Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

Percutaneous left atrial appendage closure reduces cost of care independent of the institutional cumulative caseload in patients with non-valvular atrial fibrillation.

BACKGROUND: Data on the impact of the cumulative percutaneous left atrial appendage closure (LAAC) caseload on cardiovascular outpatient and hospitalisation costs are limited. METHODS: The present single-institution analysis includes patients treated consecutively from the beginning of our LAAC experience in January 2012 until December 2016. Pre- and post-LAAC costs for hospitalisation and ambulatory visits were included. RESULTS: A total of 676 patients underwent percutaneous LAAC (using the Watchman device): 49 (2012), 78 (2013), 211 (2014), 210 (2015), and 129 (2016). LAAC procedural costs were stable over the years (overall median €9639; 2012: €9630; 2013: €10,003; 2014: €9841; 2015: €9394; 2016: €9530; p = 0.8) and there was no correlation between cumulative caseload and procedural costs (p = 0.9). Although annualised cardiovascular management costs after LAAC were lower than before LAAC (median difference between pre-LAAC and post-LAAC yearly costs: €727; 2012: €235; 2013: €1187; 2014: €716; 2015: €527; 2016: €1052; p = 0.5 among years analysed) from the beginning of the cumulative procedural experience, a significant reduction in costs was observed only from 2014 onwards. Institutional cumulative LAAC caseload and year of procedure were not related to the amount of reduction in the costs for cardiovascular care. CONCLUSION: LAAC led to cost-of-care savings from the beginning of our institutional procedural experience.

No longer a historical ailment: two cases of childhood scurvy with recommendations for bone health providers.

PURPOSE: Scurvy, due to vitamin C deficiency, is commonly referenced as a "forgotten" or "historical" disease. A growing number of case reports challenge this notion. Bone health providers are often consulted early in the presentation of scurvy to evaluate musculoskeletal complaints resulting from impaired collagen production and disrupted endochondral bone formation. In this report, we describe two cases of childhood scurvy. Our objective is to summarize the key features of scurvy for bone health providers, with the goal of raising awareness and facilitating diagnosis in future cases. CASE DESCRIPTIONS: Case one occurred in a 12-year-old non-verbal, non-ambulatory female on a ketogenic diet for refractory epilepsy. Clinical findings included hemarthrosis, transfusion dependent anemia, elevated inflammatory markers, and epiphysiolysis. Magnetic resonance imaging (MRI) revealed multi-focal bone marrow signal abnormalities and physeal irregularities. Case two occurred in a typically developing 5-year-old male presenting with limp and knee pain. Symptoms progressed despite casting and immobilization. Mild anemia, elevated inflammatory markers, and multi-focal marrow and physeal MRI abnormalities were identified. Subsequent dietary history revealed total absence of fruit or vegetable consumption. The diagnosis of scurvy was confirmed in both cases by undetectable plasma vitamin C concentrations. Treatment with vitamin C led to rapid clinical improvement. CONCLUSION: Scurvy can no longer be considered a historical diagnosis and should not be forgotten when evaluating children with musculoskeletal ailments. Early recognition of the signs, symptoms, and imaging findings of scurvy can reduce the clinical burden of this disease with the timely initiation of vitamin C therapy.

[Malignant tumors of the oral cavity]. / Tumoren der Mundhöhle.

CLINICAL/METHODICAL ISSUE: Oral cavity malignancies are the most common tumors in the field of ear, nose and throat medicine or otorhinolaryngology worldwide. It comprises a heterogeneous group of tumors, the knowledge of which is necessary to meet the different requirements of diagnostics and therapy. STANDARD RADIOLOGICAL METHODS: Computed tomography (CT), magnetic resonance imaging (MRI), sonography (US), nuclear medical procedures (NUK). PERFORMANCE: The above-mentioned diagnostics are used in a complementary manner. ACHIEVEMENTS: Early diagnosis of the tumor improves staging and thus the patient's therapy and prognosis. PRACTICAL RECOMMENDATIONS: The radiologist plays an important role in the interdisciplinary treatment of malignant tumors of the oral cavity. Despite great progress in radiotherapy, oncology and immunotherapy, surgery still plays an important role in the treatment of malignant diseases of the oral cavity.

Allogeneic donor split skin grafts for treatment of refractory ulcers in cutaneous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation-a retrospective analysis on seven patients.

Refractory skin ulcers due to severe chronic graft-versus-host disease (cGVHD) remain to be associated with significant morbidity and mortality.We performed an allogeneic donor skin transplantation in seven adult patients after allogeneic hematopoietic stem cell transplantation for cGVHD-associated refractory skin ulcers. While four patients received a split skin graft (SSG), in one patient, a full thickness skin graft for two small refractory ulcers of the ankle was performed, and one patient received in vitro expanded donor keratinocyte grafts derived from hair roots of the original unrelated donor. In one additional patient, a large deep fascial defect of the lower leg was covered with an autologous greater omentum free graft before coverage with an allogeneic SSG. An additional patient was treated with an autologous scrotal skin graft for a refractory ulcer associated with deep sclerosis of cGVHD after unrelated donor transplantation.All skin grafts engrafted and resulted in permanent coverage of the grafted ulcers without any signs of immunological mediated damage. In the patient receiving in vitro expanded keratinocyte grafts, two localized ulcers were permanently covered by donor skin while this approach failed to cover extensive circular ulcers of the lower legs.Allogeneic donor skin grafts are a valuable treatment option in refractory ulcers due to cGVHD but are restricted mainly to related donors while keratinocyte grafts from unrelated donors remain experimental. In male patients lacking a related donor, autologous scrotal skin graft may be an alternative option.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

This corrects the article DOI: 10.1038/bjc.2014.209.

Reference point insensitive molecular data analysis.

MOTIVATION: In biomedicine, every molecular measurement is relative to a reference point, like a fixed aliquot of RNA extracted from a tissue, a defined number of blood cells, or a defined volume of biofluid. Reference points are often chosen for practical reasons. For example, we might want to assess the metabolome of a diseased organ but can only measure metabolites in blood or urine. In this case, the observable data only indirectly reflects the disease state. The statistical implications of these discrepancies in reference points have not yet been discussed. RESULTS: Here, we show that reference point discrepancies compromise the performance of regression models like the LASSO. As an alternative, we suggest zero-sum regression for a reference point insensitive analysis. We show that zero-sum regression is superior to the LASSO in case of a poor choice of reference point both in simulations and in an application that integrates intestinal microbiome analysis with metabolomics. Moreover, we describe a novel coordinate descent based algorithm to fit zero-sum elastic nets. AVAILABILITY AND IMPLEMENTATION: The R-package "zeroSum" can be downloaded at https://github.com/rehbergT/zeroSum Moreover, we provide all R-scripts and data used to produce the results of this manuscript as Supplementary Material CONTACT: Michael.Altenbuchinger@ukr.de, Thorsten.Rehberg@ukr.de and Rainer.Spang@ukr.deSupplementary information: Supplementary material is available at Bioinformatics online.

Clinical significance of perioperative changes in ankle-brachial index with regard to extremity-related outcome in non-diabetic patients with critical limb ischemia.

PURPOSE: To evaluate the significance of perioperative changes in ankle-brachial index (ABI) with regard to extremity-related outcome in non-diabetic patients with critical limb ischemia (CLI) following revascularization. METHODS: The study represents a subanalysis of the multicentric Registry of First-line Treatment in Patients with CLI (CRITISCH). After exclusion of diabetic patients, conservative cases, and primary major amputation, 563 of 1200 CRITISCH patients (mean age 74 ± 10.7 years) were analyzed. This population was divided into two groups regarding perioperative ABI changes ∆ + 0.15 (Group 1) or ∆ - 0.15 (Group 2). Study endpoints were reintervention and major amputation during a mean follow-up of 14.6 ± 9 months. Logistic regression was performed in order to identify factors for ABI group affiliation. RESULTS: There were 279 patients in Group 1 (49.5%) and 284 in Group 2 (51.5%). ABI sensitivity and specificity regarding vessel patency were calculated to be 54 and 87%. A preoperative ABI ≤ 0.4 [odds ratio (OR) 7.7], patent vessels at discharge (OR 12.2), and secondary interventions (OR 2.4) were identified as factors for Group 1 affiliation. Contrariwise, previous revascularization (OR 0.6), a glomerular filtration rate ≤ 15 ml/min/1.73 m2 (OR 0.3), and TASC A lesions (OR 0.2) were associated with Group 2 affiliation. No statistical difference was found with regard to the need of reintervention. However, time to reintervention was significantly shorter in Group 2 compared to that in Group 1 (10.0 ± 9.5 months vs 12.1 ± 9.1 months; p = 0.005). Amputation rate in Group 2 was 14.4%, significantly higher compared to that in Group 1 (6.0%; p < 0.0001). CONCLUSIONS: Failure of perioperative ABI improvement is associated with a higher probability for amputation and should be valued as prognostic factor in non-diabetic patients with CLI. Patients with no/marginal improvement in ABI after revascularization require close follow-up monitoring and may benefit from early reintervention.

[Digital volume tomography : Dedicated scanner and cone beam CT with C­arm systems]. / Digitale Volumentomographie : Dedizierte Scanner und Cone-Beam-CT mit C­Arm-Systeme.

CLINICAL/METHODICAL ISSUE: Digital volume tomography (DVT) and cone-beam computed tomography (CT) with C­arm systems have become established three-dimensional imaging systems as an alternative to CT in some application areas. STANDARD RADIOLOGICAL METHODS: The technology of the systems is well developed so that they have become a competing method to CT imaging in terms of image quality and radiation exposure. PERFORMANCE: An advantage is the better spatial resolution, preferably with dedicated scanner systems, especially in the z direction. The radiation exposure of CT, cone beam CT and DVT are comparable, if the exposure parameter in CT imaging can be adjusted to the lower exposure levels. ACHIEVEMENTS: Advantages of these systems are that they can be used for imaging in a better workflow or to acquire images under conditions not possible in CT, e. g. imaging under stress in orthopedics or to take images in the corona technique with a horizontal gantry in cone-beam CT mammography PRACTICAL RECOMMENDATIONS: The use of three-dimensional imaging is becoming more frequent and will replace planar radiography in additional clinical situations. The three-dimensional imaging without superpositioning of structures has advantages in the visibility of structures and the spatial relation to other organs and structures. In guidelines and recommendations, the number of recommendations given for the use of three-dimensional imaging is increasing. This leads to a small increase in the radiation exposure of patients, a trend which is reflected in the annual reports of the Federal Office for Radiation Protection.

Heparin modification of a biomimetic bone matrix modulates osteogenic and angiogenic cell response in vitro.

In this study, the effect of heparin-modified collagen type I/hydroxyapatite (HA) nanocomposites on key processes of bone regeneration - osteogenesis and angiogenesis - was characterised in vitro. Two approaches were applied for heparin modification: it was either integrated during material synthesis (in situ) or added to the porous scaffolds after their fabrication (post). Cultivation of human bone marrow-derived stromal cells (hBMSC), in heparin-modified versus heparin-free scaffolds, revealed a positive effect of the heparin modification on their proliferation and osteogenic differentiation. The amount of heparin rather than the method used for modification influenced the cell response favouring proliferation at smaller amount (30 mg/g collagen) and differentiation at larger amount (150 mg/g collagen). A co-culture of human umbilical vein endothelial cells (HUVEC) and osteogenically induced hBMSC was applied for in vitro angiogenesis studies. Pre-vascular networks have formed in the porous structure of scaffolds which were not modified with heparin or modified with a low amount of heparin (30 mg/g collagen). The modification with higher heparin quantities seemed to inhibit tubule formation. Pre-loading of the scaffolds with VEGF influenced formation and stability of the pre-vascular structures depending on the presence of heparin: In heparin-free scaffolds, induction of tubule formation and sprouting was more pronounced whereas heparin-modified scaffolds seemed to promote stabilisation of the pre-vascular structures. In conclusion, the modification of mineralised collagen with heparin by using both approaches was found to modulate cellular processes essential for bone regeneration; the amount of heparin has been identified to be crucial to direct cell responses.

Altered immune reconstitution of B and T cells precedes the onset of clinical symptoms of chronic graft-versus-host disease and is influenced by the type of onset.

We analyzed lymphocyte subpopulations and cytokines 3 months after allogeneic hematopoietic stem cell transplantation aiming to identify predictive cellular and serum markers for chronic graft-versus-host disease (cGVHD). Samples of 49 patients (pts) (no cGVHD (n = 14), subsequent quiescent onset (n = 16), de novo onset of cGVHD (n = 19)) were analyzed in the absence of active GVHD by flow cytometry and enzyme-linked immunosorbent assay. All mean absolute cell counts are presented as cells per microliter; relative cell counts are presented as percentage of lymphocytes. Pts with subsequent de novo cGVHD had significantly higher relative and absolute counts of CD4+ T cells including higher absolute counts of CD4+ memory T cells (22.36%; 206.55/µl; 136/µl, respectively) compared to pts with subsequent quiescent onset of cGVHD (12.41%; 83.42/µl; 54.3/µl) and pts without cGVHD (10.55%) with regard to relative counts of CD4+ T cells. Similarly, significantly more relative and absolute regulatory T cell numbers (CD4+FOXP3+) were detected in pts with de novo onset of cGVHD (3.08% and 24.63/µl) compared to those in pts without (1.25% and 9.06/µl) or with quiescent onset of cGVHD (1.15% and 6.91/µl). Finally, relative B cell counts, including naïve and memory B cells, were also significantly decreased in pts developing quiescent cGVHD (0.85, 0.73, 0.12% resp.) when compared to pts with de novo onset (5.61, 5.24, 0.38%). The results demonstrate that alterations in immune reconstitution are already present before onset of clinical symptoms and differ between de novo and quiescent onset of disease.

Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO).

We describe genetic and clinical characteristics of acute myeloid leukemia (AML) patients according to age from an academic population-based registry. Adult patients with newly diagnosed AML at 63 centers in Germany and Austria were followed within the AMLSG BiO registry (NCT01252485). Between January 1, 2012, and December 31, 2014, data of 3525 patients with AML (45% women) were collected. The median age was 65 years (range 18-94). The comparison of age-specific AML incidence rates with epidemiological cancer registries revealed excellent coverage in patients < 70 years old and good coverage up to the age of 80. The distribution according to the European LeukemiaNet (ELN) risk categorization from 2010 was 20% favorable, 31% intermediate-1, 28% intermediate-2, and 21% adverse. With increasing age, the relative but not the absolute prevalence of patients with ELN favorable and intermediate-1 risk (p < 0.001), with activating FLT3 mutations (p < 0.001), with ECOG performance status < 2 (p < 0.001), and with HCT-CI comorbidity index < 3 (p < 0.001) decreased. Regarding treatment, obesity and favorable risk were associated with an intensive treatment, whereas adverse risk, higher age, and comorbidity index > 0 were associated with non-intensive treatment or best supportive care. The AMLSG BiO registry provides reliable population-based distributions of genetic, clinical, and treatment characteristics according to age.

Laparoscopic lavage versus surgical resection for acute diverticulitis with generalised peritonitis: a systematic review and meta-analysis.

This systematic review and meta-analysis investigates current evidence on the therapeutic role of laparoscopic lavage in the management of diverticular peritonitis. A systematic review of the literature was performed on PubMed until June 2016, according to preferred reporting items for systematic reviews and meta-analyses guidelines. All randomised controlled trials comparing laparoscopic lavage with surgical resection, irrespective of anastomosis or stoma formation, were analysed. After assessment of titles and full text, 3 randomised trials fulfilled the inclusion criteria. Overall the quality of evidence was low because of serious concerns regarding the risk of bias and imprecision. In the laparoscopic lavage group, there was a statistically significant higher rate of postoperative intra-abdominal abscess (RR 2.54, 95% CI 1.34-4.83), a lower rate of postoperative wound infection (RR 0.10, 95% CI 0.02-0.51), and a shorter length of postoperative hospital stay during index admission (WMD = -2.03, 95% CI -2.59 to -1.47). There were no statistically significant differences in terms of postoperative mortality at index admission or within 30 days from intervention in all Hinchey stages and in Hinchey stage III, postoperative mortality at 12 months, surgical reintervention at index admission or within 30-90 days from index intervention, stoma rate at 12 months, or adverse events within 90 days of any Clavien-Dindo grade. The surgical reintervention rate at 12 months from index intervention was significantly lower in the laparoscopic lavage group (RR 0.57, 95% CI 0.38-0.86), but these data included emergency reintervention and planned intervention (stoma reversal). This systematic review and meta-analysis did not demonstrate any significant difference between laparoscopic peritoneal lavage and traditional surgical resection in patients with peritonitis from perforated diverticular disease, in terms of postoperative mortality and early reoperation rate. Laparoscopic lavage was associated with a lower rate of stoma formation. However, the finding of a significantly higher rate of postoperative intra-abdominal abscess in patients who underwent laparoscopic lavage compared to those who underwent surgical resection is of concern. Since the aim of surgery in patients with peritonitis is to treat the sepsis, if one technique is associated with more postoperative abscesses, then the technique is ineffective. Even so, laparoscopic lavage does not appear fundamentally inferior to traditional surgical resection and this technique may achieve reasonable outcomes with minimal invasiveness.

Biomarker research with prospective study designs for the early detection of cancer.

This article describes the principles of marker research with prospective studies along with examples for diagnostic tumor markers. A plethora of biomarkers have been claimed as useful for the early detection of cancer. However, disappointingly few biomarkers were approved for the detection of unrecognized disease, and even approved markers may lack a sound validation phase. Prospective studies aimed at the early detection of cancer are costly and long-lasting and therefore the bottleneck in marker research. They enroll a large number of clinically asymptomatic subjects and follow-up on incident cases. As invasive procedures cannot be applied to collect tissue samples from the target organ, biomarkers can only be determined in easily accessible body fluids. Marker levels increase during cancer development, with samples collected closer to the occurrence of symptoms or a clinical diagnosis being more informative than earlier samples. Only prospective designs allow the serial collection of pre-diagnostic samples. Their storage in a biobank upgrades cohort studies to serve for both, marker discovery and validation. Population-based cohort studies, which may collect a wealth of data, are commonly conducted with just one baseline investigation lacking serial samples. However, they can provide valuable information about factors that influence the marker level. Screening programs can be employed to archive serial samples but require significant efforts to collect samples and auxiliary data for marker research. Randomized controlled trials have the highest level of evidence in assessing a biomarker's benefit against usual care and present the most stringent design for the validation of promising markers as well as for the discovery of new markers. In summary, all kinds of prospective studies can benefit from a biobank as they can serve as a platform for biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

Correlation of electrochromic properties and oxidation states in nanocrystalline tungsten trioxide.

Although tungsten trioxide (WO3) has been extensively studied since its electrochromic properties were first discovered, the mechanism responsible for the coloration or bleaching effect is still disputed. New insights into the coloration mechanism of electrochromic, nanocrystalline WO3 are provided in this paper by studying thin WO3 films combining the electrochemical and spectroscopic techniques. By employing in situ UV-Vis transmission spectroscopy at a fixed spectral band pass during electrochemical experiments, such as cyclic voltammetry, a two-step insertion process for both protons and lithium ions is identified, of which one step exhibits a significantly higher coloration efficiency than the other. To obtain a better understanding of the insertion process AxWO3 (A = H, Li,…) thin films were studied at different stages of intercalation using UV-Vis and X-ray photoelectron spectroscopy. The results show that the first step of the intercalation process represents the reduction from initial W(6+) to W(5+) and the second step the reduction of W(5+) to W(4+). We found that the blue coloration of this nanocrystalline tungsten trioxide is mainly due to the presence of W(4+) rather than that of W(5+).

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

Damage control surgery for abdominal emergencies.

BACKGROUND: Damage control surgery is a management sequence initiated to reduce the risk of death in severely injured patients presenting with physiological derangement. Damage control principles have emerged as an approach in non-trauma abdominal emergencies in order to reduce mortality compared with primary definitive surgery. METHODS: A PubMed/MEDLINE literature review was conducted of data available over the past decade (up to August 2013) to gain information on current understanding of damage control surgery for abdominal surgical emergencies. Future directions for research are discussed. RESULTS: Damage control surgery facilitates a strategy for life-saving intervention for critically ill patients by abbreviated laparotomy with subsequent reoperation for delayed definitive repair after physiological resuscitation. The six-phase strategy (including damage control resuscitation in phase 0) is similar to that for severely injured patients, although non-trauma indications include shock from uncontrolled haemorrhage or sepsis. Minimal evidence exists to validate the benefit of damage control surgery in general surgical abdominal emergencies. The collective published experience over the past decade is limited to 16 studies including a total of 455 (range 3-99) patients, of which the majority are retrospective case series. However, the concept has widespread acceptance by emergency surgeons, and appears a logical extension from pathophysiological principles in trauma to haemorrhage and sepsis. The benefits of this strategy depend on careful patient selection. Damage control surgery has been performed for a wide range of indications, but most frequently for uncontrolled bleeding during elective surgery, haemorrhage from complicated gastroduodenal ulcer disease, generalized peritonitis, acute mesenteric ischaemia and other sources of intra-abdominal sepsis. CONCLUSION: Damage control surgery is employed in a wide range of abdominal emergencies and is an increasingly recognized life-saving tactic in emergency surgery performed on physiologically deranged patients.

Robust optimization strategies for contour uncertainties in online adaptive radiation therapy.

Objective.Online adaptive radiation therapy requires fast and automated contouring of daily scans for treatment plan re-optimization. However, automated contouring is imperfect and introduces contour uncertainties. This work aims at developing and comparing robust optimization strategies accounting for such uncertainties.Approach.A deep-learning method was used to predict the uncertainty of deformable image registration, and to generate a finite set of daily contour samples. Ten optimization strategies were compared: two baseline methods, five methods that convert contour samples into voxel-wise probabilities, and three methods accounting explicitly for contour samples as scenarios in robust optimization. Target coverage and organ-at-risk (OAR) sparing were evaluated robustly for simplified proton therapy plans for five head-and-neck cancer patients.Results.We found that explicitly including target contour uncertainty in robust optimization provides robust target coverage with better OAR sparing than the baseline methods, without increasing the optimization time. Although OAR doses first increased when increasing target robustness, this effect could be prevented by additionally including robustness to OAR contour uncertainty. Compared to the probability-based methods, the scenario-based methods spared the OARs more, but increased integral dose and required more computation time.Significance.This work proposed efficient and beneficial strategies to mitigate contour uncertainty in treatment plan optimization. This facilitates the adoption of automatic contouring in online adaptive radiation therapy and, more generally, enables mitigation also of other sources of contour uncertainty in treatment planning.

Fecal Microbiota Transfer in Acute Graft-versus-Host Disease following Allogeneic Stem Cell Transplantation.

Background: Acute graft-versus-host disease (GvHD) is a major and sometimes lethal complication following allogeneic stem cell transplantation (aSCT). In the last 10 years, a massive loss of microbiota diversity with suppression of commensal bacteria and their protective metabolites has been identified as a major risk factor of GvHD. Summary: Since 2018, several studies have been published showing some efficacy of fecal microbiota transfer (FMT) in aSCT patients. FMT was used (1) to eliminate antibiotic resistant bacteria, (2) to restore microbiota diversity after hematopoietic recovery, or (3) in most cases to treat steroid-resistant GvHD. Overall response rates between 30 and 50% have been reported, but randomized trials are still pending. Newer approaches try to evaluate the role of prophylactic FMT in order to prevent GvHD and other complications. Although aSCT patients are heavily immunosuppressed, no major safety concerns regarding FMT have been reported so far. Key Message: FMT is a promising approach for modulation of GvHD after aSCT and should be further explored in randomized trials.

DiffuseRT: predicting likely anatomical deformations of patients undergoing radiotherapy.

Objective. Predicting potential deformations of patients can improve radiotherapy treatment planning. Here, we introduce new deep-learning models that predict likely anatomical changes during radiotherapy for head and neck cancer patients.Approach. Denoising diffusion probabilistic models (DDPMs) were developed to generate fraction-specific anatomical changes based on a reference cone-beam CT (CBCT), the fraction number and the dose distribution delivered. Three distinct DDPMs were developed: (1) theimage modelwas trained to directly generate likely future CBCTs, (2) the deformable vector field (DVF) model was trained to generate DVFs that deform a reference CBCT and (3) thehybrid modelwas trained similarly to the DVF model, but without relying on an external deformable registration algorithm. The models were trained on 9 patients with longitudinal CBCT images (224 CBCTs) and evaluated on 5 patients (152 CBCTs).Results. The generated images mainly exhibited random positioning shifts and small anatomical changes for early fractions. For later fractions, all models predicted weight losses in accordance with the training data. The distributions of volume and position changes of the body, esophagus, and parotids generated with the image and hybrid models were more similar to the ground truth distribution than the DVF model, evident from the lower Wasserstein distance achieved with the image (0.33) and hybrid model (0.30) compared to the DVF model (0.36). Generating several images for the same fraction did not yield the expected variability since the ground truth anatomical changes were only in 76% of the fractions within the 95% bounds predicted with the best model. Using the generated images for robust optimization of simplified proton therapy plans improved the worst-case clinical target volume V95 with 7% compared to optimizing with 3 mm set-up robustness while maintaining a similar integral dose.Significance. The newly developed DDPMs generate distributions similar to the real anatomical changes and have the potential to be used for robust anatomical optimization.