Fractal analysis of extracellular matrix for observer-independent quantification of intestinal fibrosis in Crohn's disease.

Prevention of intestinal fibrosis remains an unresolved problem in the treatment of Crohn's disease (CD), as specific antifibrotic therapies are not yet available. Appropriate analysis of fibrosis severity is essential for assessing the therapeutic efficacy of potential antifibrotic drugs. The aim of this study was to develop an observer-independent method to quantify intestinal fibrosis in surgical specimens from patients with CD using structural analysis of the extracellular matrix (ECM). We performed fractal analysis in fibrotic and control histological sections of patients with surgery for CD (n = 28). To specifically assess the structure of the collagen matrix, polarized light microscopy was used. A score to quantify collagen fiber alignment and the color of the polarized light was established. Fractal dimension as a measure for the structural complexity correlated significantly with the histological fibrosis score whereas lacunarity as a measure for the compactness of the ECM showed a negative correlation. Polarized light microscopy to visualize the collagen network underlined the structural changes in the ECM network in advanced fibrosis. In conclusion, observer-independent quantification of the structural complexity of the ECM by fractal analysis is a suitable method to quantify the degree of intestinal fibrosis in histological samples from patients with CD.

B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation.

Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1-/- mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.

CT Attenuation of Hepatic Pancreatic Cancer Metastases Correlates with Prognostically Detrimental Metastatic Necrosis.

Percutaneous CT-guided biopsy is a frequently performed procedure for the confirmation and molecular workup of hepatic metastases of pancreatic ductal adenocarcinoma (PDAC). Tumor necrosis of primary PDAC has shown a negative prognostic impact in recent studies. This study aims to examine predictability in CT scans and the prognostic impact of necrosis in hepatic metastases of PDAC. In this tertiary-center retrospective cohort study, we included 36 patients with hepatic metastases of PDAC who underwent CT-guided hepatic biopsies. Normalized attenuation of the biopsied metastasis was determined in venous phase contrast-enhanced planning scans obtained prior to biopsy by automatic, threshold-based 3D segmentation and manual, blinded 2D segmentation. A board-certified pathologist specialized in hepatic pathology histologically quantified the tumor necrosis and cellularity of the biopsy cylinders. We found a significant inverse-linear correlation between normalized attenuation and the fraction of necrosis (Pearson's r = 0.51, p < 0.001 for automatic 3D segmentation or Pearson's r = 0.52, p < 0.001 for manual 2D segmentation), whereas no correlation was found with tumor cellularity. Additionally, we discovered that patients with a fraction of necrosis ≥ 20% in metastases had a significantly shorter overall survival (p < 0.035). In summary, tumor necrosis of PDAC metastases can be estimated from contrast-enhanced CT scans, which could help to improve biopsy sample pattern planning. In addition, liver metastatic necrosis may serve as a prognostic biomarker in PDAC.

[Co-occurrence of Whipple's disease and hyperparathyroidism - coincidence or causal relationship?] / Gemeinsames Auftreten von Morbus Whipple und Hyperparathyreoidismus ­ Zufall oder kausaler Zusammenhang?

Whipple's disease is a rare infectious disease with multiple clinical manifestations. The disease is named after George Hoyt Whipple, who first recorded the illness in 1907 after conducting the autopsy of a 36-year-old man with weight loss, diarrhea, and arthritis. Under the microscope, Whipple discovered a rod-shaped bacterium in the patient's intestinal wall, which was not confirmed as a new bacterial species until 1992, when it was named Tropheryma whipplei.Recurrence of Whipple's disease can occur years after an initial diagnosis and often manifests with extraintestinal symptoms such as arthritides or skin efflorescences, years before a gastrointestinal complaint. However, the simultaneous occurrence of primary hyperparathyroidism in the present case is a hitherto unknown clinical picture and opens up new questions and perspectives in the context of diagnostics and therapy.

Perioperative Low-Dose Prednisolone Treatment Has Beneficial Effects on Postoperative Recovery and Anastomotic Healing in a Murine Colitis Model.

BACKGROUND AND AIMS: High-dose glucocorticoid treatment has been identified as a risk factor for anastomotic leakage in patients with inflammatory bowel disease [IBD] undergoing bowel resection surgery. By contrast, active disease during surgery is also associated with elevated morbidity. Perioperative low-dose treatment might be beneficial regarding postoperative outcomes by controlling disease activity. The present study is the first to investigate the dose-dependent effect of perioperative prednisolone therapy in a murine IBD model combining dextran sodium sulphate [DSS] colitis with intestinal anastomosis surgery. METHODS: In 84 10-week-old wild-type mice, a colorectal anastomosis was performed using a microsurgical technique. Half the animals received induction of chemical colitis with 2% DSS via drinking water prior to surgery. In both groups, one-third of the animals received daily oral administration of high-dose [0.533 mg/kg] and one-third low-dose [0.133 mg/kg] prednisolone. Evaluation was performed on postoperative days 3 and 7. RESULTS: While high-dose prednisolone treatment led to an increased anastomotic leakage rate in mice under colitis, low-dose prednisolone treatment limited preoperative disease activity and did not influence the leakage rate. Histological examination showed a beneficial effect of low-dose prednisolone treatment on microscopic abscess formation at the anastomotic site in DSS mice as well as an increased anastomotic healing score. CONCLUSIONS: We demonstrate a beneficial effect of perioperative short-term low-dose prednisolone treatment on intestinal anastomotic healing in the context of colitis. Perioperative use of short-term low-dose prednisolone treatment might be beneficial in IBD patients who need to undergo surgery during active disease.

A nationwide population-based study on the clinical and economic burden of anastomotic leakage in colorectal surgery.

AIM: Anastomotic leakage (AL) is one of the most dreaded complications in colorectal surgery. In 2013, the International Classification of Diseases code K91.83 for AL was introduced in Germany, allowing nationwide analysis of AL rates and associated parameters. The aim of this population-based study was to investigate the current incidence, risk factors, mortality, clinical management, and associated costs of AL in colorectal surgery. METHODS: A data query was performed based on diagnosis-related group data of all hospital cases of inpatients undergoing colon or sphincter-preserving rectal resections between 2013 and 2018 in Germany. RESULTS: A total number of 690,690 inpatient cases were included in this study. AL rates were 6.7% for colon resections and 9.2% for rectal resections in 2018. Regarding the treatment of AL, the application of endoluminal vacuum therapy increased during the studied period, while rates of relaparotomy, abdominal vacuum therapy, and terminal enterostomy remained stable. AL was associated with significantly increased in-house mortality (7.11% vs. 20.11% for colon resections and 3.52% vs. 11.33% for rectal resections in 2018) and higher socioeconomic costs (mean hospital reimbursement volume per case: 14,877€ (no AL) vs. 37,521€ (AL) for colon resections and 14,602€ (no AL) vs. 30,606€ (AL) for rectal resections in 2018). CONCLUSIONS: During the studied time period, AL rates did not decrease, and associated mortality remained at a high level. Our study provides updated population-based data on the clinical and economic burden of AL in Germany. Focused research in the field of AL is still urgently necessary to develop targeted strategies to prevent AL, improve patient care, and decrease socioeconomic costs.

Gastrectomy for cancer beyond life expectancy. A comprehensive analysis of oncological gastric surgery in Germany between 2008 and 2018.

Introduction: Major gastric surgery for distal esophageal and gastric cancer has a strong impact on the quality of life, morbidity, and mortality. Especially in elderly patients reaching their life expectancy, the responsible use and extent of gastrectomy are imperative to achieve a balance between harm and benefit. In the present study, the reimbursement database (German Diagnosis Related Groups (G-DRG) database) of the Statistical Office of the Federal Republic of Germany was queried to evaluate the morbidity and mortality of patients aged above or below 75 years following gastrectomy. Material and methods: All patients in Germany undergoing subtotal gastrectomy (ST), total gastrectomy (T), or gastrectomy combined with esophagectomy (TE) for gastric or distal esophageal cancer (International Statistical Classification of Diseases and Related Health Problems Version 10 (ICD-10) C15.2, C15.5, and C16.0-C16.9) between 2008 and 2018 were included. Intraoperative and postoperative complications as well as comorbidities, in-hospital mortality, and the extent of surgery were assessed by evaluating ICD-10 and operation and procedure key (Operationen- und Prozedurenschlüssel) codes. Results: A total of 67,389 patients underwent oncologic gastric resection in Germany between 2008 and 2018. In total, 21,794 patients received ST, 41,825 received T, and 3,466 received TE, respectively. In 304 cases, the combinations of these, in fact, mutually exclusive procedures were encoded. The proportion of patients aged 75 years or older was 51.4% (n = 11,207) for ST, 32.6% (n = 13,617) for T, and 28.1% (n = 973) for TE. The in-hospital mortality of elderly patients was significantly increased in all three groups. (p < 0.0001) General complications such as respiratory failure (p = 0.0054), acute renal failure (p < 0.0001), acute myocardial failure (p < 0.0001), and the need for resuscitation (ST/T: p < 0.0001/TE: p = 0.0218) were significantly increased after any kind of gastrectomy. Roux-en Y was the most commonly applied reconstruction technique in both young and elderly patients. Regarding lymphadenectomy, systematic D2 dissection was performed less frequently in older patients than in the younger collective in the case of ST and T as well as D3 dissection. Peritonectomy and hyperthermic intraperitoneal chemotherapy were uncommon in elderly patients alongside ST and T compared to younger patients (p < 0.0001). Conclusion: The clinical outcome of major oncological gastric surgery is highly dependent on a patient's age. The elderly show a tremendously increased likelihood of in-hospital mortality and morbidity.

The Effect of Anti-Tumor Necrosis Factor-Alpha Therapy within 12 Weeks Prior to Surgery on Postoperative Complications in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

The rate of abdominal surgical interventions and associated postoperative complications in inflammatory bowel disease (IBD) patients is still substantially high. There is an ongoing debate as to whether or not patients who undergo treatment with anti-tumor necrosis factor-alpha (TNF-α) agents may have an increased risk for general and surgical postoperative complications. Therefore, a systematic review and meta-analysis was conducted in order to assess the effect of anti-TNF-α treatment within 12 weeks (washout period) prior to abdominal surgery on 30-day postoperative complications in patients with IBD. The results of previously published meta-analyses examining the effect of preoperative anti-TNF-α treatment on postoperative complications reported conflicting findings which is why we specifically focus on the effect of anti-TNF-α treatment within 12 weeks prior to surgery. PubMed, Cochrane, Scopus, Web of Science, World Health Organization Trial Registry, ClinicalTrials.gov and reference lists were searched (June 1995−February 2022) to identify studies, investigating effects of anti-TNF-α treatment prior to abdominal surgery on postoperative complications in IBD patients. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated and subgroup analyses were performed. In this case, 55 cohort studies (22,714 patients) were included. Overall, postoperative complications (OR, 1.23; 95% CI, 1.04−1.45; p = 0.02), readmission (OR, 1.39; 95% CI, 1.11−1.73; p = 0.004), and intra-abdominal septic complications (OR, 1.89; 95% CI, 1.44−2.49; p < 0.00001) were significantly higher for anti-TNF-α-treated patients. Significantly higher intra-abdominal abscesses and readmission were found for anti-TNF-α-treated CD patients (p = 0.05; p = 0.002). Concomitant treatment with immunosuppressives in <50% of anti-TNF-α-treated patients was associated with significantly lower mortality rates (OR, 0.32; 95% CI, 0.12−0.83; p = 0.02). Anti-TNF-α treatment within 12 weeks prior to surgery is associated with higher short-term postoperative complication rates (general and surgical) for patients with IBD, especially CD.

Anastomotic Rings and Inflammation Values as Biomarkers for Leakage of Stapled Circular Colorectal Anastomoses.

Reliable markers to predict or diagnose anastomotic leakage (AL) of stapled circular anastomoses following colorectal resections are an important clinical need. Here, we aim to quantitatively investigate the morphology of anastomotic rings as an early available prognostic marker for AL and compare them to established inflammatory markers. We perform a prospective single-center cohort study, including patients undergoing stapled circular anastomosis between August 2020 and August 2021. The predictive value of the anastomotic ring configuration and the neutrophil-to-lymphocyte ratio (NLR) regarding anastomotic leakage is examined by ROC analyses and compared to the C-reactive protein (CRP) as an established marker. We included 204 patients, of which 19 suffered from anastomotic leakage (LEAK group), while in 185 patients the anastomoses healed well (HEAL group). The minimal height of the anastomotic rings as a binary classifier had a good ROC-AUC of 0.81 but was inferior to the NLR at postoperative day (POD) 5, with an excellent ROC-AUC of 0.93. Still, it was superior to the NLR at POD 3 (0.74) and the CRP at POD 3 (ROC-AUC 0.54) and 5 (ROC-AUC 0.70). The minimal height of the anastomotic rings as indicator for technically insufficient anastomoses is a good predictor of AL, while postoperatively the NLR was superior to the CRP in prediction of AL.

Annexin A1 based inflammation resolving mediators and nanomedicines for inflammatory bowel disease therapy.

Inflammatory bowel diseases (IBD) such as Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, progressive, and relapsing disorders of the gastrointestinal tract (GIT), characterised by intestinal epithelial injury and inflammation. Current research shows that in addition to traditional anti-inflammatory therapy, resolution of inflammation and repair of the epithelial barrier are key biological requirements in combating IBD. Resolution mediators include endogenous lipids that are generated during inflammation, e.g., lipoxins, resolvins, protectins, maresins; and proteins such as Annexin A1 (ANXA1). Nanoparticles can specifically deliver these potent inflammation resolving mediators in a spatiotemporal manner to IBD lesions, effectively resolve inflammation, and promote a return to homoeostasis with minimal collateral damage. We discuss these exciting and timely concepts in this review.

Quantification of Bacterial DNA from Infected Human Root Canals Using qPCR and DAPI after Disinfection with Established and Novel Irrigation Protocols.

The removal of bacterial infections within the root canal system is still a challenge. Therefore, the cleansing effect of established and new irrigation-protocols (IP) containing silver diamine fluoride (SDF) 3.8% on the whole root canal system was analyzed using quantitative PCR (qPCR) and 4',6-diamidino-phenylindole-(DAPI)-staining. Extracted human premolars were instrumented up to F2 (ProTaper Gold) under NaCl 0.9% irrigation and incubated with Enterococcus faecalis for 42 days. Subsequently, different ultrasonically agitated IP were applied to the roots: control (no irrigation), 1. NaOCl 3%, EDTA 20%, CHX 2%, 2. NaOCl 3%, EDTA 20%, 3. NaOCl 3%, EDTA 20%, SDF 3.8%, 4. SDF 3.8%, and 5. NaCl 0.9%. One half of the root was investigated fluorescent-microscopically with DAPI. The other half was grinded in a cryogenic mill and the bacterial DNA was quantified with qPCR. The qPCR results showed a statistically significant reduction of bacteria after the application of IP 1, 2, and 3 compared to the control group. While IP 4 lead to a bacterial reduction which was not significant, IP 5 showed no reduction. These data corresponded with DAPI staining. With qPCR a new molecular-biological method for the investigation of the complete root canal system was implemented. The novel IP 3 had an equally good cleansing effect as the already established IP.

[Endometriosis and Menopause]. / Endometriose und Klimakterisches Syndrom.

Endometriosis and Menopause Abstract. Endometriosis is supposed to affect only women in their reproductive years, but endometriotic lesions can reactivate in menopause and cause significant complaints in these patients. Altered needs and co-morbidities of the women request a different approach in therapy than in the younger ages. Reduction in chronic pain on the one hand and alleviation of climacteric symptoms, like hot-flushes and vaginal dryness, on the other hand, are main concerns to the physician in charge. Consequently, keeping the balance between the hypoestrogenic state, which is necessary to reduce activity and size of endometriotic lesions, and hormone replacement therapy (HRT) to relief menopausal complaints, depicts the key in treating these women. Progesterons, GnRH-analoga (with addback) and intrauterine devices depict the basic therapeutic strategy in perimenopausal women. In case of uncertain sonographic findings or intractable symptoms, a surgical approach (and histology) should be performed. Aromatase inhibitors, melatonin, oral GnRH-antagonists and ablation of the endometrium (in bare dysmenorrhea) represent promising alternatives to the established therapy. Requesting an HRT, it is important to add progesterone for at least two years, even in the patients with a prior hysterectomy to avoid a recurrence of residual lesions.

An Automated Measurement Method for the Endodontic Working Width of Lower Molars by Means of Parametric Models Using Cone-beam Computed Tomographcy and Micro-Computed Tomography.

INTRODUCTION: A new method for the approximation of the root canal's cross-sectional shape and its working width using cone-beam computed tomographic (CBCT) or micro-computed tomographic (micro-CT) imaging was introduced. METHODS: Scanned data from 29 extracted human mandibular first and second molar distal root canals without instrumentation were reconstructed and analyzed with a self-developed measurement algorithm. The 3-dimensional volume models were sliced perpendicular to the vertical axis. Using different 2-dimensional parametric models, the contour of each root canal slice was approximated and used to determine the canal's cross-sectional dimensions. The measurements of minor width, major width, and the root canal's conicity were statistically analyzed using analysis of variance. RESULTS: The measured minor and major widths of the investigated root canals were significantly higher (probability value P < .05) when evaluated by CBCT images than the results obtained from micro-CT data. Both dimensions increased starting from the apical foramen (P < .01). The narrowest measured canal widths were 0.19-0.24 mm for CBCT imaging and 0.09-0.21 mm for micro-CT imaging in the apical part. The maximum values for conicity were between 13% and 17% in the cervical third. CONCLUSIONS: The 3-dimensional imaging data from CBCT and micro-CT imaging enabled a valuable anatomic assessment of the root canal's cross-sectional working width along the canal up to the physiological foramen in order to determine an adequate apical diameter as well as the correct measured taper in the cervical and medial part.

Crohn's disease: a population-based study of surgery in the age of biological therapy.

PURPOSE: Despite primary conservative therapy for Crohn's disease, a considerable proportion of patients ultimately needs to undergo surgery. Presumably, due to the increased use of biologics, the number of surgeries might have decreased. This study aimed to delineate current case numbers and trends in surgery in the era of biological therapy for Crohn's disease. METHODS: Nationwide standardized hospital discharge data (diagnosis-related groups statistics) from 2010 to 2017 were used. All patients who were admitted as inpatient Crohn's disease cases in Germany were included. Time-related development of admission numbers, rate of surgery, morbidity, and mortality of inpatient Crohn's disease cases were analyzed. RESULTS: A total number of 201,165 Crohn's disease cases were included. Within the analyzed time period, the total number of hospital admissions increased by 10.6% (n = 23,301 vs. 26,069). While gender and age distribution remained comparable, patients with comorbidities such as stenosis formation (2010: 10.1%, 2017: 13.4%) or malnutrition (2010: 0.8%, 2017: 3.2%) were increasingly admitted. The total number of all analyzed operations for Crohn's disease increased by 7.5% (2010: n = 1567; 2017: n = 1694). On average, 6.8 ± 0.2% of all inpatient patients received ileocolonic resections. Procedures have increasingly been performed minimally invasive (2010: n = 353; 2017: n = 687). The number of postoperative complications remained low. CONCLUSION: Despite the development of novel immunotherapeutics, the number of patients requiring surgery for Crohn's disease remains stable. Interestingly, patients have been increasingly hospitalized with stenosis and malnutrition. The trend towards more minimally invasive operations has not relevantly changed the rate of overall complications.

Mapping of the Micro-Mechanical Properties of Human Root Dentin by Means of Microindentation.

The extensive knowledge of root dentin's mechanical properties is necessary for the prediction of microstructural alterations and the teeth's deformations as well as their fracture behavior. Standardized microindentation tests were applied to apical, medial, and cervical root sections of a mandibular human first molar to determine the spatial distribution of the hard tissue's properties (indentation modulus, indentation hardness, Martens hardness, indentation creep). Using an indentation mapping approach, the inhomogeneity of mechanical properties in longitudinal as well as in transversal directions were measured. As a result, the tooth showed strongly inhomogeneous material properties, which depended on the longitudinal and transversal positions. In the transversal cutting planes of the cervical, medial, apical sections, the properties showed a comparable distribution. A statistical evaluation revealed an indentation modulus between 12.2 GPa and 17.8 GPa, indentation hardness between 0.4 GPa and 0.64 GPa and an indentation creep between 8.6% and 10.7%. The established standardized method is a starting point for further investigations concerning the intensive description of the inhomogeneous mechanical properties of human dentin and other types of dentin.

[Reconstruction following gastrectomy]. / Rekonstruktionen nach Gastrektomie.

Minimally invasive surgical techniques with respect to the treatment of gastric cancer have progressed rapidly over the last few years. Especially in Asia, where the incidence of gastric cancer is ten times higher than in Europe, surgery for gastric cancer is steadily evolving, especially regarding laparoscopic and robot-assisted procedures. This review first discusses the different options for reconstruction of the gastrointestinal passage after gastrectomy, ranging from Billroth procedures to the latest developments, such as the double tract reconstruction. In particular, the possibility of function-preserving partial gastrectomy, such as proximal and distal gastric resection and the corresponding reconstruction techniques are presented. The latest studies and technical developments are presented, especially with respect to laparoscopically assisted, completely laparoscopic and robot-assisted gastrectomies.

Influence of a novel deep-learning based reconstruction software on the objective and subjective image quality in low-dose abdominal computed tomography.

OBJECTIVES: Modern reconstruction and post-processing software aims at reducing image noise in CT images, potentially allowing for a reduction of the employed radiation exposure. This study aimed at assessing the influence of a novel deep-learning based software on the subjective and objective image quality compared to two traditional methods [filtered back-projection (FBP), iterative reconstruction (IR)]. METHODS: In this institutional review board-approved retrospective study, abdominal low-dose CT images of 27 patients (mean age 38 ± 12 years, volumetric CT dose index 2.9 ± 1.8 mGy) were reconstructed with IR, FBP and, furthermore, post-processed using a novel software. For the three reconstructions, qualitative and quantitative image quality was evaluated by means of CT numbers, noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) in six different ROIs. Additionally, the reconstructions were compared using SNR, peak SNR, root mean square error and mean absolute error to assess structural differences. RESULTS: On average, CT numbers varied within 1 Hounsfield unit (HU) for the three assessed methods in the assessed ROIs. In soft tissue, image noise was up to 42% lower compared to FBP and up to 27% lower to IR when applying the novel software. Consequently, SNR and CNR were highest with the novel software. For both IR and the novel software, subjective image quality was equal but higher than the image quality of FBP-images. CONCLUSION: The assessed software reduces image noise while maintaining image information, even in comparison to IR, allowing for a potential dose reduction of approximately 20% in abdominal CT imaging. ADVANCES IN KNOWLEDGE: The assessed software reduces image noise by up to 27% compared to IR and 48% compared to FBP while maintaining the image information.The reduced image noise allows for a potential dose reduction of approximately 20% in abdominal imaging.