Augmentation of Meniscal Repair With Platelet-Rich Plasma: A Systematic Review of Comparative Studies.

BACKGROUND: The effect of platelet-rich plasma (PRP) augmentation for meniscal repair (MR) is unclear, as current evidence is limited to small, mostly nonrandomized studies. PURPOSE: To systematically review the literature to evaluate the efficacy and safety of MR with PRP augmentation. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify studies (level of evidence 1-3) that compared the clinical efficacy of MR performed with versus without PRP. The search phrase used was platelet-rich plasma meniscus. Patients were assessed based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the visual analog scale (VAS) for pain, the Lysholm score, the Knee injury and Osteoarthritis Outcome Score (KOOS), the subjective International Knee Documentation Committee (IKDC) score, and treatment failure. RESULTS: We identified 6 studies (2 studies with level 1 evidence; 4 studies with level 3 evidence) that met inclusion criteria, for a total of 309 patients undergoing MR with PRP (mean age, 31.9 years) and 445 patients without PRP augmentation (mean age, 29.6 years). The mean follow-up was 32.8 months (range, 12-72 months). Overall, 17.0% of PRP patients experienced MR failure compared with 22.1% of non-PRP patients. No differences in VAS, Lysholm, or subjective IKDC scores were found between groups except in 1 study, in which postoperative subjective IKDC scores were significantly better in the PRP group (P < .01). Another study found significantly better postoperative WOMAC scores among PRP patients, and 2 studies found significantly better KOOS subscores among PRP patients. CONCLUSION: There are a limited number of high-quality studies comparing outcomes and healing rates between patients undergoing MR with versus without PRP augmentation. Based on the available evidence, patients undergoing MR with PRP augmentation experience similar clinical outcomes at midterm follow-up when compared with conventional MR, and additional studies are needed to determine the efficacy of MR augmented with PRP.

Lynch syndrome screening in gynaecological cancers: results of an international survey with recommendations for uniform reporting terminology for mismatch repair immunohistochemistry results.

AIMS: Lynch syndrome (LS) is associated with an increased risk of developing endometrial carcinoma (EC) and ovarian carcinoma (OC). There is considerable variability in current practices and opinions related to screening of newly diagnosed patients with EC/OC for LS. An online survey was undertaken to explore the extent of these differences. METHODS AND RESULTS: An online questionnaire was developed by a panel of experts and sent to all members of the British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP). Anonymised results were received and analysed. Thirty-six BAGP and 44 ISGyP members completed the survey. More than 90% of respondents were aware of the association of LS with both EC and OC, but 34% were not aware of specific guidelines for LS screening. Seventy-one per cent of respondents agreed that universal screening for LS should be carried out in all newly diagnosed EC cases, with immunohistochemistry (IHC) alone as the preferred approach. Only 36% of respondents currently performed IHC or microsatellite instability testing on all newly diagnosed EC cases, with most of the remaining respondents practising selective screening, based on clinical or pathological features or both. A significant minority of respondents (35%) believed that patient consent was required before performance of mismatch repair (MMR) protein IHC. Almost all respondents favoured the use of standardised terminology for reporting MMR protein staining results, and this is proposed herein. CONCLUSION: There is wide support for universal LS screening in patients with EC, but this survey highlights areas of considerable variation in practice.

Conservative management of CIN2: National Audit of British Society for Colposcopy and Cervical Pathology members' opinion.

There is no doubt that organised cervical screening programmes have significantly reduced the rates of cervical cancer by detection and treatment of high-grade cervical intraepithelial neoplasia (CIN2, CIN3). National UK guidelines do not differentiate between CIN2 and CIN3 as separate entities and recommend treatment for both, although a degree of uncertainty exists regarding the natural history of CIN2. This national survey of British Society for Colposcopy and Cervical Pathology members aimed to assess attitudes towards conservative management (CM) of CIN2 in the UK and identify potential selection criteria. In total, 511 members responded (response rate 32%); 55.6% offered CM for selective cases; 12.4% for all cases; 16.4% had formal guidelines. Most agreed age group was >40yrs (83%), HPV 16/18 positive (51.4%), smoking (60%), immuno-compromise (74.2%), and large lesion size (80.8%) were relative contraindications for CM. 75.9% favoured six-monthly monitoring, with 80.2% preferring excisional treatment for persistent high-grade disease. Many UK colposcopists manage CIN2 conservatively without formal guidelines. Potential selection criteria should be investigated by a multicentre study. Impact statement Although anecdotally some colposcopists manage many women with CIN2 conservatively, this National Audit of British Society for Colposcopy and Cytopathology members, we believe, is the first time this has been formally recorded. The survey assesses current attitudes towards conservative management (CM) of CIN2 and seeks to identify potential selection criteria that could be used to identify suitable women. It received over 500 responses and significantly, identified many colposcopists recommending CM of CIN2 for patients despite the lack of any formal guidance regarding this approach. The greater majority of respondents were keen to consider participating in a multicentre trial on CM of CIN2 targeting the UK screening population (25-64 years). The paper has international relevance as ACOG and ASCCP have recently changed their guidance for the management of CIN2 in younger women and now recommend CM with monitoring rather than first line ablative or excisional treatment due to concerns regarding overtreatment, especially in women who have not yet completed their family.

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.

Endometrial Adenocarcinoma in SurePath™ Cervical Samples: Cytological Features Revisited.

OBJECTIVE: The cytomorphological criteria of malignant endometrial lesions in cervical samples are less well described than those of cervical lesions. We wished to investigate if there were features in SurePath™ liquid-based cytology samples that would facilitate more accurate differentiation between benign and malignant endometrial cells. STUDY DESIGN: This was a two-phase study, with a review of all SurePath™ samples reported as endometrial adenocarcinoma (n = 42) evaluating 12 cytological features in the first phase. In phase 2 (test set), all initial cases plus an additional 83 cases were reviewed using these 12 cytological features to predict the outcome. RESULTS: Out of 12 cytological features evaluated in phase 1 (training set), nuclear chromatin pattern, apoptotic bodies and tingible body macrophages were found to be the most significant features determining malignant histological outcome. These 12 cytological features were re-evaluated in phase 2 (n = 125). Of 125 cases, 54 had a benign and 71 had a malignant or premalignant histological outcome, with a positive predictive value of 56.8%. CONCLUSION: Granular nuclear chromatin, tingible body macrophages and apoptosis in the background are the most significant factors in determining whether endometrial cells present in cervical samples represent malignancy or are benign. Using these features, relatively accurate predictions of endometrial pathology can be made.

A study of cellular counting to determine minimum thresholds for adequacy for liquid-based cervical cytology using a survey and counting protocol.

BACKGROUND: Liquid-based cytology (LBC) for cervical screening would benefit from laboratory practice guidelines that define specimen adequacy for reporting of slides. The evidence base required to define cell adequacy should incorporate both ThinPrep™ (TP; Hologic, Inc., Bedford, MA, USA) and SurePath™ (SP; BD Diagnostics, Burlington, NC, USA), the two LBC systems used in the UK cervical screening programmes. OBJECTIVES: The objectives of this study were to determine (1) current practice for reporting LBC in England, Wales and Scotland, (2) a reproducible method for cell counting, (3) the cellularity of slides classified as inadequate, negative or abnormal and (4) the impact of varying cellularity on the likelihood of detecting cytological abnormalities. DESIGN: The study involved four separate arms to pursue each of the four objectives. (1) A questionnaire survey of laboratories was conducted. (2) A standard counting protocol was developed and used by three experienced cytopathologists to determine a reliable and reproducible cell counting method. (3) Slide sets which included a range of cytological abnormalities were each sent to three laboratories for cell counting to study the correlation between cell counts and reported cytological outcomes. (4) Dilution of LBC samples by fluid only (unmixed) or by dilution with a sample containing normal cells (mixed) was performed to study the impact on reporting of reducing either the total cell count or the relative proportion of abnormal to normal cells. SETTING: The study was conducted within the cervical screening programmes in England, Wales and Scotland, using routinely obtained cervical screening samples, and in 56 participating NHS cervical cytology laboratories. PARTICIPANTS: The study involved only routinely obtained cervical screening samples. INTERVENTIONS: There was no clinical intervention. MAIN OUTCOME MEASURES: The main outcome measures were (1) reliability of counting method, (2) correlation of reported cytology grades with cellularity and (3) levels of detection of abnormal cells in progressively diluted cervical samples. RESULTS: Laboratory practice varied in terms of threshold of cellular adequacy and of morphological markers of adequacy. While SP laboratories generally used a minimum acceptable cell count (MACC) of 15,000, the MACC employed by TP laboratories varied between 5000 and 15,000. The cell counting study showed that a standard protocol achieved moderate to strong inter-rater reproducibility. Analysis of slide reporting from laboratories revealed that a large proportion of the samples reported as inadequate had cell counts above a threshold of 15,000 for SP, and 5000 and 10,000 for TP. Inter-rater unanimity was greater among more cellular preparations. Dilution studies demonstrated greater detection of abnormalities in slides with counts above the MACC and among slides with more than 25 dyskaryotic cells. CONCLUSIONS: Variation in laboratory practice demonstrates a requirement for evidence-based standards for designating a MACC. This study has indicated that a MACC of 15,000 and 5000 for SP and TP, respectively, achieves a balance in terms of maintaining sensitivity and low inadequacy rates. FUTURE WORK: The findings of this study should inform the development of laboratory practice guidelines. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Adult granulosa cell tumour-like areas occurring in ovarian epithelial neoplasms: report of a case series with investigation of FOXL2 mutation status.

AIMS: To look for FOXL2 mutation in rare ovarian epithelial lesions showing stromal components with morphological features of adult granulosa cell tumour (AGCT). METHODS AND RESULTS: We report the 402C→G FOXL2 mutation status in five epithelial ovarian lesions in women aged 45-77 years showing stromal proliferations that were morphologically indistinguishable from AGCT. The lesions were mucinous cystadenoma, mixed epithelial cystadenoma, endometriotic cyst, mucinous borderline tumour (intestinal type), and mucinous carcinoma. In one case, the AGCT component formed a discrete nodule, and in the others it was distributed within the septa and cyst walls. FOXL2 mutation was present in two cases and absent in three cases. One mutation-positive case showed an AGCT nodule abutting a mucinous borderline tumour, interpreted as a collision tumour. The other positive case had an AGCT component within the septa of a mucinous carcinoma, and both components are likely to be neoplastic. In the three cases without FOXL2 mutation, the stromal component most likely represents a non-neoplastic AGCT-like proliferation. CONCLUSIONS: Areas typical of AGCT are rarely associated with epithelial ovarian lesions. These are heterogeneous and likely to be truly neoplastic in only a subset of cases. FOXL2 mutation testing may be useful in confirming a true neoplastic AGCT component.

Cytology, liquid-based cytology and automation.

Quality-assured, comprehensive, cytology-based population screening programmes have resulted in a substantial decline in the incidence of, and mortality from, cervical cancer. Cytology classification systems divide squamous cell abnormalities into low grade and high grade. Women with high-grade squamous abnormalities, cytology suggestive of glandular neoplasia, or invasive disease are referred immediately for investigation. Previously, the optimal management of women with low-grade cytology was uncertain. The introduction of liquid-based cytology has improved specimen adequacy and laboratory productivity, and also provided the platform for human papillomavirus testing for triage of low-grade abnormality, follow up after treatment and, ultimately, primary screening with triage to cytology, particularly in HPV-vaccinated populations. Liquid-based cytology is also ideal for automation-assisted reading of cervical cytology samples; however, recent studies have reported that automation-assisted reading is less sensitive than manual reading and does not reduce the risk of cervical cancer.

Reactive fibroblastic and myofibroblastic proliferation of the vulva (Cyclist's Nodule): A hitherto poorly described vulval lesion occurring in cyclists.

Perineal nodules occurring in male cyclists are reported in the literature, although the histologic features are not extensively documented. There has been little description of similar lesions in the female population. We describe 4 cases in which a vulval nodule or swelling developed in competitive female cyclists aged 15 to 45 years. The lesions were unilateral and occurred on the right or left labium majus (2 cases each). The histologic features were similar in all cases and consisted of a haphazard admixture of adipose tissue, variably cellular hyalinized tissue containing bland spindle-shaped fibroblasts, blood vessels, and nerve fibers. In some areas, thick cords of fibrous tissue imparted a keloid-like appearance. Other histologic features included plump mesenchymal cells with round or ovoid nuclei and abundant eosinophilic cytoplasm resulting in an epithelioid, plasmacytoid, or ganglion-like appearance (2 cases), a lymphocytic infiltrate around blood vessels (3 cases), foci of fat necrosis (1 case), and collections of elastic fibers (2 cases). One case recurred, the histologic features of the recurrent lesion being identical to the original. The overall morphologic appearances, especially in the cases with plump mesenchymal cells, bore some resemblance to proliferative fasciitis. Immunohistochemically, the cells were estrogen receptor positive and the plump mesenchymal cells were smooth muscle actin positive, in keeping with myofibroblasts. Desmin, S100, CD34, and HMGA2 were negative. Pathologists should be aware of this pseudoneoplastic lesion occurring on the vulva, which arises in a specific clinical setting and has the potential to be misdiagnosed as a variety of other mesenchymal lesions. We term this lesion as reactive fibroblastic and myofibroblastic proliferation of the vulva or "cyclist's nodule."