 443 DKD patients who were started on DDP-4 inhibitor therapy in 2019. Their hemoglobin level at baseline (6-12 months before treatment), pretreatment (0-6 months before treatment), and post-treatment periods (within 6 months after DPP-4 inhibitor), concomitant estimated glomerular filtration rate (eGFR), HbA1c, peripheral blood white cell and platelet counts were reviewed. The severity of kidney failure was classified according to the Kidney Disease: Improving Global Outcomes stages. The hemoglobin level had a small but significant decline from 11.98 ± 2.07 to 11.87 ± 2.12 g/dL from pretreatment to post-treatment period (paired Student t test, P < .0001). From the pre- to post-treatment period, the decline of hemoglobin level was 0.10 ± 0.89 g/dL, which was significantly less than that from baseline to pretreatment period (0.24 ± 0.90 g/dL, P = .0008). The change in hemoglobin level had a positive correlation with the change in HbA1c level (R = 0.218, P < .0001), but did not correlate with the type of DPP-4 inhibitor or pretreatment eGFR. There was no significant change in peripheral blood white cell or platelet count during the same period. DPP-4 inhibitor ameliorates hemoglobin decline in DKD. The effect of DPP-4 inhibitor on hemoglobin is statistically significant but clinically modest, and did not correlate with the concomitant change in kidney function.

Social Drivers of Mental Health: A U.S. Study Using Machine Learning.

INTRODUCTION: Social drivers of mental health can be compared on an aggregated level. This study employed a machine learning approach to identify and rank social drivers of mental health across census tracts in the U.S. METHODS: Data for 38,379 census tracts in the U.S. were collected from multiple sources in 2021. Two measures of mental health problems-self-reported depression and self-assessed poor mental health-among adults and three domains of social drivers (behavioral, environmental, and social) were analyzed on the basis of the unit of census tracts using the Extreme Gradient Boosting machine learning approach in 2022. The leading social drivers were found in each domain in the main sample and in the subsamples divided on the basis of poverty and racial segregation. RESULTS: The three domains combined explained more than 90% of the variance of both mental illness indicators. Self-reported depression and self-assessed poor mental health differed in major social drivers. The two outcome indicators had one overlapping correlate from the behavioral domain: smoking. Other than smoking, climate zone and racial composition were the leading correlates from the environmental and social domains, respectively. Census tract characteristics moderated the impacts of social drivers on mental health problems; the major social drivers differed by census tract poverty and racial segregation. CONCLUSIONS: Population mental health is highly contextualized. Better interventions can be developed on the basis of census tract-level analyses of social drivers that characterize the upstream causes of mental health problems.

Long-term health and human capital effects of in utero exposure to an industrial disaster: a spatial difference-in-differences analysis of the Bhopal gas tragedy.

OBJECTIVES: Globalisation and industrialisation can increase economic opportunity for low/middle-income nations, but these processes may also increase industrial accidents and harm workers. This paper examines the long-term, cohort-based health effects of the Bhopal gas disaster (BGD), one of the most serious industrial accidents in history. DESIGN: This retrospective analysis uses geolocated data on health and education from India's National Family Health Survey-4 (NFHS-4) and the 1999 Indian Socio-Economic Survey by the National Sample Survey Organization (NSSO-1999) to examine the health effects of exposure to the BGD among men and women aged 15-49 years living in Madhya Pradesh in 2015-2016 (women n=40 786; men n=7031 (NFHS-4) and n=13 369 (NSSO-1999)), as well as their children (n=1260). A spatial difference-in-differences strategy estimated the relative effect of being in utero near Bhopal relative to other cohorts and to those further from Bhopal separately for each dataset. RESULTS: We document long-term, intergenerational impacts of the BGD, showing that men who were in utero at the time were more likely to have a disability that affected their employment 15 years later, and had higher rates of cancer and lower educational attainment over 30 years later. Changes in the sex ratio among children born in 1985 suggest an effect of the BGD up to 100 km from the accident. CONCLUSIONS: These results indicate social costs stemming from the BGD that extend far beyond the mortality and morbidity experienced in the immediate aftermath. Quantifying these multigenerational impacts is important for policy consideration. Moreover, our results suggest that the BGD affected people across a substantially more widespread area than has previously been demonstrated.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

Maternal hemoglobin levels and adverse pregnancy outcomes: individual patient data analysis from 2 prospective UK pregnancy cohorts.

BACKGROUND: Hemoglobin (Hb) is a modifiable risk factor for adverse pregnancy outcomes. Studies have reported conflicting associations between maternal Hb levels and adverse pregnancy outcomes, including preterm birth (PTB), low birth weight (LBW), and perinatal mortality. OBJECTIVE: In this study, we aimed to estimate the shape and magnitude of associations between maternal Hb levels in early (7-12 wk gestation) and late pregnancy (27-32 wk gestation) and pregnancy outcomes in a high-income setting. METHODS: We used data from 2 UK population-based pregnancy cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and Pregnancy Outcome Prediction Study (POPS). We used multivariable logistic regression models to examine the relationship between Hb and pregnancy outcomes, adjusting for maternal age, ethnicity, BMI, smoking status, and parity. Main outcome measures were PTB, LBW, small for gestational age (SGA), pre-eclampsia (PET), and gestational diabetes mellitus (GDM). RESULTS: Mean Hb in ALSPAC were 12.5 g/dL (SD = 0.90) and 11.2 g/dL (SD = 0.92) in early and late pregnancy, respectively, and 12.7 g/dL (SD = 0.82) and 11.4 g/dL (SD = 0.82) in POPS. In the pooled analysis, there was no evidence of associations between a higher Hb in early pregnancy (7-12 wk gestation) and PTB (OR per 1 g/dL of Hb: 1.09; 95% CI: 0.97, 1.22), LBW (1.12: 0.99, 1.26), and SGA (1.06; 0.97, 1.15). Higher Hb in late pregnancy (27-32 wk gestation) was associated with PTB (1.45: 1.30, 1.62), LBW (1.77: 1.57, 2.01), and SGA (1.45: 1.33, 1.58). Higher Hb in early and late pregnancy was associated with PET in ALSPAC (1.36: 1.12, 1.64) and (1.53: 1.29, 1.82), respectively, but not in POPS (1.17:0.99, 1.37) and (1.03: 0.86, 1.23). There was an association with a higher Hb and GDM in ALSPAC in both early and late pregnancy [(1.51: 1.08, 2.11) and (1.35: 1.01, 1.79), respectively], but not in POPS [(0.98: 0.81, 1.19) and (0.83: 0.68, 1.02)]. CONCLUSIONS: Higher maternal Hb may identify the risk of adverse pregnancy outcomes. Further research is required to investigate if this association is causal and to identify the underlying mechanisms.

Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function.

Human trophoblast cultures provide powerful tools to model key processes of placental development. In vitro trophoblast studies to date have relied on commercial media that contains nonphysiological levels of nutrients, and the impact of these conditions on trophoblast metabolism and function is unknown. Here, we show that the physiological medium (Plasmax) with nutrient and metabolite concentrations recapitulating human plasma improves human trophoblast stem cell (hTSC) proliferation and differentiation compared with standard medium (DMEM-F12). hTSCs cultured in Plasmax-based medium also show altered glycolytic and mitochondrial metabolism, as well as reduced S-adenosylmethionine/S-adenosyl-homocysteine ratio compared with DMEM-F12-based medium. These findings demonstrate the importance of the nutritional environment for phenotyping cultured human trophoblasts.

A novel surgical treatment of type 3 congenital elbow luxation in a dog.

Congenital luxation of the ulnar and radius is a rare orthopaedic condition in the dog. This case report describes a novel surgical treatment for congenital elbow luxation in a medium-breed dog. A 6-week-old Kelpie presented for left forelimb lameness and deformity. Radiographs and computed tomography (CT) confirmed the diagnosis of unilateral ulnar and radius luxation. The surgical repair involved open reduction followed by fixation with an extraarticular pin and a transarticular external fixator. The outcome of surgery was improved leg function and weight-bearing, however, reluxation of the radial head was diagnosed 7 weeks following surgery. This technique may offer an alternative surgical option to improve clinical signs, as well as insight into improving the management of this condition.

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial.

PURPOSE: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. PATIENTS AND METHODS: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. RESULTS: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. CONCLUSIONS: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious. See related commentary by Gonzalez-Ochoa and Oza, p. 2563.

Is Reflex Germline BRCA1/2 Testing Necessary in Women Diagnosed with Non-Mucinous High-Grade Epithelial Ovarian Cancer Aged 80 Years or Older?

Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad's myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs.

Maternal serum levels of soluble fms-like tyrosine kinase-1 and placental growth factor at 20 and 28 weeks of gestational age and the risk of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear. OBJECTIVE: This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks' gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth. STUDY DESIGN: The biomarkers were measured in maternal serum at 20- and 28-weeks' gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks' gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification. RESULTS: Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks' gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61-0.92]; P=.006 and 0.71 [0.59-0.87]; P=.0009, respectively). At 28 weeks' gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks' gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13-1.63]; P=.001) and the soluble fms-like tyrosine kinase-1:placental growth factor ratio (1.50 [1.30-1.73]; P<.0001), and a strong negative association with the rate of increase in placental growth factor (0.71 [0.61-0.82]; P<.0001). Women who were in the highest decile of increase in the soluble fms-like tyrosine kinase-1:placental growth factor ratio and the lowest decile of femur length growth between 20 and 28 weeks' gestation had approximately 9-fold risk of spontaneous preterm birth (9.27 [4.21-20.37]; P<.0001). Competing-risks regression yielded similar results. CONCLUSION: Changing levels of soluble fms-like tyrosine kinase-1 and placental growth factor are indicative of placental dysfunction and are strongly associated with the risk of spontaneous preterm birth, especially when combined with slower fetal femur length growth.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction.

BACKGROUND: Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR. METHODS: We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls. RESULTS: The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81). CONCLUSIONS: We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.