Search

Jesse Demuytere,1,* Charlotte Carlier,1,* Leen Van de Sande,1 Anne Hoorens,2 Kaat De Clercq,3 Silvia Giordano,4 Lavinia Morosi,4 Cristina Matteo,4 Massimo Zucchetti,4 Enrico Davoli,4 Jo Van Dorpe,2 Chris Vervaet,3 Wim Ceelen1 1Department of GI Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent, Belgium; 2Department of Pathology, Ghent University Hospital, Ghent, Belgium; 3Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium; 4Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri - IRCCS, Milano, Italy*These authors contributed equally to this workCorrespondence: Wim Ceelen, Department of GI Surgery, Ghent University Hospital, Route 1275, Corneel Heymanslaan 10, Ghent, B-9000, Belgium, Tel +32 9 332 6251, Email Wim.ceelen@ugent.beBackground: Epithelial ovarian cancer is associated with high mortality due to diagnosis at later stages associated with peritoneal involvement. Several trials have evaluated the effect of intraperitoneal treatment. In this preclinical study, we report the efficacy, pharmacokinetics and pharmacodynamics of intraperitoneal treatment with two approved nanomolecular formulations of paclitaxel (nab-PTX and mic-PTX) in a murine ovarian cancer xenograft model.Methods: IC50 was determined in vitro on three ovarian cancer cell lines (OVCAR-3, SK-OV-3 and SK-OV-3-Luc IP1). EOC xenografts were achieved using a modified subperitoneal implantation technique. Drug treatment was initiated 2 weeks after engraftment, and tumor volume and survival were assessed. Pharmacokinetics and drug distribution effects were assessed using UHPLC-MS/MS and MALDI imaging mass spectrometry, respectively. Pharmacodynamic effects were analyzed using immunohistochemistry and transmission electron microscopy using standard protocols.Results: We demonstrated sub-micromolar IC50 concentrations for both formulations on three EOC cancer cell lines in vitro. Furthermore, IP administration of nab-PTX or mic-PTX lead to more than 2-fold longer survival compared to a control treatment of IP saline administration (30 days in controls, 66 days in nab-PTX treated animals, and 76 days in mic-PTX animals, respectively). We observed higher tissue uptake of drug following nab-PTX administration when compared to mic-PTX, with highest uptake after 4 hours post-treatment, and confirmed this lower uptake of mic-PTX using HPLC on digested tumor samples. Furthermore, apoptosis was not increased in tumor implants up to 24h post-treatment.Conclusion: Intraperitoneal administration of both nab-PTX and mic-PTX results in a significant anticancer efficacy and survival benefit in a mouse OC xenograft model.Keywords: ovarian, peritoneal, paclitaxel, nanomedicine

Abstract Background Fibroblast activation protein (FAP), a transmembrane serine protease overexpressed by cancer-associated fibroblasts in the tumor stroma, is an interesting biomarker for targeted radionuclide theranostics. FAP-targeting radiotracers have demonstrated to be superior to [18F]FDG PET/CT in various solid cancers. However, these radiotracers have suboptimal tumor retention for targeted radionuclide therapy (TRT). We aimed to develop a novel FAP-targeting pharmacophore with improved pharmacokinetics by introducing a substitution at the 8-position of (4-quinolinoyl)-glycyl-2-cyanopyrrolidine, which allows for conjugation of a chelator, dye, or other payloads. Results Here we showed the synthesis of DOTA-conjugated eFAP-6 and sulfo-Cyanine5-conjugated eFAP-7. After chemical characterization, the uptake and specificity of both tracers were determined on FAP-expressing cells. In vitro, [111In]In-eFAP-6 demonstrated a superior affinity and a more rapid, although slightly lower, peak uptake than gold standard [111In]In-FAPI-46. Confocal microscopy demonstrated a quick FAP-mediated internalization of eFAP-7. Studies with HT1080-huFAP xenografted mice confirmed a more rapid uptake of [177Lu]Lu-eFAP-6 vs. [177Lu]Lu-FAPI-46. However, tumor retention at 24 h post injection of [177Lu]Lu-eFAP-6 was lower than that of [177Lu]Lu-FAPI-46, hereby currently limiting its use for TRT. Conclusion The superior affinity and faster tumor accumulation of eFAP-6 over FAPI-46 makes it a suitable compound for radionuclide imaging. After further optimization, the eFAP series has great potential for various oncological interventions, including fluorescent-guided surgery and effective targeted radionuclide theranostics.

A woman presented with cough, fever, and dyspnea during a twin pregnancy following a 13th in vitro fertilization procedure. Ultimately, she was diagnosed with miliary tuberculosis and tuberculostatic treatment was initiated, complicated by drug-induced hepatotoxicity. In retrospect, previous pelvic tuberculosis had likely been overlooked. This case report highlights the need to recognize tuberculosis as a cause of infertility even in low-incidence countries and emphasizes that the peripartum period is a major risk factor for drug-induced liver injury.

Summary: Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel method to treat patients with peritoneal metastases (PM). We aimed to study the tolerability, safety, pharmacokinetics, and tumour response of nanoparticle albumin bound paclitaxel (NAB-PTX) during PIPAC in a Phase I study. Methods: Eligible patients with biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin underwent three PIPAC treatments using NAB-PTX with a four-week interval. The dose of NAB-PTX was escalated from 35 to 140 mg/m2 using a Bayesian design to estimate the maximum tolerated dose (MTD). Findings: Twenty-three patients were included; thirteen (65%) patients combined PIPAC therapy with continued systemic chemotherapy. The most frequent toxicities were liver toxicity and anaemia. Treatment resulted in seven (35%) responders, six (30%) non-responders and seven (35%) patients with stable PM. Systemic absorption of NAB-PTX was slow, with median peak plasma concentrations reached after 3 to 4 h. Median NAB-PTX tumour tissue concentrations suggested accumulation: 14.6 ng/mg, 19.2 ng/mg and 40.8 ng/mg after the first, second and third PIPAC procedure respectively. EORTC QoL and VAS scores remained stable. Overall survival after one year was 57%. Interpretation: PIPAC with NAB-PTX results in a favourable PK profile and promising anticancer activity in patients with unresectable PM. The MTD and recommended Phase II clinical trial dose are 140 mg/m2. In patients with impaired hepatobiliary function, a dose of 112.5 mg/m2 is recommended. Funding: Kom op tegen Kanker (Flemish League against Cancer).

We examined perceived self-other differences (self-uniqueness) in appraisals of one’s risk of an infectious disease (COVID-19), one’s adherence to behavioural precautionary measures against the disease, and the impact of these measures on one’s life. We also examined the relationship of self-uniqueness with information seeking and trust in sources of information about the disease. We administered an online survey to a community sample (N = 8696) of Dutch-speaking individuals, mainly in Belgium and The Netherlands, during the first lockdown (late April-Mid June 2020). As a group, participants reported that they were less likely to get infected or infect others or to suffer severe outcomes than average (unrealistic optimism) and that they adhered better than average to behavioural precautionary measures (illusory superiority). Except for participants below 25, who reported that they were affected more than average by these measures (egocentric impact bias), participants also generally reported that they were less affected than average (allocentric impact bias). Individual differences in self-uniqueness were associated with differences in the number of information sources being used and trust on these sources. Higher comparative optimism for infection, self-superiority, and allocentric impact perception were associated with information being sought from fewer sources; higher self-superiority and egocentric impact perception were associated with lower trust. We discuss implications for health communication.

Neoplastic pancreatic cysts are associated with invasive pancreatic cancer, but their origins and evolutionary relationships are unclear. Here, the authors present the evolutionary analysis of neoplastic cysts and report them as precursors of invasive pancreatic cancer, and that SMAD4/TGFBR2 alterations are likely drivers of invasion in a subset of cases.

Men with obesity often present with low testosterone (T) and sex hormone-binding globulin (SHBG) levels. Several mechanisms for this have been proposed, but as SHBG is secreted by hepatocytes and sex steroids undergo hepatic metabolization, this study investigates whether severity and histological components of nonalcoholic fatty liver disease (NAFLD) are associated with sex steroid levels in obese men. This cross-sectional study included 80 obese men (age: 46 ± 11 years; body mass index: 42.2 ± 5.5 kg m−2). Serum levels of total T and estradiol (E2) were measured using liquid chromatography coupled with tandem mass spectroscopy (LC/MS-MS) and SHBG and gonadotropins by immunoassay. Liver biopsies were evaluated using Steatosis, Activity, and Fibrosis scoring. Participants with steatohepatitis had similar median (1stquartile–3rd quartile) total T levels (7.6 [5.0–11.0] nmol l−1 vs 8.2 [7.2–10.9] nmol l−1; P = 0.147), lower calculated free T (cFT) levels (148.9 [122.9–188.8] pmol l−1 vs 199.5 [157.3–237.6] pmol l−1; P = 0.006), and higher free E2/T ratios (10.0 [6.4–13.9] x10-3 vs 7.1 [5.7–10.7] x10-3;

Purpose: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. Objective: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. Methods: This cross-sectional study included 78 obese subjects (mean ag e 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insuli n levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. Results: A positive association between overall NAFLD Activity Score and HOMA-IR was found (rs = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, gluc ose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammat ory foci or higher stage of fibrosis. These findings were independent of age, BMI, t riglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. Conclusion: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assess ed, preventing or mitigating this inflammatory response in obesity might be of imp ortance in controlling obesity-related metabolic disturbances.

The design of photoswitches which operate in the visible light regime, show a large separation of absorption bands and are functional in various solvents is challenging. Here the authors report Iminothioindoxyls as visible-light operated photoswitches with a band separation of 100 nm.

Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The backbone of treatment is immunosuppressive medication, typically prednisolone as induction therapy and azathioprine as a maintenance therapy. Side effects of the long-term use of systemic corticosteroids are well known and have led to the use of alternative induction regimens. An attractive alternative is budesonide, a nonhalogenated glucocorticosteroid characterized by a high first-pass effect in the liver (90%), resulting in a high topical anti-inflammatory activity and a low systemic activity. It should be stressed that budesonide is contraindicated in patients with established cirrhosis with portal hypertension and portocaval shunting. In this case report, we present the first case of adrenal insufficiency following treatment with budesonide for AIH.

Background. Malaria is an important health and economic burden in sub-Saharan Africa. Conventional economic evaluations typically consider only direct costs to the health care system and government budgets. This paper quantifies the potential impact of malaria vaccination on the wider economy, using Ghana as an example. Methods. We used a computable general equilibrium model of the Ghanaian economy to estimate the macroeconomic impact of malaria vaccination in children under the age of 5, with a vaccine efficacy of 50% against clinical malaria and 20% against malaria mortality. The model considered changes in demography and labor productivity, and projected gross domestic product (GDP) over a time frame of 30 years. Vaccine coverage ranging from 20% to 100% was compared with a baseline with no vaccination. Results. Malaria vaccination with 100% coverage was projected to increase the GDP of Ghana over 30 years by US$6.93 billion (in 2015 prices) above the baseline without vaccination, equivalent to an increase in annual GDP growth of 0.5%. Projected GDP per capita would increase in the first year due to immediate reductions in time lost from work by adults caring for children with malaria, then decrease for several years as reductions in child mortality increase the number of dependent children, then show a sustained increase after Year 11 due to long-term productivity improvements in adults resulting from fewer malaria episodes in childhood. Conclusion. Investing in improving childhood health by vaccinating against malaria could result in substantial long-term macroeconomic benefits when these children enter the workforce as adults. These macroeconomic benefits are not captured by conventional economic evaluations and constitute an important potential benefit of vaccination.

Background: The use of dermoscopy improves the diagnosis of skin cancer significantly in trained dermatologists. However, to evaluate its cost-effectiveness in daily practice, not only sensitivity but also the excision rate is important. Objective: We examined the diagnostic accuracy of cases from a true population-based sample scored by general dermatologists. Methods: One hundred twenty-six dermatologists were randomly assigned to 145 digital cases of lesions detected at a skin cancer screening. This resulted in 4,655 case evaluations using a web application. Accuracy of diagnosis and treatment was correlated with the histological diagnosis or expert opinion. Results: The larger portion (89.7%) of the participating dermatologists reported using their dermatoscope daily. The odds of making a correct diagnosis of melanoma using dermoscopy was 5.38 compared with naked-eye examination (NEE). Dermoscopy increased sensitivity for skin cancer diagnosis from 70.6% to 84.6%, but this was associated with a small but significant decrease in specificity of 3.5%. To detect 1 skin cancer, 5.23 lesions had to be biopsied/excised in this sample and this was not significantly improved by dermoscopic evaluation. Dermoscopy significantly increased the confidence about making a correct diagnosis, especially in seborrheic keratosis, Bowen disease, and melanoma. Conclusions: Dermoscopy significantly improved diagnostic accuracy, the sensitivity of skin cancer detection, and the confidence in diagnosis especially for seborrheic keratosis, Bowen disease, and melanoma. However, this finding was not reflected in a significant reduction in the number needed to excise in this sample.

Cancer Associated Fibroblasts (CAFs) form a major component of the tumour microenvironment, they have a complex origin and execute diverse functions in tumour development and progression. As such, CAFs constitute an attractive target for novel therapeutic interventions that will aid both diagnosis and treatment of various cancers. There are, however, a few limitations in reaching successful translation of CAF targeted interventions from bench to bedside. Several approaches targeting CAFs have been investigated so far and a few CAF-targeting tracers have successfully been developed and applied. This includes tracers targeting Fibroblast Activation Protein (FAP) on CAFs. A number of FAP-targeting tracers have shown great promise in the clinic. In this review, we summarize our current knowledge of the functional heterogeneity and biology of CAFs in cancer. Moreover, we highlight the latest developments towards theranostic applications that will help tumour characterization, radioligand therapy and staging in cancers with a distinct CAF population.

Johann Weyer (1515/1516-1588)’s book De praestigiis daemonum, et incantationibus ac veneficiis (On devilish delusions and on enchantments and poisonings), first published in Basel in 1563, counts as a systematic attack on witch theories and witch trials. Vera Hoorens argues that Weyer wrote it not only to defend the witches but also and, perhaps even more, as an instrument to criticise the Catholic Church. This reinterpretation solves the problems that are associated with the traditional interpretation of De praestigiis daemonum, including the variety of its contents, Weyer’s seemingly enigmatic source use, and his having written the book before and not during the increase in witch trials. The article answers a numberof questions that are raised by the reinterpretation, including those surrounding Weyer’s religious persuasion, why contemporaries and historians almost unanimously viewed De praestigiis daemonum as a treatise against witch trials, and the extent to which he truly cared about the witches. Waarom schreef Jan Wier De praestigiis daemonum? Jan Wier (1515/1516-1588)’s boek De praestigiis daemonum, et incantationibus ac veneficiis (Over duivelse begoochelingen en over betoveringen en gifmengerijen), waarvan de eerste editie in 1563 in Basel verscheen, geldt als een systematische aanval op heksentheorieën en heksenprocessen. Vera Hoorens betoogt dat Wier het niet enkel schreef om de heksen te verdedigen, maar ook, en misschien nog wel meer, als een instrument voor zijn kritiek op de Katholieke Kerk. Deze herinterpretatie lost de problemen op die geassocieerd zijn met de traditionele interpretatie van De praestigiis daemonum, namelijk de verscheidenheid van zijn inhoud, Wiers schijnbaar raadselachtig bronnengebruik, en het feit dat hij zijn boek schreef voordat en niet terwijl de heksenprocessen toenamen. Dit artikel beantwoordt een aantal vragen die de voorgestelde herinterpretatie oproept, zoals wat Wiers religieuze overtuiging was, waarom tijdgenoten en historici De praestigiis daemonum bijna unaniem zagen als een traktaat tegen de heksenprocessen, en in welke mate Wier echt om de heksen gaf.

Erdheim-Chester disease (ECD) is a rare non-Langerhans’ cell histiocytosis. Mild but permanent juxta-articular bone pain in mainly knees and ankles is the most frequent associated symptom. Despite the pathognomonic radiographic findings, most cases are still diagnosed by the pathologist. The lesions consist of lipid-storing CD 68 +/ CD 1a – non- Langerhans’ cell histiocytes, most frequently localized in bone but also involving multiple organ systems in the body. We present a case report in which the diagnosis of ECD was established with 99mTc MDP bone SPECT/CT.

Although the gastrointestinal tract is a fairly frequent site of melanoma metastases, reports of small bowel intussusception caused by melanoma are very rare. We report the case of a 77-year-old man who was admitted to our hospital with epigastric pain, melena and anaemia. After clinical examination, laboratory evaluation and radiological work-up the diagnosis of a jejunal intussusception was made. Exploratory laparoscopy revealed a large tumour arising from the jejunum, approximately 20 cm distal to the angle of Treitz. Small bowel resection with an end-to-end anastomosis was performed. Histological examination showed an intestinal melanoma. There are different theories concerning the origin of malignant melanoma in the small bowel. Although the small and large intestines normally contain no melanocytes, these cells have occasionally been found in the alimentary and respiratory tracts and even in lymph nodes, which supports the theory of a primary origin of melanoma at these sites. Since this was a solitary intestinal lesion and there was no history of cutaneous melanoma, we conclude that this could be an example of a very rare primary melanoma of the small intestine.

Ileocolic invagination in the adult may be caused by adenocarcinoma and lead to intestinal obstruction. We report a case of a cecal adenocarcinoma that was complicated by an ileocolic invagination in a 38 year old female, diagnosed on a contrast enhanced CT scan of the abdomen and highlights the importance of contrast enhanced CT for diagnosis of ileocolic invagination.

The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death.

Johann Weyer (1515/1516-1588)’s book De praestigiis daemonum, et incantationibus ac veneficiis (On devilish delusions and on enchantments and poisonings), first published in Basel in 1563, counts as a systematic attack on witch theories and witch trials. Vera Hoorens argues that Weyer wrote it not only to defend the witches but also and, perhaps even more, as an instrument to criticise the Catholic Church. This reinterpretation solves the problems that are associated with the traditional interpretation of De praestigiis daemonum, including the variety of its contents, Weyer’s seemingly enigmatic source use, and his having written the book before and not during the increase in witch trials. The article answers a number of questions that are raised by the reinterpretation, including those surrounding Weyer’s religious persuasion, why contemporaries and historians almost unanimously viewed De praestigiis daemonum as a treatise against witch trials, and the extent to which he truly cared about the witches. Waarom schreef Jan Wier De praestigiis daemonum? Jan Wier (1515/1516-1588)’s boek De praestigiis daemonum, et incantationibus ac veneficiis (Over duivelse begoochelingen en over betoveringen en gifmengerijen), waarvan de eerste editie in 1563 in Basel verscheen, geldt als een systematische aanval op heksentheorieën en heksenprocessen. Vera Hoorens betoogt dat Wier het niet enkel schreef om de heksen te verdedigen, maar ook, en misschien nog wel meer, als een instrument voor zijn kritiek op de Katholieke Kerk. Deze herinterpretatie lost de problemen op die geassocieerd zijn met de traditionele interpretatie van De praestigiis daemonum, namelijk de verscheidenheid van zijn inhoud, Wiers schijnbaar raadselachtig bronnengebruik, en het feit dat hij zijn boek schreef voordat en niet terwijl de heksenprocessen toenamen. Dit artikel beantwoordt een aantal vragen die de voorgestelde herinterpretatie oproept, zoals wat Wiers religieuze overtuiging was, waarom tijdgenoten en historici De praestigiis daemonum bijna unaniem zagen als een traktaat tegen de heksenprocessen, en in welke mate Wier echt om de heksen gaf.

Johann Weyer (1515/1516-1588)’s book De praestigiis daemonum, et incantationibus ac veneficiis (On devilish delusions and on enchantments and poisonings), first published in Basel in 1563, counts as a systematic attack on witch theories and witch trials. Vera Hoorens argues that Weyer wrote it not only to defend the witches but also and, perhaps even more, as an instrument to criticise the Catholic Church. This reinterpretation solves the problems that are associated with the traditional interpretation of De praestigiis daemonum, including the variety of its contents, Weyer’s seemingly enigmatic source use, and his having written the book before and not during the increase in witch trials. The article answers a number of questions that are raised by the reinterpretation, including those surrounding Weyer’s religious persuasion, why contemporaries and historians almost unanimously viewed De praestigiis daemonum as a treatise against witch trials, and the extent to which he truly cared about the witches. Waarom schreef Jan Wier De praestigiis daemonum? Jan Wier (1515/1516-1588)’s boek De praestigiis daemonum, et incantationibus ac veneficiis (Over duivelse begoochelingen en over betoveringen en gifmengerijen), waarvan de eerste editie in 1563 in Basel verscheen, geldt als een systematische aanval op heksentheorieën en heksenprocessen. Vera Hoorens betoogt dat Wier het niet enkel schreef om de heksen te verdedigen, maar ook, en misschien nog wel meer, als een instrument voor zijn kritiek op de Katholieke Kerk. Deze herinterpretatie lost de problemen op die geassocieerd zijn met de traditionele interpretatie van De praestigiis daemonum, namelijk de verscheidenheid van zijn inhoud, Wiers schijnbaar raadselachtig bronnengebruik, en het feit dat hij zijn boek schreef voordat en niet terwijl de heksenprocessen toenamen. Dit artikel beantwoordt een aantal vragen die de voorgestelde herinterpretatie oproept, zoals wat Wiers religieuze overtuiging was, waarom tijdgenoten en historici De praestigiis daemonum bijna unaniem zagen als een traktaat tegen de heksenprocessen, en in welke mate Wier echt om de heksen gaf.

Johann Weyer (1515/1516-1588)’s book De praestigiis daemonum, et incantationibus ac veneficiis (On devilish delusions and on enchantments and poisonings), first published in Basel in 1563, counts as a systematic attack on witch theories and witch trials. Vera Hoorens argues that Weyer wrote it not only to defend the witches but also and, perhaps even more, as an instrument to criticise the Catholic Church. This reinterpretation solves the problems that are associated with the traditional interpretation of De praestigiis daemonum, including the variety of its contents, Weyer’s seemingly enigmatic source use, and his having written the book before and not during the increase in witch trials. The article answers a number of questions that are raised by the reinterpretation, including those surrounding Weyer’s religious persuasion, why contemporaries and historians almost unanimously viewed De praestigiis daemonum as a treatise against witch trials, and the extent to which he truly cared about the witches. Waarom schreef Jan Wier De praestigiis daemonum? Jan Wier (1515/1516-1588)’s boek De praestigiis daemonum, et incantationibus ac veneficiis (Over duivelse begoochelingen en over betoveringen en gifmengerijen), waarvan de eerste editie in 1563 in Basel verscheen, geldt als een systematische aanval op heksentheorieën en heksenprocessen. Vera Hoorens betoogt dat Wier het niet enkel schreef om de heksen te verdedigen, maar ook, en misschien nog wel meer, als een instrument voor zijn kritiek op de Katholieke Kerk. Deze herinterpretatie lost de problemen op die geassocieerd zijn met de traditionele interpretatie van De praestigiis daemonum, namelijk de verscheidenheid van zijn inhoud, Wiers schijnbaar raadselachtig bronnengebruik, en het feit dat hij zijn boek schreef voordat en niet terwijl de heksenprocessen toenamen. Dit artikel beantwoordt een aantal vragen die de voorgestelde herinterpretatie oproept, zoals wat Wiers religieuze overtuiging was, waarom tijdgenoten en historici De praestigiis daemonum bijna unaniem zagen als een traktaat tegen de heksenprocessen, en in welke mate Wier echt om de heksen gaf.

Abstract The mucus layer in the gastrointestinal (GI) tract is considered to be the first line of defense to the external environment. Alteration in mucus components has been reported to occur during intestinal nematode infection in ruminants, but the role of mucus in response to abomasal parasites remains largely unclear. The aim of the current study was to analyze the effects of an Ostertagia ostertagi infection on the abomasal mucus biosynthesis in cattle. Increased gene expression of MUC1, MUC6 and MUC20 was observed, while MUC5AC did not change during infection. Qualitative changes of mucins, related to sugar composition, were also observed. AB-PAS and HID-AB stainings highlighted a decrease in neutral and an increase in acidic mucins, throughout the infection. Several genes involved in mucin core structure synthesis, branching and oligomerization, such as GCNT3, GCNT4, A4GNT and protein disulphide isomerases were found to be upregulated. Increase in mucin fucosylation was observed using the lectin UEA-I and through the evaluation of fucosyltransferases gene expression levels. Finally, transcription levels of 2 trefoil factors, TFF1 and TFF3, which are co-expressed with mucins in the GI tract, were also found to be significantly upregulated in infected animals. Although the alterations in mucus biosynthesis started early during infection, the biggest effects were found when adult worms were present on the surface of the abomasal mucosa and are likely caused by the alterations in mucosal cell populations, characterized by hyperplasia of mucus secreting cells.

Abstract Background Mucins are large glycoproteins implicated in protection of all mucosal surfaces. In humans and rodents, the mucin gene family has been well described and previous studies have investigated the distribution and function of mucins in the gastrointestinal (GI) tract. In contrast, little data is available on the mucin gene family in polygastric species, such as cattle. The aim of the current study was to identify all members of the bovine mucin family by genome mining and subsequently investigate the transcription pattern of these mucins in the GI tract. Results Nine bovine membrane-associated mucins (MUC1, MUC3A, MUC4, MUC12, MUC13, MUC15, MUC16, MUC20 and MUC21) and six secreted mucins (MUC2, MUC5AC, MUC5B, MUC6, MUC7 and MUC19) were identified in the bovine genome. No homologues could be identified for MUC3B, MUC8 and MUC17. In general, domain architecture of the membrane-associated mucins was found to be similar between humans and cattle, while the protein architecture of the gel-forming mucins appeared to be less conserved. Further analysis of the genomic organization indicated that the previously reported bovine submaxillary mucin (BSM) may be part of a larger gene encoding for MUC19. Analysis of the transcription profile showed that the secreted mucins were transcribed from the abomasum onwards, whereas the membrane associated mucins MUC1 and MUC20 were transcribed throughout the whole GI tract. In contrast to humans, MUC5B transcript was found in both the small and large intestine, but was absent in oesophageal tissue. Conclusions This study provides the first characterization of the mucin gene family in cattle and their transcriptional regulation in the GI tract. The data presented in this paper will allow further studies of these proteins in the physiology of the GI tract in ruminants and their interactions with pathogens.

A 20-year-old man was presented with ulcerative gastritis and duodenitis complicated by pyloric stenosis. Helicobacter pylori infection was excluded, and the lesions did not respond to treatment with proton pump inhibitors. No other parts of the intestinal tract showed signs of inflammation. Histopathological review showed signs of chronic inflammation with granuloma formation. A tentative diagnosis of isolated upper gastrointestinal (UGI) Crohn’s disease was performed. However, additional work-up revealed significantly positive IgG4 staining as well as elevated IgG4 serum levels. Since granulomatous disease is unlikely in IgG4-related disease, an eventual diagnosis of overlapping IgG4-related disease and Crohn’s disease (CD) was performed. Treatment with systemic steroids and anti-TNF in combination with azathioprine led to rapid symptomatic improvement. In this article, we review the available literature on IgG4-related gastroduodenitis, granulomatous gastritis, and upper GI CD. We suggest the possibility that IgG4-infiltration may be a marker of severely active inflammatory bowel disease rather than a separate disease entity.

PURPOSE: Portal hypertension (PHT) and its sequelae are the most clinically important manifestations in cystic fibrosis-related liver disease (CFLD). This paper aimed to evaluate the safety and efficacy of a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) to prevent PHT-related complications in pediatric patients with CFLD. METHODS: This was a prospective single-arm study on pediatric patients with CFLD, signs of PHT, and preserved liver function who underwent a pre-emptive TIPS in a single tertiary CF center between 2007 and 2012. The long-term safety and clinical efficacy were assessed. RESULTS: A pre-emptive TIPS was performed on seven patients with a mean age of 9.2 years (± standard deviation: 2.2). The procedure was technically successful in all patients, with an estimated median primary patency of 10.7 years [interquartile range (IQR) 0.5–10.7)]. No variceal bleeding was observed during the median follow-up of 9 years (IQR 8.1–12.9). In two patients with advanced PHT and rapidly progressive liver disease, severe thrombocytopenia could not be stopped. Subsequent liver transplantation revealed biliary cirrhosis in both patients. In the remaining patients with early PHT and milder porto-sinusoidal vascular disease, symptomatic hypersplenism did not occur, and liver function remained stable until the end of the follow-up. Inclusion for pre-emptive TIPS was discontinued in 2013 following an episode of severe hepatic encephalopathy. CONCLUSION: TIPS is a feasible treatment with encouraging long-term primary patency to avoid variceal bleeding in selected patients with CF and PHT. However, as the progression of liver fibrosis, thrombocytopenia, and splenomegaly is inevitable, the clinical benefits due to pre-emptive placement appear to be minor.

Abstract Background The treatment of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) has evolved with a wider application of neoadjuvant chemotherapy (NACHT). The aim of this study was to identify predictive factors for survival in BR and LA PDAC. Methods Clinicopathologic data of patients with BR and LA PDAC who underwent surgical exploration between January 2011 and June 2021 were retrospectively collected. Survival from the date of surgery was estimated using the Kaplan-Meier method. Simple and multiple Cox proportional hazards models were fitted to identify factors associated with survival. Surgical resection was analyzed in combination with the involvement of lymph nodes as this last was only known after a formal resection. Results Ninety patients were surgically explored (BR: 45, LA: 45), of which 51 (57%) were resected (BR: 31, LA: 20). NACHT was administered to 43 patients with FOLFIRINOX being the most frequent regimen applied (33/43, 77%). Major complications (Clavien-Dindo grade III and IV) occurred in 7.8% of patients and 90-day mortality rate was 3.3%. The median overall survival since surgery was 16 months (95% CI 12-20) in the group which underwent surgical resection and 10 months (95% CI 7-13) in the group with an unresectable tumor (p=0.001). Cox proportional hazards models showed significantly lower mortality hazard for surgical resection compared to no surgical resection, even after adjusting for National Comprehensive Cancer Network (NCCN) classification and administration of NACHT [surgical resection with involved lymph nodes vs no surgical resection (cHR 0.49; 95% CI 0.29-0.82; p=0.007)]. There was no significant difference in survival between patients with BR and LA disease (cHR= 1.01; 95% CI 0.63-1.62; p=0.98). Conclusions Surgical resection is the only predictor of survival in patients with BR and LA PDAC, regardless of their initial classification as BR or LA. Our results suggest that surgery should not be denied to patients with LA PDAC a priori. Prospective studies including patients from the moment of diagnosis are required to identify biologic and molecular markers which may allow a better selection of patients who will benefit from surgery.

Background/Objectives: There is currently no guidance on how to interpret the global degrees of activity (worsening) and repigmentation (improvement) in vitiligo. Stratification into global degrees can be completed for static evaluations (e.g., visible disease activity signs) and dynamic assessments (e.g., evolution over time). For the latter, the Vitiligo Disease Activity Score (VDAS15&60) and Vitiligo Disease Improvement Score (VDIS15&60) were recently validated. Methods: In the current study, a Physician Global Assessment (PGA) for disease activity (worsening) and repigmentation (improvement) was evaluated for validity (construct) and reliability (inter- and intrarater) based on a photo set of 66 patients. Subsequently, the PGA activity (worsening) and repigmentation (improvement) were used to stratify the Vitiligo Extent Score plus (VESplus), VDAS15&60 or VDIS15&60 into three global categories (slightly, moderately and much worse/improved), based on ROC analysis. Results: For the VESplus, cut-off values for the categories ‘slightly, moderately and much worse’ were >0.3%, >27.71% and >128.75% BSA (relative changes in the affected total BSA), respectively. For the categories ‘slightly, moderately and much improved’, they were >0%, >4.87% and >36.88% BSA (relative changes in the affected total BSA), respectively. The optimal cut-off values of the number of active (VDAS15) body areas were >0 areas for slightly worse, >2 areas for moderately worse and >7 for much worse. For VDIS15, the cut-off values for slightly improved and moderately improved were >0 and >1. For VDAS60 and VDIS60, the cut-off points were >0.5, >3, >9.5 and >0.5 and >1.5, respectively. The results should be interpreted with caution in patients with extensive vitiligo due to the rather limited disease extent of the included patient population (VESplus (median: 3.2%)). Conclusions: This research will aid in the development of more detailed international definitions.

Immune-related hepatitis (irH) is a fairly frequent complication of immune checkpoint inhibitors (ICIs). Its management is generally based on withholding ICIs and on the rapid initiation of corticosteroids, which is successful in 63 to 96% of cases. Mycofenolate mofetil (MMF) is accepted as a second-line immunosuppressant in the case of the failure of corticosteroids. In rare cases, though, irH is also resistant to MMF and may lead to liver failure. There are no standard third-line treatments and current guidelines are based on a limited number of case reports. We present a case of a metastatic melanoma patient with an immune-related hepatitis refractory to corticosteroids and MMF, that was successfully reversed with tacrolimus. Unfortunately, this was complicated with a serious infection and progressive disease, which illustrates the complexity of treatment of steroid-refractory immunotherapy-related adverse events. Furthermore, we provided a literature review regarding the management of steroid-refractory hepatitis and proposed a strategy to circumvent the current uncertainties in the management of steroid-refractory irH.

Introduction Currently, the healthcare sector is under tremendous financial pressure, and many acknowledge that a dramatic shift is required as the current system is not sustainable. Furthermore, the quality of care that is delivered varies strongly. Several solutions have been proposed of which the conceptual framework known as value-based healthcare (VBHC) is further explored in this study for psoriasis. Psoriasis is a chronic inflammatory skin disease, which is associated with a high disease burden and high treatment costs. The objective of this study is to investigate the feasibility of using the VBHC framework for the management of psoriasis.Methods and analysis This is a prospective clinical study in which new patients attending the psoriasis clinic (PsoPlus) of the Ghent University Hospital will be followed up during a period of 1 year. The main outcome is to determine the value created for psoriasis patients. The created value will be considered as a reflection of the evolution of the value score (ie, the weighted outputs (outcomes) divided by weighted inputs (costs)) obtained using data envelopment analysis. Secondary outcomes are related to comorbidity control, outcome evolution and treatment costs. In addition, a bundled payment scheme will be determined as well as potential improvements in the treatment process. A total of 350 patients will be included in this trial and the study initiation is foreseen on 1 March 2023.Ethics and dissemination This study has been approved by the Ethics Committee of the Ghent University Hospital. The findings of this study will be disseminated by various means: (1) publication in one or more peer-reviewed dermatology and/or management journals, (2) (inter)national congresses, (3) via the psoriasis patient community and (4) through the research team’s social media channels.Trial registration number NCT05480917.

Defects in primary or motile cilia result in a variety of human pathologies, and retinal degeneration is frequently associated with these so-called ciliopathies. We found that homozygosity for a truncating variant in CEP162, a centrosome and microtubule-associated protein required for transition zone assembly during ciliogenesis and neuronal differentiation in the retina, caused late-onset retinitis pigmentosa in 2 unrelated families. The mutant CEP162-E646R*5 protein was expressed and properly localized to the mitotic spindle, but it was missing from the basal body in primary and photoreceptor cilia. This impaired recruitment of transition zone components to the basal body and corresponded to complete loss of CEP162 function at the ciliary compartment, reflected by delayed formation of dysmorphic cilia. In contrast, shRNA knockdown of Cep162 in the developing mouse retina increased cell death, which was rescued by expression of CEP162-E646R*5, indicating that the mutant retains its role for retinal neurogenesis. Human retinal degeneration thus resulted from specific loss of the ciliary function of CEP162.

Since the introduction of new molecular techniques, the diagnostic landscape of soft tissue and bone tumors has expanded greatly over the past few years. The use of new molecular techniques has led to the identification of new genetic alterations and, therefore, to a better understanding of tumorigenesis, tumor detection and classification. Furthermore, methylation profiling has emerged as a classification tool for soft tissue and bone tumors. Molecular pathology also plays an important role in the determination of patient prognosis and in the identification of targets that can be used for targeted therapy. As a result, molecular pathology has gained a more prominent role in the daily practice of the surgical pathologist. This review delves into various molecular techniques applied in the surgical pathology of soft tissue and bone tumors. It highlights their applications through the analysis of five specific cases.

Skin cancer is a significant global health issue, placing a growing burden on individuals and society. Conventional diagnostic methods like visual examination and biopsy have limitations in invasiveness and accuracy. As a result, alternative tools such as infrared thermography have gained attention in skin cancer diagnosis. Tissue-mimicking phantoms have been instrumental in facilitating research in this field, offering controlled environments. While they do not fully replicate human skin complexity, physical skin models provide stability, ease of fabrication, and control over properties. Agarose phantoms are employed in this study. This research focused on testing and comparing cooling techniques for human skin in the context of skin cancer diagnosis using dynamic infrared thermography. Six cooling methods were investigated: a cool pack, an aluminum medal, ice, alcohol, a vortex cooler and a Zimmer Cryo 6 cooler. The experimental setup involved an infrared camera (Optris Xi400) with microscope optics positioned above an agar phantom mimicking flat skin and an ulcerating skin lesion. Based on experiments conducted on the skin phantom, it was observed that convective cooling methods offered more consistent and uniform cooling. Conversely, conductive methods proved effective for flat objects but posed challenges in achieving uniform cooling for bulging skin or ulcerated lesions. Ice or alcohol were deemed unsuitable due to artifacts influencing the infrared radiation and thermal camera view. A decision matrix assessed cooling techniques based on criteria such as uniformity, repeatability, view obstruction, efficiency, workload, patient comfort, clinical suitability, noise exposure, consumables, additional equipment, and price. The Zimmer Cryo 6 cooler emerged as the most suitable cooling method after evaluating various factors.

Protein-truncating variants in α-1,3-glucosyltransferase (ALG8) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of ALG8-associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype–phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.

Introduction Basal cell carcinomas (BCCs) represent 70% of all skin cancers. These tumours do not metastasise but are locally invasive if left untreated. There is a high incidence of BCC in the elderly, and clinicians frequently face important treatment dilemmas. The approach to BCC in the elderly should be investigated thoroughly.Methods and analysis Data on health-related quality of life (HrQoL), survival and complication rate will be examined in a treatment and a non-treatment arm (1:1 allocation). In the non-treatment arm, in vivo biological behaviour of low-risk BCCs in elderly patients will be examined. The main objective is to combine tumour characteristics with demographic data, in order to determine whether treatment will positively affect the patients’ HrQoL within a predetermined time frame. A monocentric randomised controlled trial (RCT) was designed at the Ghent University Hospital. The study population consists of patients with the minimum age of 75 years and a new diagnosis of (a) low-risk BCC(s). Patients in the treatment arm will receive standard care. Patients in the non-treatment arm will be closely monitored: the tumour will be intensively evaluated using multispectral dermoscopy, reflectance confocal microscopy and high-definition optical coherence tomography. All patients will be asked to fill in a questionnaire concerning their HrQoL at consecutive time points. Patient-reported side effects will be evaluated via an additional questionnaire.Primary outcomes will include the difference in HrQoL and the difference in complication risks (treatment vs non-treatment) at different time points of the study. Secondary endpoints are the evolution of the BCCs in the non-treatment arm and the long-term survival in both study arms. Tertiary endpoint is the treatment effectiveness in the treatment arm. The sample size calculation was performed and resulted in a target sample size of 272 patients in this study with a 1:1 allocation.Ethics and dissemination Subjects can withdraw from participating in this study at any time for any reason without any consequences. Approval for this study was received from the Ethics Committee of the Ghent University Hospital on 26 August 2021.The results of this RCT will be submitted for publication in one or more international, peer-reviewed medical journals, regardless of the nature of the study results.Trial registration number ClinicalTrials.gov (NCT05110924).

Introdução: O cancro cutâneo não-melanoma (CCNM) é uma das neoplasias mais frequentes a nível mundial, com 7,7 milhões de novos casos estimados em 2017 pelo Global Burden of Disease Cancer Collaboration. O presente estudo teve como objetivo estimar a prevalência e mortalidade por CCNM em Portugal Continental, de forma a quantificar a importância da doença no contexto português. Tal foi conseguido através da adaptação, parametrização e validação de um modelo económico integrando os vários estadios do CCNM. Métodos: Foi utilizado um modelo populacional de incidência cumulativa para modelizar a população adulta em Portugal Continental em 2010, seguida ao longo do tempo até ao ano de 2019. A população foi estratificada em várias coortes definidas por sexo e faixa etária. O modelo utilizado considerou as duas patologias mais frequentes, o carcinoma basocelular (CBC) e o carcinoma espinocelular (CEC), e reflete a epidemiologia e progressão natural destas duas patologias. Os seguintes estadios foram considerados no modelo: livre de lesão, CCNM não diagnosticado, diagnóstico e tratamento, seguimento e morte. As várias coortes foram seguidas ao longo do tempo, tendo sido registada a sua progressão através dos diferentes estadios. Resultados: O modelo estimou um total de 308 674 pessoas com CBC e de 71 423 pessoas com CEC, em Portugal Continental, em 2019, perfazendo um rácio de 4,3 casos de CBC para cada caso de CEC. As mulheres apresentam uma prevalência mais elevada de CBC do que os homens com cerca de 56,7% dos casos. Conclusão: Observou-se que 36% do total de casos de CBC e 73% do total de casos de CEC se encontram em estadios mais precoces. O modelo estimou um total de 1638 mortes por CEC IV ao longo do período de modelização, o que corresponde a um óbito por cada 44 casos de CEC nesse período.

Green synthesis of gold nanoparticles (AuNPs) using microorganisms has been generally studied aiming for high-yield production and morphologies appropriated for various applications, such as bioremediation, (bio)sensors, and (bio)catalysis. Numerous approaches showed the individual effect of factors influencing the synthesis of AuNPs with limited analysis of the governing factors enhancing the production and desired quality of the precipitates. This study proposes a fractional-factorial design to investigate the simultaneous influence of seven environmental factors (cell concentration, temperature, anoxic/oxic conditions, pH, gold concentration, electron donor type, and bacterial species) on the recovery yield and synthesis of targeted AuNPs. Various sizes and morphologies of the AuNPs were obtained by varying the environmental factors studied. The factors with significant effects (i.e., 0.2 mM Au and pH 5) were selected according to statistical analysis for optimal removal of 88.2 ± 3.5% of gold and with the production of valuable 50 nm AuNPs, which are known for their enhanced sensitivity. Implications of the cytochrome-C on the bacterial mechanisms and the provision of electron donors via an electrochemical system are further discussed. This study helps develop gold recovery and nanoparticle synthesis methods, focusing on the determining factor(s) for efficient, low-cost, green synthesis of valuable materials.

(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients.

Objective. To investigate the clinicopathological characteristics of gastrointestinal stromal tumor (GIST) with significant cystic changes and to assess the molecular genetic characteristics. Methods. In a 68-year-old man, a large abdominal tumoral mass was discovered incidentally. Computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the presence of a large cystic lesion with multiple contrast-enhancing septae and papillary projections. No clear connection with any of the surrounding organs was identified. Malignancy could not be excluded, and surgery was indicated. During surgery, the large mass was found to be attached by a narrow stalk to the large curvature of the stomach. Results. The histological features and immunohistiochemical profile of the tumor cells (positivity for CD117 and CD34) were consistent with a gastrointestinal stromal tumor with a high risk of progressive disease according to the Fletcher classification. Diagnosis was confirmed by mutational analysis; this demonstrated mutation in exon 14 of PDGFRA. During the followup of 97 months, the patient had a cancer-free survival. Conclusions. This case demonstrates that gastrointestinal stromal tumors (GISTs) with extensive cystic degeneration should be considered in the differential diagnosis of a cystic abdominal mass.