Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer

ObjectiveIn the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline.MethodsFrom the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016–1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS.ResultsIn 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles.ConclusionCoverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.     

Immunoblot and Polymerase Chain Reaction to Diagnose Ocular Syphilis and Neurosyphilis in HIV-positive and HIV-negative Patients

ABSTRACT

Purpose: To evaluate immunoblot (IB) and polymerase chain reaction (PCR) to diagnose ocular- and neurosyphilis.

Methods: Prospective cross-sectional study. Aqueous humor (AH) and cerebrospinal fluid (CSF) samples were tested for treponemal DNA or antibodies to treponemal antigens.

Results: Thirteen of 106 cases had positive syphilis serology of which 69.2% were HIV+ (median CD4+ = 181 cells/µL). Four cases met CDC criteria for neurosyphilis (3 confirmed, 1 probable) and 2 additional cases required neurosyphilis treatment according to UpToDate algorithms. All AH and CSF samples tested PCR negative. Five cases were CSF IB+ and 3 cases AH IB+. Using our classification, eight patients had confirmed neurosyphilis, one had probable neurosyphilis, three had confirmed ocular syphilis and nine had probable ocular syphilis.

Conclusion: Our findings suggest that IB of AH and CSF provides additional evidence to diagnose ocular and neurosyphilis and allows us to classify them as probable or confirmed.     

Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as ‘multiple-classifier’ ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

E-scooter injuries referred to the oral and maxillofacial surgical service at Christchurch Hospital: a retrospective observational study and cost analysis of 17-months of data

Personal and shared stand-up electronic scooters (e-scooters) have rapidly increased in popularity, leading to an increase in the number of patients with e-scooter-related trauma presenting to hospital Emergency departments. This study aimed to assess the patterns of oral and maxillofacial trauma directly related to e-scooter use and provide a cost-analysis related to the management of these patients. A retrospective, controlled interval study was conducted to examine all patients referred to the oral and maxillofacial surgical service at Christchurch Hospital, New Zealand, who sustained facial injury as a result of e-scooter accidents between 15 October 2018 and 15 April 2020. A total of 30 patients with e-scooter-related facial injuries were referred to the maxillofacial service and required a total of 23 operative procedures. The majority of patients (70%) were aged between 20-39 years and 63.3% were male. Two-thirds reported having consumed alcohol before the e-scooter accident. The total estimated cost for the treatment of patients was $298,054 NZD. E-scooter-related maxillofacial trauma represents an emerging mechanism of injury that is associated with significant facial trauma and results in a treatment cost that adds significant burden on the health care system.     

HIV Prevention Among Young Women in South Africa: Understanding Multiple Layers of Risk

Despite concerted prevention efforts, young South African women remain at the epicenter of the HIV epidemic. Although these women have grown up in a community powerfully affected by HIV, systematic investigation into how this “second generation” of HIV-affected youth navigates HIV risk is lacking. This study qualitatively explored a complex interplay of factors influencing HIV risk among young pregnant women in KwaZulu-Natal, South Africa. We conducted in-depth interviews with 35 pregnant women (22 HIV-uninfected and 13 HIV-infected) aged 18–21, 18 healthcare providers, and focus groups with 19 community stakeholders. Among the young women, HIV knowledge was high, and many reported taking some action to prevent pregnancy or HIV; however, these efforts were not routinely implemented. Themes related to HIV acquisition risk from all participants were organized using a socioecological framework and revolved around individual and developmental experiences (personal experience with HIV, perceived invincibility), family barriers (lack of adult supervision, pressure to leave school), relational barriers (lack of disclosure and partner communication, “burn out” around attempts to discuss condom use with partners, overdependence on partners), community-level barriers (township environment, lack of structured activities), and social barriers (poverty, HIV-related stigma). Some novel concepts emerged from the data, including an understanding of how overdependence on the romantic relationship may develop. Current HIV prevention efforts, including traditional HIV counseling and testing, condom distribution, and biomedical agents for HIV prevention, are unlikely to be effective without a broader, ecological up-to-date understanding of the evolving, intertwined, and complex constellation of factors that drive HIV risk behavior in this high-risk population.     

Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters

Introduction: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known.

Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed.

Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.     

A cost-efficiency analysis of a mobile dental clinic in the public services.

During 1997, the Gauteng Oral Health Services implemented a Mobile Oral Health Care System (MOHCS) in the province. For the first year (1997/98) one mobile dental clinic was utilised in the West Rand region of the province and services were provided by dentists, dental therapists and oral hygienists. The purpose of the MOHCS is to provide an accessible and affordable comprehensive oral health care service of high quality and standard. The aim of this study was to determine the cost-efficiency of the mobile dental clinic utilised in the West Rand region over the first year of implementation. After consultation with all stakeholders, an operational plan was finalised. The plan included a traveling schedule, clinicians available for service delivery, and a management information system (MIS). Statistics on dental materials, consumables, treatment provided, etc. were collected and analysed. During the study period 2072 patients received dental treatment at 38 different sites in the region. At an average cost of R56.50 (+/- US$11) per patient, services to the value of R92.45 (+/- US$18) per patient were delivered during 104 working days. Of the 1477 patients treated by a dentist or dental therapist, 53% were treated by extracting 1026 teeth, and 27% by restoring 570 teeth. For oral hygiene patients, 67% received an oral hygiene procedure and 13% received fissure sealants. With a net margin ratio of 0,39 and a breakeven point of 1173,46 patients and 58,90 days, an accessible and cost-efficient service was provided to health districts in the West Rand region.     

Are changes in the extent of left ventricular dyssynchrony as assessed by speckle tracking associated with response to cardiac resynchronization therapy?

Echocardiographic assessment of left ventricular (LV) dyssynchrony is used to predict response to cardiac resynchronization therapy (CRT). However, the association between reduction in the extent of speckle tracking based LV-dyssynchrony and echocardiographic response to CRT has not been explored yet. The aim of this study was to assess the changes in the extent of LV dyssynchrony as a result of CRT and its association with echocardiographic response to CRT in a large consecutive series of patients. We studied 138 patients with standard CRT indication. Time-based speckle tracking longitudinal strain (maximal delay between 6-segments in 4-chamber view) was performed to assess LV-dyssynchrony at baseline and after a mean follow-up of 22 ± 8 months. Echocardiographic CRT response was defined as a reduction in LV end-systolic volume ≥15 %. Mean age was 68 ± 8 years (30 % female). Mean LV ejection fraction (LVEF) was 26 ± 7 %. Ninety six patients (70 %) were classified as echocardiographic responders. In the total study group, LV-dyssynchrony decreased from 196 ± 89 ms at baseline to 180 ± 105 ms during follow-up, P = 0.01. Of note, in responders there was a pronounced reduction in LV dyssynchrony (198 ± 88 ms at baseline vs 154 ± 50 ms after CRT, P < 0.001), whereas in non-responders there was a significant increase (191 ± 92 ms at baseline vs 243 ± 160 ms after CRT, P = 0.04). After multivariate analysis, decreased in LV-dyssynchrony, wider QRS duration and non-ischemic etiology were independently and significantly associated with CRT response. Changes in the extent of LV dyssynchrony as measured by speckle tracking after CRT are independently associated with response to CRT.     

Fulminant falciparum malaria

A case of fulminant falciparum malaria with a 35% parasitaemia, shock and subcoma was treated successfully by using parenteral chemotherapy, exchange transfusion, dexamethasone, circulatory support and mechanical ventilation. Pathophysiology and complications of falciparum malaria are discussed. The treatment of severe malaria should aim for a fast reduction in parasitaemia and toxic products. An exchange transfusion can be additive to parenteral chemotherapy. Blocking the over-reacting cell-mediated immune response, aggressive shock treatment, prevention of secondary infections and maintaining normoglycaemia might reduce morbidity and mortality of fulminant falciparum malaria.