Decision-Making Under Uncertainty: Beyond Probabilities

This position paper reflects on the state-of-the-art in decision-making under uncertainty. A classical assumption is that probabilities can sufficiently capture all uncertainty in a system. In this paper, the focus is on the uncertainty that goes beyond this classical interpretation, particularly by employing a clear distinction between aleatoric and epistemic uncertainty. The paper features an overview of Markov decision processes (MDPs) and extensions to account for partial observability and adversarial behavior. These models sufficiently capture aleatoric uncertainty but fail to account for epistemic uncertainty robustly. Consequently, we present a thorough overview of so-called uncertainty models that exhibit uncertainty in a more robust interpretation. We show several solution techniques for both discrete and continuous models, ranging from formal verification, over control-based abstractions, to reinforcement learning. As an integral part of this paper, we list and discuss several key challenges that arise when dealing with rich types of uncertainty in a model-based fashion

Maintaining fixation by children in a virtual reality version of pupil perimetry

The assessment of visual field sensitivities in young children continues to be a challenge. Children often do not sit still, fail to fixate stimuli for longer durations, and have limited verbal capacity to report visibility. We investigated the use of a head-mounted VR display, gaze-contingent flicker pupil perimetry (gcFPP), and three fixation stimulus conditions to determine best practices for optimal fixation and pupil response quality. A total of twenty children (3-11y) passively fixated a dot, counted the repeated appearance of an animated character, and watched an animated movie in separate trials of 80s each. We presented large flickering patches at different eccentricities and angles in the periphery to evoke pupillary oscillations (20 locations, 4s per location). The results showed that gaze precision and accuracy did not differ significantly across the fixation conditions but pupil amplitudes were strongest for the dot and count task. We recommend the use of the fixation counting task for pupil perimetry because children enjoyed it the most and it achieved strongest pupil responses. The VR set-up appears to be an ideal apparatus for children to allow free range of movement, an engaging visual task, and reliable eye measurements

One-Year Morbidity Following Videoscopic Inguinal Lymphadenectomy for Stage III Melanoma

Simple Summary Inguinal lymphadenectomy (the removal of lymph nodes in the groin) is currently part of the treatment options for stage III melanoma patients. Surgery can be performed using one large inguinal incision (open approach) or a few smaller incisions (videoscopic approach). Previous research has already shown less severe complications and comparable oncologic outcomes after the videoscopic approach. Postoperative lymphedema following inguinal lymphadenectomy is a well-known problem which can potentially decrease quality of life. With the arrival of adjuvant systemic treatment options, less invalidating surgery is highly desirable. However, lymphedema and quality of life have only been investigated after the open approach. Therefore, we evaluated lymphedema and quality of life following videoscopic inguinal lymphadenectomy for stage III melanoma. The videoscopic inguinal lymphadenectomy is a feasible approach due to the comparable lymphedema incidence and normalization of quality of life during follow-up. Purpose: We aimed to elucidate morbidity following videoscopic inguinal lymphadenectomy for stage III melanoma. Methods: Melanoma patients who underwent a videoscopic inguinal lymphadenectomy between November 2015 and May 2019 were included. The measured outcomes were lymphedema and quality of life. Patients were reviewed one day prior to surgery and postoperatively every 3 months for one year. Results: A total number of 34 patients were included for participation; 19 (55.9%) patients underwent a concomitant iliac lymphadenectomy. Lymphedema incidence was 40% at 3 months and 50% at 12 months after surgery. Mean interlimb volume difference increased steadily from 1.8% at baseline to 6.9% at 12 months (p = 0.041). Median Lymph-ICF-LL total score increased from 0.0 at baseline to 12.0 at 3 months, and declined to 8.5 at 12 months (p = 0.007). Twelve months after surgery, Lymph-ICF-LL scores were higher for females (p = 0.021) and patients that received adjuvant radiotherapy (p = 0.013). The Median Distress Thermometer and EORTC QLQ-C30 summary score recovered to baseline at 12 months postoperatively (p = 0.747 and p = 0.203, respectively). Conclusions: The onset of lymphedema is rapid and continues to increase up to one year after videoscopic inguinal lymphadenectomy. Quality of life recovers to the baseline value

Maintaining fixation by children in a virtual reality version of pupil perimetry

The assessment of the visual field in young children continues to be a challenge. Children often do not sit still, fail to fixate stimuli for longer durations, and have limited verbal ca-pacity to report visibility. Therefore, we introduced a head-mounted VR display with gaze-contingent flicker pupil perimetry (VRgcFPP). We presented large flickering patches at different eccentricities and angles in the periphery to evoke pupillary oscillations, and three fixation stimulus conditions to determine best practices for optimal fixation and pupil response quality. A total of twenty children (3-11y) passively fixated a dot, counted the re-peated appearance of an animated character(counting task), and watched an animated movie in separate trials of 80s each (20 patch locations, 4s per location).The results showed that gaze precision and accuracy did not differ significantly across the fixation conditions but pupil amplitudes were strongest for the dot and count task. The VR set-up appears to be an ideal apparatus for children to allow free range of movement, an engaging visual task, and reliable eye measurements. We recommend the use of the fixation count-ing task for pupil perimetry because children enjoyed it the most and it achieved strongest pupil responses

Crypt fusion as a homeostatic mechanism in the human colon.

OBJECTIVE: The crypt population in the human intestine is dynamic: crypts can divide to produce two new daughter crypts through a process termed crypt fission, but whether this is balanced by a second process to remove crypts, as recently shown in mouse models, is uncertain. We examined whether crypt fusion (the process of two neighbouring crypts fusing into a single daughter crypt) occurs in the human colon. DESIGN: We used somatic alterations in the gene cytochrome c oxidase (CCO) as lineage tracing markers to assess the clonality of bifurcating colon crypts (n=309 bifurcating crypts from 13 patients). Mathematical modelling was used to determine whether the existence of crypt fusion can explain the experimental data, and how the process of fusion influences the rate of crypt fission. RESULTS: In 55% (21/38) of bifurcating crypts in which clonality could be assessed, we observed perfect segregation of clonal lineages to the respective crypt arms. Mathematical modelling showed that this frequency of perfect segregation could not be explained by fission alone (p<10-20). With the rates of fission and fusion taken to be approximately equal, we then used the distribution of CCO-deficient patch size to estimate the rate of crypt fission, finding a value of around 0.011 divisions/crypt/year. CONCLUSIONS: We have provided the evidence that human colonic crypts undergo fusion, a potential homeostatic process to regulate total crypt number. The existence of crypt fusion in the human colon adds a new facet to our understanding of the highly dynamic and plastic phenotype of the colonic epithelium.wellcome trust royal societ

Study on intracranial meningioma using PET ligand investigation during follow-up over years (SIMPLIFY)

Purpose Radiologic follow-up of patients with a meningioma at the skull base or near the venous sinuses with magnetic resonance imaging (MRI) after stereotactic radiotherapy (SRT) and neurosurgical resection(s) can be difficult to interpret. This study evaluates the addition of C-11-methionine positron emission tomography (MET-PET) to the regular MRI follow-up. Methods This prospective pilot study included patients with predominantly WHO grade I meningiomas at the skull base or near large vascular structures. Previous SRT was part of their oncological treatment. A MET-PET in adjunct to their regular MRI follow-up was performed. The standardized uptake value (SUV) was determined for the tumor and the healthy brain, on the pre-SRT target delineation MET-PET and the follow-up MET-PET. Tumor-to-normal ratios were calculated, and C-11-methionine uptake over time was analyzed. Agreement between the combined MRI/MET-PET report and the MRI-only report was determined using Cohen's kappa. Results Twenty patients with stable disease underwent an additional MET-PET, with a median follow-up of 84 months after SRT. Post-SRT SUV T/N ratios ranged between 2.16 and 3.17. When comparing the pre-SRT and the post-SRT MET-PET, five categories of SUV T/N ratios did not change significantly. Only the SUVpeak T/N-cortex decreased significantly from 2.57 (SD 1.02) to 2.20 (SD 0.87) [p = 0.004]. A kappa of 0.77 was found, when comparing the MRI/MET-PET report to the MRI-only report, indicating no major change in interpretation of follow-up data. Conclusion In this pilot study, C-11-methionine uptake remained remarkably high in meningiomas with long-term follow-up after SRT. Adding MET-PET to the regular MRI follow-up had no impact on the interpretation of follow-up imaging

LKB1 as the ghostwriter of crypt history

Familial cancer syndromes present rare insights into malignant tumor development. The molecular background of polyp formation and the cancer prone state in Peutz-Jeghers syndrome remain enigmatic to this day. Previously, we proposed that Peutz-Jeghers polyps are not pre-malignant lesions, but an epiphenomenon to the malignant condition. However, Peutz-Jeghers polyp formation and the cancer-prone state must both be accounted for by the same molecular mechanism. Our contribution focuses on the histopathology of the characteristic Peutz-Jeghers polyp and recent research on stem cell dynamics and how these concepts relate to Peutz-Jeghers polyposis. We discuss a protracted clonal evolution scenario in Peutz-Jeghers syndrome due to a germline LKB1 mutation. Peutz-Jeghers polyp formation and malignant transformation are separately mediated through the same molecular mechanism played out on different timescales. Thus, a single mechanism accounts for the development of benign Peutz-Jeghers polyps and for malignant transformation in Peutz-Jeghers syndrome

Immunosuppressive niche engineering at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC

Endoscopic tissue sampling - Part 2 : Lower gastrointestinal tract. European Society of Gastrointestinal Endoscopy (ESGE) Guideline

1: ESGE suggests performing segmental biopsies (at least two from each segment), which should be placed in different specimen containers (ileum, cecum, ascending, transverse, descending, and sigmoid colon, and rectum) in patients with clinical and endoscopic signs of colitis.Weak recommendation, low quality of evidence. 2: ESGE recommends taking two biopsies from the right hemicolon (ascending and transverse colon) and, in a separate container, two biopsies from the left hemicolon (descending and sigmoid colon) when microscopic colitis is suspected.Strong recommendation, low quality of evidence. 3: ESGE recommends pancolonic dye-based chromoendoscopy or virtual chromoendoscopy with targeted biopsies of any visible lesions during surveillance endoscopy in patients with inflammatory bowel disease. Strong recommendation, moderate quality of evidence. 4: ESGE suggests that, in high risk patients with a history of colonic neoplasia, tubular-appearing colon, strictures, ongoing therapy-refractory inflammation, or primary sclerosing cholangitis, chromoendoscopy with targeted biopsies can be combined with four-quadrant non-targeted biopsies every 10 cm along the colon. Weak recommendation, low quality of evidence. 5: ESGE recommends that, if pouch surveillance for dysplasia is performed, visible abnormalities should be biopsied, with at least two biopsies systematically taken from each of the afferent ileal loop, the efferent blind loop, the pouch, and the anorectal cuff.Strong recommendation, low quality of evidence. 6: ESGE recommends that, in patients with known ulcerative colitis and endoscopic signs of inflammation, at least two biopsies be obtained from the worst affected areas for the assessment of activity or the presence of cytomegalovirus; for those with no evident endoscopic signs of inflammation, advanced imaging technologies may be useful in identifying areas for targeted biopsies to assess histologic remission if this would have therapeutic consequences. Strong recommendation, low quality of evidence. 7: ESGE suggests not biopsying endoscopically visible inflammation or normal-appearing mucosa to assess disease activity in known Crohn's disease.Weak recommendation, low quality of evidence. 8: ESGE recommends that adequately assessed colorectal polyps that are judged to be premalignant should be fully excised rather than biopsied.Strong recommendation, low quality of evidence. 9: ESGE recommends that, where endoscopically feasible, potentially malignant colorectal polyps should be excised en bloc rather than being biopsied. If the endoscopist cannot confidently perform en bloc excision at that time, careful representative images (rather than biopsies) should be taken of the potential focus of cancer, and the patient should be rescheduled or referred to an expert center.Strong recommendation, low quality of evidence. 10: ESGE recommends that, in malignant lesions not amenable to endoscopic excision owing to deep invasion, six carefully targeted biopsies should be taken from the potential focus of cancer.Strong recommendation, low quality of evidence