Lone Sunde

Background: The impact of Pass/Fail or Tiered grade assessment for exams in undergraduate medical education has caused much debate, but there is little data to inform decision-making. The increasing number of medical schools transitioned to a Pass/Fail assessment has raised concerns about medical students’ academic performance. In 2018, during the undergraduate medical curriculum reform at the Faculty of Medicine, Aalborg University changed some exams from Pass/Fail to Tiered grade and vice versa for other exams. These changes provide an opportunity to evaluate the different assessment forms. Objective: This study aimed to evaluate medical students’ academic performance at the final licensing exam in relation to the exam grading principle. Methods: This single-center cohort study at Aalborg University Medical School, North Denmark Region, assesses the change from 2-digit Tiered grade to Pass/Fail evaluation and vice versa of undergraduate medical students’ exams after the 4th and 5th year clinical training modules from Autumn 2015 through Spring 2023. The primary outcome was (1) the average grades at the final licensing exam and (2) the number of students failing exams during the previous two years. Results: Among the total of 7634 exams, 7164 4th and 5th year clinical training exams were included in the comparisons, of which 3047 (42.5%) were Pass/Fail exams and 4117 (57.5%) were Tiered grade exams. The frequency of students failing exams was 3.3% (n=101/3047) at Pass/Fail and 1.97% (81/4117) with Tiered grade exams ( P <.001). This difference was leveled out when counting the near-failure tiered grade as Fail. Tiered grade exams did not differ between semesters ( P =.99) nor show a time trend at the 4th year ( P =.66). The final licensing exam grades were unaltered ( P =.47). Conclusions: Contrary to our expectation, Pass/Fail exams exhibited a higher fail rate compared to Tiered grade exams without lowering the final academic performance. These results suggest that a shift from Tiered grades to Pass/Fail assessment redirects the focus from rewarding high performance to ensuring standards are maintained among underperforming students.

The Danish Hereditary Non-Polyposis Colorectal Cancer Register (HNPCC-R) has formed the basis for many epidemiologic studies supporting risk stratification and both national and international guidelines on surveillance. However, the HNPCC-R is based on voluntary reporting and the completeness of registration is unknown. Hence, we aimed to assess the validity and completeness of the colorectal cancer (CRC) registrations in the HNPCC-R. We combined the registrations in the HNPCC-R with the registrations in the national Danish Cancer Registry (DCR), which is validated and based on mandatory reporting, and matched the cases from each register using a 13-step algorithm based on unique, national Central Population Registration number, date of diagnosis, location, and morphology thus identifying 9160 verified CRCs in 49,799 individuals. The overall agreement between the registers was 85%, and the completeness of the HNPCC-R was 95%. The DCR had the highest number of registrations before 1975, and the HNPCC-R had the highest number of registrations after 1985—especially more synchronous and metachronous cases. In conclusion, data from the HNPCC-R on CRC are valid and should be preferred for studies on CRC in families with a heritable increased risk of colorectal cancer—especially in Lynch syndrome, which is known for multiple CRCs, though a combination of both registers would secure the most optimal dataset.

Background: Gestational trophoblastic disease comprises hydatidiform moles and a rare group of malignancies that derive from trophoblasts. Although there are typical morphological features that may distinguish hydatidiform moles from non-molar products of conception, such features are not always present, especially at early stages of pregnancy. Furthermore, mosaic/chimeric pregnancies and twin pregnancies make pathological diagnosis challenging while trophoblastic tumours can also pose diagnostic problems in terms of their gestational or non-gestational origin. Objectives: The aim of this study was to show that ancillary genetic testing can be used to aid diagnosis and clinical management of GTD. Methods: Each author identified cases where genetic testing, including short tandem repeat (STR) genotyping, ploidy analysis, next-generation sequencing, and immunostaining for p57, the product of the imprinted gene CDKN1C, facilitated accurate diagnosis and improved patient management. Representative cases were chosen to illustrate the value of ancillary genetic testing in different scenarios. Outcome: Genetic analysis of placental tissue can aid in determining the risk of developing gestational trophoblastic neoplasia, facilitating discrimination between low risk triploid (partial) and high risk androgenetic (complete) moles, discriminating between a hydatidiform mole twinned with a normal conceptus and a triploid conception and identification of androgenetic/biparental diploid mosaicism/chimerism. STR genotyping of placental tissue and targeted gene sequencing of patients can identify women with an inherited predisposition to recurrent molar pregnancies. Genotyping can distinguish gestational from non-gestational trophoblastic tumours using tissue or circulating tumour DNA and can also identify the causative pregnancy which is the key prognostic factor for placental site and epithelioid trophoblastic tumours. Conclusions and Outlook: STR genotyping and p57 immunostaining have been invaluable to the management of gestational trophoblastic disease in many situations. The use of next-generation sequencing and of liquid biopsies is opening up new pathways for GTD diagnostics. Development of these techniques has the potential to identify novel biomarkers of GTD and further refine diagnosis.

Peutz–Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%–15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2–83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1^RC/RC) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system. Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.

Background: In gestational trophoblastic disease, the prognosis is related to the genetic constitution. In some cases, taking a biopsy is contraindicated.Methods: In a pregnant woman, ultrasound scanning suggested hydatidiform mole. To explore if the genetic constitution can be established without taking a biopsy (or terminating the pregnancy), cell‐free DNA and circulating gestational trophoblasts were isolated from maternal blood before evacuation of the uterus. The evacuated tissue showed the morphology of a complete hydatidiform mole. Without prior whole‐genome amplification, short tandem repeat analysis of 24 DNA markers was performed on the samples, and on DNA isolated from evacuated tissue, and from the blood of the patient and her partner.Results: Identical genetic results were obtained in each of three circulating gestational trophoblasts and the evacuated tissue, showing that this conceptus had a diploid androgenetic nuclear genome. In contrast, analysis of cell‐free DNA was less informative and less specific due to the inherent presence of cell‐free DNA from the patient.Conclusion: Our results show that it is possible to isolate and analyze circulating gestational trophoblasts originating in a pregnancy without maternal nuclear genome. For diagnosing gestational trophoblastic diseases, genotyping circulating gestational trophoblasts appears to be superior to analysis of cell‐free DNA.